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Background Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.Methods We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).Findings Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35.2 months (IQR 31.5-41.3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths.Interpretation Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, nonrandomized, open-label, phase Ib study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1- year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100–400 mg), and the MTD was not reached. Safety was similar between schedules; no tumor lysis syndrome occurred during dose-finding. Schedule B and Ven 400 mg were chosen for expansion. The most frequent grade 3–4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3–4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory tumor lysis syndrome cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16 of 49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit (clinicaltrial gov. Identifier: NCT01671904).

Robust polyclonal humoral immune responses have the potential to generate a diverse set of antibodies to neutralize and eliminate viruses such as SARS-CoV-2 and protect against transmission, re-infection and the evolution of variants that evade immunity. CD73 is present on subsets of human B and T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into immunosuppressive adenosine. We have developed a humanized anti-CD73 antibody, mupadolimab (CPI-006), that blocks CD73 enzymatic activity and activates CD73POSB cells, thereby inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of the adenosine modulatory activity. These effects suggest mupadolimab may enhance the magnitude, diversity, and duration of anti-viral responses in patients with COVID-19. This hypothesis was tested in a dose escalation phase 1 trial in 29 hospitalized patients with COVID-19. Single doses of 0.3 mg/kg – 5 mg/kg mupadolimab were well tolerated with no drug related adverse events. Doses greater than 0.3 mg/kg resulted in rapid generation of IgG and IgM to SARS-CoV-2 significantly above titers measured in convalescent controls, with elevated IgG titers sustained for more than 6 months beyond presentation of symptoms. Based on these findings, a randomized double-blind, placebo-controlled Phase 3 study in hospitalized patients was initiated. The primary endpoint was proportion of patients alive and free from respiratory failure within 28 days. This trial was discontinued early during the period of waning COVID-19 incidence after enrolling 40 patients. Although underpowered, results from this trial suggest improvement in the primary and key secondary endpoints in patients treated with single doses of 2 mg/kg and 1 mg/kg compared to placebo. The presumed mechanism of action, stimulation of B cells, may represent a novel approach to immunotherapy of COVID-19 and other viral infections.

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

Background The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and ...

Early data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment.

Background CD73 is present on subsets of B and T cells and is involved in lymphocyte activation. CPI-006 is a humanized IgG1, Fcγ receptor deficient anti-CD73 that has agonistic properties. In vitro studies and ongoing cancer clinical trials show that CPI-006 binds to B cells leading to expression of CD69, trafficking to lymph nodes, immunoglobulin class switching, transformation to plasmablasts and generation of memory B cells.1 Recently, a patient in the cancer trial with asymptomatic COVID-19 developed high titers of neutralizing anti-SARS-CoV-2 antibodies following administration of CPI-006. A phase 1 trial in COVID-19 was initiated to evaluate the use of CPI-006 to enhance anti-viral immune response (NCT04464395). Methods Single intravenous dose escalation with N=5 per cohort of 0.3, 1.0, 3.0 and 5.0 mg/kg. Pt eligibility included PCR positive nasal swab for COVID-19; hospitalized with O2 saturation of ≥92% on Results 10 pts have been treated in the first 2 cohorts; median age 64 (range 28–76) and all had comorbidities: diabetes (4), hypertension (2), obesity (7) and/or cancer (2). Median duration of symptoms prior to CPI-006 was 8 days (range 1–21 days). No treatment-related adverse events were reported. There was no correlation between duration of symptoms and baseline anti-viral titers. Kinetics of anti-SARS-CoV-2 response to spike protein are shown for 7 pts with follow-up ≥ 7 days post CPI-006 (figure 1). One pt with lymphopenia (600/mm3) had delayed response to CPI-006; all other pts generated antibody response by Day 7 post-CPI-006 to both spike and RBD. Increasing titers of IgG and IgM antibodies were observed out to 28 days post treatment. In one pt examined, memory B cells increased from 1.81% to 4.83% of B cells 28 days after treatment with serum IgG titers to spike and to RBD of >1:50,000. 2 of 2 pts had increase in both CD4 and CD8 T effector memory cells at day 28. All pts were discharged (median 4 days) with clinical improvement. Conclusions CPI-006 is well tolerated in COVID-19 pts. Low baseline titers of antibodies to virus were increased following CPI-006 in all treated pts. Immunomodulation with CPI-006 represents a novel therapy for COVID-19 aimed at stimulating more robust and prolonged anti-SARS-CoV-2 immunity potentially after infection or with vaccination. Trial Registration NCT04464395 Ethics Approval The study was approved by Temple University Hospital’s Ethics Board, Western IRB, approval number 1-1317457-1. Reference Luke J, Powderly J, Merchan J, Barve M, Hotson A, Mobasher M, Kwei L, Luciano G, Buggy J, Piccione E, Miller R. Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers. J Clin Oncol 2019; 37:15 suppl, 2505.

COVID-19 is a global pandemic that has resulted in over 800,000 deaths. Robust humoral anti-viral immune responses have the potential to generate a diverse set of neutralizing antibodies to eliminate viruses and protect against re-infection, transmission, and the evolution of mutations that escape targeted therapeutics. CD73 is present on the majority of human B cells and a subset of T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into adenosine, which can be immunosuppressive. Here we report on CPI-006, a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that blocks CD73 enzymatic activity and directly activates CD73POS B cells, inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of adenosine. Immunophenotypic analysis of peripheral blood from advanced cancer patients receiving CPI-006 revealed evidence of B cell activation, clonal expansion, and development of memory B cells. These immune effects suggested that CPI-006 may be effective at enhancing the magnitude, diversity, and duration of humoral and cellular responses to viruses such as SARS-CoV-2. We have therefore initiated a Phase 1, single-dose, dose-escalation trial in hospitalized patients with mild to moderate COVID-19. The objectives of this trial are to evaluate the safety of CPI-006 in COVID-19 patients and to determine effects of CPI-006 on anti-SARS-CoV-2 antibody responses and the development of memory B cell and T cells. Ten patients have been enrolled in the trial receiving doses of 0.3 mg/kg or 1.0 mg/kg. All evaluable patients had low pre-treatment serum levels of anti-viral antibodies to the SARS-CoV-2 trimeric spike protein and its receptor binding domain, independent of the duration of their COVID-19 related symptoms prior to enrollment. Anti-viral antibody responses were induced 7 days after CPI-006 treatment and titers continued to rise past Day 56. Increases in the frequency of memory B cells and effector/memory T cells were observed 28 days after treatment. These preliminary results suggest that CPI-006 activates B cells and may enhance and prolong anti-SARS-CoV-2 antibody responses in patients with COVID-19. This approach may be useful for treating COVID-19 or as an adjuvant to enhance the efficacy of vaccines.

BackgroundMupadolimab (mupa) is a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that has agonistic properties.1 CD73 is involved in production of adenosine and in cellular trafficking. Mupa reacts with the majority of circulating B cells leading to activation and expression of differentiation markers CD69, CD138 and CD38, and transformation into plasmablasts with secretion of IgM and IgG. B cell activation provided the rationale to develop mupa for immunotherapy of cancer and Covid-19. Intratumor HPV specific B cells have been reported in HNSCC.2 This report describes properties of mupa and the early signs of clinical activity in HPV+ HNSCC.MethodsELISA and flow cytometry were used to measure binding of anti-CD73. Humanized NSG-SGM3 mice were used to evaluate effects of Mupa on human anti-SARS CoV2 spike protein (SP) response. CD73 expression in biopsies was measured by immunohistochemistry. Mupa (IV q 3 weeks) with or without pembrolizumab is being evaluated in an ongoing phase 1 trial in patients with refractory cancers.ResultsMupa binding to CD73 was blocked by APCP, an analog of adenosine diphosphate that locks CD73 in the closed conformation, indicating mupa binding to the open conformation. Cross blocking and cellular internalization studies showed that mupa is distinct from other anti-CD73 antibodies such as MEDI9447 and AD2. NSG-SGM3 mice were immunized with 50 µg SP subcutaneously and treated with mupa 10mg/kg or control IgG IP. Mupa treated animals mounted an antigen specific human anti-SP response; no antibody responses were seen in controls (P=0.02). In the dose-escalation portion of the phase 1 trial, mupa doses of ≥12 mg/kg saturated CD73 sites on circulating B cells. High stromal CD73 expression was observed in HPV+ HNSCC biopsies from 5 evaluable patients with chemotherapy and anti-PD1 refractory disease, and tumor regression was seen in 2 of these patients receiving 7 and 16 cycles of ≥12 mg/kg mupa without pembrolizumab. Safety of mupa+pembrolizumab was evaluated in 16 patients with no MTD reached and no changes in serum immunoglobulins. Transient reductions in circulating CD73 B cells were observed consistent with redistribution to lymphoid tissues.ConclusionsCD73 plays a role in B cell activation and differentiation. Mupa is an antibody with agonistic activity that stimulates B cells and enhances antigen specific antibody production. This activity supports a strategy to combine mupa with pembrolizumab to enhance both humoral and cellular immunity in the treatment of viral associated cancers such as HPV+HNSCC, and viral infections.Trial RegistrationNCT03454451ReferencesWillingham S, Criner G, Hill C, Hu S, Rudnick J, Daine-Matsuoka B, Hsieh J, Mashhedi H, Hotson A, Brody J, Marron T, Piccione E, Buggy J, Mahabhashyam S, Jones W, Mobasher M, Miller R. Characterization and Phase 1 trial of a B cell activating anti-CD73 antibody for the immunotherapy of COVID-19. medRxiv, 2020; https://doi.org/10.1101/2020.09.10.20191486.Wieland A, Patel M, Cardenas M, Eberhardt C, Hudson W, Obeng R, Griffith C, Wang X, Chen Z, Kissick H, Saba N, Ahmed R. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 2020; https://doi.org/10.1038/s41586-020-2931-3.Ethics ApprovalThe study was approved by Western IRB, approval number 1-1066703-1. Participants gave informed consent before taking part.

Background: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components, including ITK, are maintained which suggests malignant T cells exploit this growth and survival pathway to their advantage. Antigen-presenting cells, abundant in the lymphoma microenvironment, also may provide antigen to drive TCR signaling through ITK. CPI-818 is a first-in-class, irreversible ITK inhibitor with selectivity for ITK. In preclinical studies, CPI-818 blocks TCR signaling in vitro and is efficacious in murine models and canines with T-cell lymphomas. We report results from the dose escalation portion of an ongoing phase 1/1b trial of CPI-818 in patients with relapsed/refractory T-cell lymphoma (CPI-818-001 study, NCT03952078). The trial is being conducted at sites in the United States, Australia, and South Korea. Methods: In dose-escalation, cohorts (3+3 design) enrolled patients with cutaneous and peripheral T-cell lymphoma who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; ECOG status 0-1; and adequate organ function. CPI-818 was administered in ascending dose levels (100, 200, 400, 600mg BID) continuously for up to sixteen 21-day cycles, until progression or unacceptable toxicity. In dose expansion, PTCL-NOS and CTCL patients are receiving CPI-818 at a dose of 600 mg BID. The primary objectives of the study are to evaluate the safety and to establish the maximum tolerated dose (MTD) or the maximum administered dose of CPI-818. Safety events will be assessed according to the NCI-CTCAEv5. Secondary objectives include evaluating pharmacokinetics and efficacy as assessed by the investigator using standard response criteria at the end of every 3 cycles. ITK occupancy in peripheral blood T cells and tumor tissue as well as biomarkers associated with anti-tumor activity in tumor and blood samples are being evaluated. Results: In dose-escalation, sixteen patients were enrolled in four cohorts: 100 mg BID (n=4), 200 mg BID (n=3), 400 mg BID (n=5), and 600 mg BID (n=4). No dose-limiting toxicities were observed in any of these cohorts and the MTD was not reached. Treatment related adverse events (TRAEs) were reported in 9 (47.4%) patients and were all Grade 1-2 in severity. The most common (>1 patient) were fatigue (15.8%), nausea (10.5%), and rash (10.5%) and no infections were reported. By flow cytometry, no consistent changes in circulating non-malignant or total T cell number or phenotype were observed. Pharmacodynamic analysis revealed ITK engagement by CPI-818 in all cohorts when CPI-818 is dosed BID. With increasing dose, the trough ITK occupancy in both blood and tissue increased. At doses of 200 mg and greater, trough occupancies were >75%. Near complete ITK inhibition (98%) was achieved at 600 mg BID and therefore, this dose was selected as the expansion cohort dose and higher doses were not explored. Reduction in serum cytokines including IL2 (six of eight patients), IFNg (eight of eight patients), and TNFa (eight of eight patients) was observed 24hr post-dose in patients treated with doses of 400 and 600mg, but not at lower doses. In dose escalation, a total of four PTCL patients were enrolled at doses of 200 mg BID or greater. A confirmed complete response was achieved in one PTCL-NOS patient in the 200mg BID cohort. Among 7 CTCL patients enrolled, a Nodal CR, improved mSWAT and slowing of Sézary cell expansion were seen (Figure 1). Given the safety profile, the PK/PD findings, and the early signs of efficacy, PTCL-NOS and CTCL cohorts were expanded at 600mg BID. To date, two patients with PTCL-NOS and one patient with CTCL have been recently enrolled in expansion cohorts. Conclusion: The dose-escalation part of the CPI-818-001 trial demonstrated that the 100, 200, 400 and 600 mg BID doses are well tolerated. Clinical activity was observed in both PTCL-NOS and CTCL. Reduction of serum levels of canonical T cell cytokines is consistent with on-mechanism drug inhibition of inflammatory T cell pathways. Disease specific expansion cohorts for PTCL-NOS and CTCL are enrolling patients at a dose of 600 mg BID. Disclosures Khodadoust: Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Feldman:Abbvie: Honoraria; Pharmacyclics: Honoraria, Other, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Bayer: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Kim:miRagen: Research Funding; Elorac: Research Funding; Neumedicine: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Solingenix: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mehta-Shah:Karyopharm Therapeutics: Consultancy; Verastem: Research Funding; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus: Research Funding; Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Genetech/Roche: Research Funding. Kim:Mundipharma: Research Funding; Donga: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Horwitz:ASTEX: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy. Buggy:Corvus Pharmaceuticals: Consultancy, Current Employment, Current equity holder in publicly-traded company. Hotson:Corvus Pharmaceuticals: Current Employment. Hill:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Munneke:Corvus Pharmaceuticals: Current Employment. Mahabhashyam:Corvus Pharmaceuticals: Current Employment. Miller:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Janc:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mobasher:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+ T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfh cell, Treg, and PD-1+ CD8+ T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells.

Summary Background Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. Methods In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0–1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. Findings The derived model consisted of four factors (one point each; serum β2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin Interpretation We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. Funding Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.

Summary Background Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding AbbVie and Genentech.

5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as > 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p < 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822 .

129 Background: Adenosine, generated by the ectonucleotidase CD73, mediates immunosuppression within the tumor microenvironment by triggering adenosine 2A receptors (A2AR) on immune cells. Tumor CD73 expression may be prognostic in prostate cancer. We evaluated the clinical activity of adenosine blockade using A2AR antagonist, ciforadenant, with or without the anti-PDL-1 antibody, atezolizumab (atezo), in advanced mCRPC patients (pts) in an ongoing phase 1 trial. Methods: Eligibility required measurable disease and up to 5 prior systemic therapies. Prior anti- PD-(L)1 was allowed. Ciforadenant was administered orally BID as monotherapy at 50-200mg or 100mg in combination with atezo 840mg IV Q 2 weeks (wks). Safety and efficacy were evaluated by CTCAE4, RECIST1.1 and PCWG2. Serum was obtained for measurement of cytokines. Results: Of 33 enrolled pts, 10 received ciforadenant monotherapy and 23 in combination with atezo. As of 10/21/19, 14 pts are evaluable for response and described further. Median prior therapies is 3 (range 2-6) with median follow-up 10.8 (4-33) wks. Metastatic burden included 4 node only, 2 bone plus node, and 8 visceral metastases. Five pts experienced tumor regression: 2 ciforadenant monotherapy (tumor reductions 12%, 17%); and 3 combination (tumor reductions 4%, 27%, 42%). The pt with a partial response had PSA decline from 98 ng/mL to

This study investigated the safety and efficacy of obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) in patients with advanced diffuse large B-cell lymphoma (DLBCL) and explored the impact of cell-of-origin (COO) on patient outcomes. Patients (N = 100) received obinutuzumab (1000 mg on the days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-8) plus CHOP (cycles 1-6). For patients without grade ≥3 infusion-related reactions (IRRs) to standard-rate obinutuzumab infusion, a shorter duration of infusion (SDI) was evaluated. Overall and complete response rates, as determined according to the Cheson et al. criteria by investigators/independent radiological facility, were 82.0/75.0% and 55.0/58.0%, respectively. SDI of 120 minutes and 90 minutes were well tolerated with no grade ≥3 IRRs. Among all patients, IRRs typically occurred during cycle 1, day 1. G-CHOP is active and has an acceptable safety profile in the first-line treatment of patients with advanced DLBCL. Clinical Trials: NCT01414855DLBCL.

International audience; BACKGROUND: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. RESULTS: After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P\textless0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). CONCLUSIONS: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

To the editor: In chronic lymphocytic leukemia (CLL), the median age at diagnosis is 72 years, and most patients requiring therapy have coexisting medical conditions. Venetoclax is a potent BH3-mimetic compound that selectively antagonizes BCL-2 and has shown efficacy as monotherapy and with

Introduction ITK is a tyrosine kinase critical to T cell receptor (TCR) signaling. Overexpression of this gene has been reported in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Genomic analyses have demonstrated the contribution of aberrant TCR signaling in the pathogenesis of T-cell lymphomas (TCL). RLK, a closely related kinase, is co-expressed with ITK in T and NK cells, and is partially functionally redundant with ITK signaling. In NK cells, ITK has been shown to be involved in FcγRIII signaling and antibody-dependent cellular cytotoxicity (ADCC). However, the relative contribution of ITK vs RLK in ADCC is not well understood. Thus, selective inhibition of ITK, but not other signal transduction components such as RLK, may be an effective strategy to treat TCL while preserving normal T and NK cell functions. CPI-818 is an orally bioavailable, covalent inhibitor of ITK with >100-fold selectivity over RLK and BTK. It was well tolerated and exhibited anti-tumor activity in companion dogs with spontaneous TCL (2019 AACR Annual Meeting Abstract #1313). A phase 1/1b trial with CPI-818 in human TCL has been initiated (NCT03952078). Here we present preclinical evidence that CPI-818 inhibits the proliferation of human malignant T cells with relative sparing of normal lymphocytes and report early results from the clinical trial. Methods Eligible patients for the dose-escalation/expansion trial of CPI-818 have relapsed/refractory TCL (PTCL, CTCL and others). Starting dose of CPI-818 is 100 mg BID continuously. The objectives of the study are to evaluate the safety and tolerability of CPI-818 in ascending dose levels; evaluate pharmacokinetics/pharmacodynamics and potential biomarkers. In in vitro studies, T cells from the blood of Sézary syndrome patients were stimulated for 6 days with αCD3/CD28. Sézary cells were identified by antibodies to specific TCR Vβ. For assays of ADCC, αCD20-coated lymphoma B cells were cultured with NK cells from multiple healthy donors for 18 h with inhibitors. In animal studies, mice received control or CPI-818-formulated diet (300 mg/kg/day). C57BL/6 mice were vaccinated with keyhole limpet hemocyanin (KLH) or subcutaneously implanted with the TCL line EL4. MRL/lpr mice began treatment at 9 weeks old. Lymph nodes were calipered weekly. Spleens and lungs were harvested at 22 weeks. Results Mouse models were studied to assess the impact of CPI-818 on normal, autoreactive and malignant T cells in vivo. No changes in total blood cell counts or T, B, NK cell subsets in lymphoid organs were seen in normal mice receiving daily doses of CPI-818 sufficient to continuously inhibit ITK for 28 days. Immune responses to antigen re-challenge were not affected in these mice, as determined by levels of antibody or CD4 T cell response to vaccination with KLH. In mice with established EL4 lymphoma, administration of CPI-818 reduced the growth of tumors at the primary site and in the draining lymph nodes (P values Sézary cells from 3 of 3 patients tested in vitro were more sensitive to growth inhibition with CPI-818 than autologous normal CD4 or CD8 cells, or T cells from a healthy donor (Figure 1). CPI-818 showed minimal inhibition of NK-mediated ADCC (5%), whereas CP-2193, an ITK/RLK dual inhibitor with an IC50 for ITK comparable to CPI-818, reduced ADCC by 50%. CPI-818 has been administered to two patients at the first dose level cohort (100 mg BID) with no DLTs, and with no changes to B, T, and NK cell counts in blood during the first dosing cycle (21 days). Pharmacokinetic and occupancy studies have revealed 80% and 50% occupancy of ITK at peak and trough drug levels, respectively in peripheral blood T cells. Conclusions CPI-818 is a selective covalent ITK inhibitor that has greater antiproliferative effects on malignant and autoreactive T cells compared to normal T cells. The drug has a minimal impact on NK mediated ADCC compared with a less selective inhibitor that also blocks RLK. Preliminary data from a phase 1/1b study shows CPI-818 at 100 mg BID was tolerable with acceptable bioavailability and ITK occupancy. Further dose escalation is ongoing. Disclosures Ng: Corvus Pharmaceuticals, Inc.: Employment, Equity Ownership. Mobasher:Corvus Pharmaceuticals: Employment, Equity Ownership. Yeung:Corvus Pharmaceuticals: Employment, Equity Ownership. Hotson:Corvus Pharmaceuticals: Employment, Equity Ownership. Hill:Corvus Pharmaceuticals: Employment, Equity Ownership. Madriaga:Corvus Pharmaceuticals: Employment, Equity Ownership. Dao-Pick:Corvus Pharmaceuticals: Employment, Equity Ownership. Verner:Corvus Pharmaceuticals: Employment, Equity Ownership. Radeski:Corvus Pharmaceuticals: Research Funding. Khodadoust:Corvus Pharmaceuticals: Research Funding. Kim:Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Horizon: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding. Miller:Corvus Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Buggy:Corvus Pharmaceuticals: Employment, Equity Ownership. Janc:Corvus Pharmaceuticals: Employment, Equity Ownership.

Background: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components are maintained, which suggests malignant cells may exploit this growth and survival pathway to their advantage. Professional antigen-presenting cells abundant in the lymphoma microenvironment may provide antigen to drive TCR signaling through ITK, which is expressed in a variety of T-cell lymphomas. CPI-818 is a first-in-class, irreversible ITK inhibitor with a high degree of selectivity for ITK. By inhibiting ITK, CPI-818 blocks signaling pathways and is efficacious in murine models of T-cell lymphomas. Furthermore, the safety and efficacy of CPI-818 in companion dogs with spontaneously-occurring T-cell lymphomas have been evaluated. Following oral, BID dosing of CPI-818 to dogs, evidence of anti-tumor activity including complete and partial responses was observed. CPI-818 was well tolerated in dogs with no change in normal lymphocyte counts. Thus, the preclinical evidence supports the evaluation of CPI-818 in clinical trials in patients with T-cell malignancies. To test this clinically, a phase 1/1b dose-escalation and dose-expansion trial of CPI-818 has been initiated in patients with relapsed/refractory T-cell lymphoma. Methods: The trial will enroll patients with various types of T-cell lymphoma (PTCL and CTCL) who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; have ECOG status 0-1; adequate organ function; and without any other condition that would contraindicate the use of the investigational product. A dose Escalation part with 3 + 3 (+ optional 3) design will consist of up to 6 ascending dose levels (100, 200, 400, 600, 900, and 1200 mg) of CPI-818. In the Dose Expansion part, there will be 4 disease-specific expansion cohorts (AITL, PTCL-NOS, CTCL and other T-cell lymphoma), and each cohort may enroll up to a maximum of 28 subjects/cohort based on a two-stage expansion design- Study Details in Figure 1. Patients will receive CPI-818 orally BID at the assigned dose level continuously up to sixteen 21-day cycles, until progression or unacceptable toxicity. The primary objectives of the study are to evaluate the safety and tolerability of CPI-818 in ascending dose levels and to establish the maximum tolerated dose or the maximum administered dose of CPI-818. Secondary objectives include evaluating pharmacokinetics/ pharmacodynamics, assessing the anti-tumor activity of CPI-818 and identifying potential biomarker signals. Adverse events and dose-limiting toxicities of CPI-818 will be assessed. The PK profile of CPI-818 will be characterized by PK parameters in plasma. Efficacy will be assessed by the investigator using standard response criteria: Lugano Classification for PTCL patients, Consensus Statement for Response for CTCL patients, and the international consensus modification of Japan Clinical Oncology Group criteria for adult T-cell lymphoma patients. ITK occupancy/engagement in peripheral blood T cells and potential predictive biomarkers associated with anti-tumor activity in tumor tissue and blood samples will be evaluated. Study Status: This study is currently enrolling. US NIH Clinical Trials Registration Number NCT03952078. Disclosures Mobasher: Corvus Pharmaceuticals: Employment, Equity Ownership. Miller:Corvus Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Janc:Corvus Pharmaceuticals: Employment, Equity Ownership. Kwei:Corvus Pharmaceuticals: Employment, Equity Ownership. Buggy:Corvus Pharmaceuticals: Employment, Equity Ownership. Luciano:Corvus Pharmaceuticals: Employment, Equity Ownership. Mohammady:Corvus Pharmaceuticals: Employment, Equity Ownership. Kim:F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding. Kim:Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neumedicine: Research Funding; Elorac: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Horizon: Research Funding; Galderma: Research Funding; Merck: Research Funding; Trillium: Research Funding; miRagen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Khodadoust:Corvus Pharmaceuticals: Research Funding. Horwitz:Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Trillium: Research Funding; Mundipharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Astex: Consultancy; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Trillium: Research Funding; Miragen: Consultancy; Mundipharma: Consultancy; Portola: Consultancy. Radeski:Corvus Pharmaceuticals: Research Funding.

7502 Background: The multinational, open-label, phase 3 CLL14 trial compared fixed-duration targeted VenG treatment with chlorambucil-obinutuzumab (ClbG) in previously untreated pts with CLL and comorbidities. Here we present endpoint analyses with particular emphasis on MRD− and PFS. Methods: Pts with a CIRS score >6 and/or an estimated creatinine clearance -4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5,10-6). Results: 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). After 29 mo median follow-up, superior PFS was observed with VenG vs ClbG (HR 0.35; 95% CI 0.23–0.53; P-4, 31% vs 4% at -6 and 35% vs 15% at ≥10-6–-5, respectively. Conclusions: Fixed-duration VenG induced deep (-6 in 1/3 of pts), high, and long lasting MRD− rates (with a low rate of conversion to MRD+ status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Clinical trial information: NCT02242942.

TPS1108 Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.

2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451.

TPS2646 Background: CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. CPI-006 is a humanized IgG1 FcγR binding-deficient anti-CD73 antibody now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA) or combination with CPI-444, an oral, small molecule, selective A2aR antagonist or in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods: Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients must have: non-small cell lung, renal cell carcinoma, urothelial bladder, cervical, colorectal, ovarian, pancreatic, prostate, head and neck, triple-negative breast, endometrial, select sarcomas and non-Hodgkin lymphoma malignancies relapsed, refractory or intolerant to 1 to 5 standard therapies; aged ≥ 18 yo; adequate organ function and measurable disease. The objectives of the study are 1) evaluate the safety and tolerability of SA CPI-006, in combination with CPI-444 and in combination with pembrolizumab, 2) evaluate the pharmacokinetics of each regimen and 3) identify potential biomarker signals predictive of response. Study design in table. Study Design. Clinical trial information: NCT03454451. [Table: see text]

Introduction Chronic lymphocytic leukemia (CLL) is characterized by a profound immune suppression. In addition, CLL cells evade immune destruction by interacting with cells of the adaptive immune system, resulting in dysfunctional T cells. CD4+ T cells are skewed towards a TH2-profile and the number of regulatory T (Treg) cells, that diminish cellular immune responses, is increased in CLL patients. CD8+ T cells resemble exhausted T cells and have reduced cytotoxic, yet increased cytokine production capacity. The cytotoxic function of NK cells is impaired in CLL patients, but in contrast to CD8+ T cells their cytokine production is also compromised, presumably induced by CLL cells. These data are chiefly obtained from studies on peripheral blood (PB). Although the lymph node (LN) compartment has a central role in the pathobiology of CLL, very little is known about the composition of non-malignant lymphocytes in LN tissue. The Bcl-2 inhibitor venetoclax (Ven) is highly effective in CLL and, especially in combination with anti-CD20 monoclonal antibodies such as obinutuzumab (O), results in high rates of minimal residual disease (MRD) undetectable responses. However, the prospective effects of venetoclax on non-malignant lymphocytes in patient samples remain largely unexplored. Methods PB and LN biopsy specimens were collected at baseline from patients enrolled in the 1st-line FCR-unfit HOVON 139 / GIVE trial. Study treatment consisted of O (cycle 1-2), Ven+O (cycle 3-8) and Ven (cycle 9-14). Immune composition was analyzed by 7-color flow cytometry. Baseline PB samples were compared to paired LN samples. Moreover, PB samples of the first patients that completed 6 cycles of Ven monotherapy (cycle 14) were compared to baseline. Cytokine production and degranulation of T and NK cells was studied after stimulation of PBMCs with PMA/Ionomycin. Results Comparison of LN (n=28) vs PB (n=48) revealed a larger proportion of T cells in LN (13.2% vs 5.1% of the lymphocytes), at the expense of CLL cells, with a skewed CD4:CD8 ratio (5.2 in LN vs 1.8 in PB). Within the CD4+ T cells, significantly higher levels of both follicular T helper cells (15. 7% vs 5.2%) and Tregs (11.5% vs 6.9%) were found in LN (see Table). CD4+ T cells mostly consisted of naïve and memory T cells in both PB and LN. There were fewer CD8+ T cells and especially fewer effector CD8+ T cells in the LN in comparison to PB. CD8+ T cells in LN mostly had a naïve and memory phenotype. An increased percentage of LN-residing CD8+ T cells expressed the exhaustion marker PD-1 as compared to PB CD8+ T cells (30.4% in LN vs 12.4% in PB). We then compared PB baseline samples to PB obtained after cycle 14 (n=11). Ten patients achieved MRD undetectable levels ( Fewer CD8+ T cells expressed PD-1 after treatment. The fraction of CD8+ T cells that produced IFN-γ (69.8% vs 56.2%) and TNF-α (58.4% vs 40.3%) decreased. Degranulation of CD8+ T cells did not change upon treatment. After treatment, the capacity of NK cells to degranulate increased. In addition, a larger proportion of NK cells produced IFN-γ, suggesting recovery of NK cell function after treatment. Conclusion In conclusion, our data strengthen the view that CLL cells reside in an immune suppressive environment in the LN. Moreover, we provide the first evidence that the Ven+O regimen does not harm non-malignant lymphocyte populations other than B cells. Both the improved cytokine production of NK cells and diminished cytokine production of CD8+ T cells may point to normalization of immune function. Collectively, the phenotypical and functional changes observed may reflect the eradication of the immunosuppressive CLL clone by Ven+O and subsequent recovery of the immune microenvironment in CLL patients. Disclosures Eldering: Celgene: Research Funding. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kater:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Venetoclax (Ven) is a highly selective oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway, which is constitutively overexpressed in CLL. Efficacy and safety of VenR given for a fixed duration in R/R CLL was evaluated in the randomized Phase III MURANO study compared with standard bendamustine + rituximab (BR). A first pre-planned analysis, when the majority of patients (pts) were still on study treatment (median follow-up 23.8 mo), established a superior PFS of VenR over BR (Seymour et al. NEJM 2018). With all pts having completed therapy, we analysed long-term outcome with a median follow up of 36.0 mo. Methods Pts were randomized to receive 6 cycles of VenR followed by Ven 400mg once daily for a total of 2 yrs, or 6 cycles of BR. Disease status was assessed by CT scan at screening, Cycle (C) 4 and 2−3 mo after end of combination therapy (EOCT). During Ven single agent and at follow-up visits, response was determined by clinical assessment every 3 mo until 3 yrs of follow-up, then every 6 mo thereafter or until PD. PFS status was based on investigator assessment. Peripheral blood (PB) minimal residual disease (MRD) was analysed centrally by ASO-PCR and/or flow cytometry at C4, EOCT and every 3/6 mo thereafter. All p values are descriptive. Results In total, 389 pts were enrolled in VenR (n=194) or BR (n=195) arms. As of May 8 2018, all pts were off treatment. For BR, 154 (79%) had completed 6 cycles. In the VenR arm, 174 (90%) completed the VenR combination phase and 130 (67%) had completed 2 yrs of Ven. The remainder had PD (11%), died (1%), or withdrew due to AEs (15%) or other reason (6%). Median Ven exposure duration and relative dose intensity were 24.4 (range 0-27.9) mo and 97.4% (26-100%), respectively, overall and 17.7 (0.5-21.9) mo and 99% during Ven single-agent therapy. With a median time off Ven after 2 yrs treatment of 9.9 (1.4-22.5) mo, PFS with VenR remains superior to BR (HR, 0.16 [95% CI 0.12, 0.23]; p1% in PB at Mo 24 (when Ven single agent was scheduled to cease) and 10/16 pts had del(17p)/TP53 mutation at baseline. Clinical and cytogenetic risk factors in pts with and without PD after Mo 24 are in Table 1. In this analysis, OS improvement was seen with VenR over BR (HR, 0.50 [95% CI 0.30, 0.85]; p=0.0093; 3-yr rate: 87.9% vs 79.5%; Figure 4). Subsequent CLL-directed treatment was given after PD in 91 pts in the BR arm. 71/91 (78%) BR arm pts received novel targeted agents, including 45 who had ibrutinib and 7 who had Ven. 27/194 (14%) pts in the VenR arm received subsequent therapy: 13/27 (44%) had novel targeted agents as next treatment, including 8 pts who had ibrutinib and 3 who were re-treated with Ven. See Table 2 for a safety overview for VenR combination and Ven single-agent periods. During Ven single agent: 17/171 pts (10%) had an AE leading to drug withdrawal; 7/171 pts (4%) had an AE leading to dose reduction; 44/171 pts (26%) had a Ven dose interruption due to an AE; 7/171 pts (4%) had a fatal AE (4 other cancers, 2 cardiac, 1 pneumonia). Grade 3-4 AEs occurred in 59/171 pts (35%); the most frequent were neutropenia (20 pts, 12%), anemia (5 pts, 3%), and thrombocytopenia (3 pts, 2%). 12/171 (7%) pts had a grade 3-4 infection in the Ven single-agent phase. The total number of Richter transformation events was 7 with VenR and 6 with BR. Conclusions With all pts off treatment and 3 yrs' median follow-up, continued substantial benefit was observed with VenR, with PFS and OS superior to BR. There were no new safety signals; most pts were able to complete treatment. The rate of CLL progression in the first 12 mo after Ven completion was modest (13%), supporting the feasibility and safety of a time-limited VenR duration. The protocol has been amended to include assessment of response and durability of disease control with VenR reintroduction at PD. This updated analysis of this Phase III global randomized study demonstrates clinically meaningful benefit of the VenR chemotherapy-free regimen with a fixed duration in all pts with R/R CLL. Disclosures Seymour: AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy. Kipps:Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Gilead Sciences, Inc.: Honoraria, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Assouline:Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau. Owen:Teva: Honoraria; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Merck: Honoraria; AbbVie: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Honoraria, Research Funding. Robak:Janssen: Consultancy, Honoraria; Gilead: Consultancy; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. de la Serna:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jaeger:Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Acerta: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Punnoose:Genentech Inc: Employment; Roche: Equity Ownership. Jiang:Genentech Inc: Employment, Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Kater:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Effective therapies for R/R AML remain limited. MEK or MDM2 inhibition can downregulate MCL1, overcoming resistance to BCL2 inhibition. Preclinical synergy was seen when combining BCL2 inhibitor Ven with MEK inhibitor cobimetinib (cobi) or MDM2 inhibitor idasa (Han et al. ASH 2016; Pan et al. Cancer Cell 2017), supporting clinical evaluation in AML. Preliminary data in a Phase Ib dose-escalation study (NCT02670044) evaluating Ven+cobi/idasa in R/R AML suggested both combinations were tolerable (Daver et al. ASH 2017). However, Ven+cobi was closed due to limited clinical activity. Here we present data for additional pts, longer follow-up and biomarker analyses for Ven+idasa. Methods This ongoing, open-label, multicenter study evaluates safety, tolerability and efficacy of Ven+idasa in R/R AML or secondary AML previously treated for an antecedent hematologic disease. Pts >60 yrs of age and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. A 2-dimensional dose escalation was used to establish the maximum tolerated dose: pts received doses of Ven orally (PO) daily (400mg or 600mg) + idasa PO daily on Days 1-5 (150mg, 200mg, or 400mg) in 28-day cycles. Plasma samples were taken for PK analysis at Cycles 1 and 2 Days 1 and 5, and Cycle 4 Day 1. BCL2, BCLxL and MCL1 status and minimal residual disease (MRD) were assayed centrally at Covance Laboratories using multicolor flow cytometry. Mutation (mut) sequencing was performed by Foundation Medicine using FoundationOne Heme at screening and from last bone marrow collected on study. Results As of April 6 2018, 34 pts received Ven+idasa across all dose cohorts (Table 1). Median age: 74 (range 64-93) yrs; median prior therapies: 1 (range 1-4); ECOG performance status 2: 18%; refractory: 56%; secondary AML: 53%; adverse cytogenetics: 27%. Pre-therapy mut data were available for 32 pts; most common muts were RUNX1 14 (41%), ASXL1 11 (32%), SRSF2 11 (32%). Other significant pre-therapy muts: TP53 6 (18%), IDH2 7 (21%), IDH1 1 (3%), FLT3 4 (13%). The most common adverse events (AEs) were diarrhea (88%) and nausea (71%); the most common grade (Gr) ≥3 AEs were neutropenia (32%), febrile neutropenia (32%), thrombocytopenia (29%; Table 2). After 2 cases of Gr 3 diarrhea in the Ven 600mg cohorts, mandatory prophylaxis was implemented; no further cases of Gr ≥3 diarrhea were seen in the following 10 pts. Laboratory tumor lysis syndrome occurred in 3 pts (9%); none required treatment discontinuation. There was no apparent PK drug-drug interaction between Ven and idasa. PK was dose-proportional over the ranges tested for Ven and idasa. The recommended Phase II dose (RP2D) has not been identified yet. Across all dose cohorts, 30/34 pts were response-evaluable; the remaining 4 were still on study treatment without post-baseline response assessment. The anti-leukemic response rate (CR+CRp+CRi+MLFS+PR) was 37% (11/30). Across the 2 Ven 600mg cohorts, which are being considered for RP2D, the anti-leukemic response rate was 9/18 (50%) (Table 1, Figure 1). MRD negativity ( The median time to CR+CRp+CRi+PR (all pts) was 1.8 mo (range 0.8-2.7), with median response duration of 8.1 mo (range 0.3-9.7). Median overall survival in all pts and in the Ven 600mg cohorts was 3.9 mo and 5.3 mo (range 0.2-17.6), respectively; median follow-up was 2.9 mo (range 0-18). The anti-leukemic response rate was 86% in pts with IDH2 mut and 57% in pts with a RUNX1 mut, but only 20% in pts with a TP53 mut (Table 4). 8/20 pts with end-of-treatment mut data had either new TP53 muts or an increase in mut TP53 allele frequency (Figure 2). In 14 evaluable pts, those with AML blasts with a high ratio of BCL2:BCLxL or BCL2:MCL1 had a response rate of 100% (5/5) versus 11% (1/9) in pts with low ratios (Table 4). Conclusion Ven+idasa has a tolerable safety profile with appropriate prophylaxis in this R/R AML population. An anti-leukemic response rate of 50% was seen at dose levels being considered for RP2D (Ven 600mg + idasa 150/200mg). Overall, responses appeared deep and durable. Preliminary biomarker data indicate that the relative ratio of BCL2 to BCLxL and MCL1 may be important for Ven+idasa activity, whereas pts with baseline TP53 muts had lower response rates. To confirm the clinical benefit and safety of Ven+idasa, the combination will be further evaluated in an expansion arm, after confirmation of the RP2D. Disclosures Daver: Kiromic: Research Funding; ImmunoGen: Consultancy; Sunesis: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Karyopharm: Research Funding; Alexion: Consultancy; Pfizer: Consultancy; ARIAD: Research Funding; BMS: Research Funding; Otsuka: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy. Pollyea:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Garcia:Celgene: Consultancy. Jonas:Genentech/Roche: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Glycomimetics: Research Funding; Esanex: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Tolero: Consultancy; Forma: Research Funding; Celgene: Consultancy, Research Funding; Accelerated Medical Diagnostics: Research Funding; Kalobios: Research Funding; Daiichi Sankyo: Research Funding. Yee:Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding; Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees. Fenaux:Otsuka: Honoraria, Research Funding; Roche: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Assouline:Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding. Olin:Daiichi Sankyo, Astellas, Genentech: Research Funding. Roboz:Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Celgene Corporation: Consultancy; Orsenix: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Sandoz: Consultancy. Kirschbrown:Roche: Other: Ownership interests PLC; Genentech: Employment. Green:Genentech: Employment. Ma:Genentech: Employment. Dail:Genentech: Employment, Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Ott:Roche: Other: Ownership interests PLC. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Konopleva:Stemline Therapeutics: Research Funding. Andreeff:Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Astra Zeneca: Research Funding; Reata: Equity Ownership; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy.

Introduction While the initial approval of venetoclax (VEN), a BCL2 inhibitor, was limited to relapsed patients with del17p, the data from the phase 3 MURANO trial demonstrated significant progression-free survival (PFS) benefit with venetoclax in combination with rituximab (R) versus bendamustine + rituximab (BR) and has recently led to the expansion of this approval to any relapsed CLL patient in the USA. Furthermore, several studies have demonstrated efficacy of venetoclax in treatment-naïve patients and a prospective, open-label, multicenter, randomised phase III trial with registration purpose is ongoing to explore venetoclax in the front-line CLL setting. While ibrutinib has demonstrated efficacy in CLL when patients are treated until disease progression, venetoclax trials have a finite duration of treatment in both relapsed and first-line settings. Although we have data demonstrating the efficacy of venetoclax after B-cell receptor inhibitors, including the Bruton's tyrosine kinase inhibitor, ibrutinib (Jones et al. Lancet Oncol, 2018), limited data are available on the efficacy of ibrutinib after venetoclax (Mato AR. Haematol 2018; Anderson M. Blood 2017). Methods We undertook this US multicenter retrospective chart-review data analysis to explore the outcomes of ibrutinib treatment given after venetoclax, in previously ibrutinib-naïve patients treated for R/R CLL. Results Data are available on eleven patients from four centers. Their median time from diagnosis to first therapy was 33.9 (range 4.0-53.0) months and median number of therapies prior to venetoclax was two (range 1-10). One patient had previously received both idelalisib and lenalidomide, but for all other patients venetoclax was their first targeted inhibitor for R/R CLL. The median time from diagnosis to venetoclax therapy was 77.8 (range 14.9-159.6) months. Prior to venetoclax initiation, four of eleven patients had del(17p), six of eleven had del(11q) and three had complex karyotype. Five of six evaluable patients had unmutated IGHV. Seven of eleven had a lymph node ≥ 5 cm. Ten of eleven patients achieved a partial response (PR) to venetoclax and the univariate median time to clinical progression on venetoclax was 19.0 (range 6.0-58.0) months, with a median time on venetoclax of 19.0 (range 1.2-57.5) months. One of eleven patients achieved stable disease on venetoclax, and remained on drug for 19 months. Reasons for discontinuation of venetoclax were: disease progression (n=8), withdrawal of consent (n=1), and allogeneic stem cell transplant after PR (n=2). The median time to ibrutinib treatment initiation, after discontinuing venetoclax, was 1.0 (range 0.1-30.8) month. For all eleven patients, ibrutinib was their next therapy after venetoclax. Ten of eleven patients achieved a PR to ibrutinib. The eleventh patient, who has only been on ibrutinib treatment for 1 month and continues on ibrutinib, has so far achieved stable disease. The time on ibrutinib therapy ranged from 0.5 to 30 months, with only three patients having discontinued. Of the responders, one patient progressed with Richter's transformation at 13 months on therapy and subsequently died. Two other patients stopped ibrutinib, one for an adverse event (AE) [atrial fibrillation and brain abscess] after 11.6 months, and a second for pneumonia that was ultimately fatal after 30 months on ibrutinib. Other notable AEs included one with major bleeding and five of eleven with joint pain. Two patients had ibrutinib dose reductions for fatigue and general malaise. Conclusions With the limitations of a very small dataset, we conclude that the efficacy and toxicity profile of ibrutinib appears similar in the relapsed setting after venetoclax as in patients not yet exposed to venetoclax. A larger dataset is being explored and will be presented at the meeting. Disclosures Brown: Beigene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Loxo: Consultancy; Celgene: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy; Gilead: Consultancy, Research Funding; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Sun Pharmaceutical Industries: Research Funding; Roche/Genentech: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Surface Oncology: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding. Chang:Celgene: Research Funding; Genentech: Research Funding. Ma:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Biondo:Roche: Equity Ownership; Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Mun:Genentech: Employment, Equity Ownership. Mato:AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Prime Oncology: Speakers Bureau; Acerta: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Celgene: Consultancy; Regeneron: Research Funding.

Introduction: Several prognostic models for overall survival (OS) in chronic lymphocytic leukemia (CLL) have been developed, but none were derived for patients (pts) with relapsed or refractory (R/R) CLL treated in the era of novel agents. We used a comprehensive approach to derive and validate a novel risk model for OS in 2,475 pts with R/R CLL who received therapy in randomized phase 3 trials evaluating ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) vs control arms, or the Mayo Clinic CLL Database (MCCD). Methods: In collaboration with Janssen, Gilead, Pharmacyclics, and Genentech/Roche, the analysis included 2,475 pts from 6 multicenter randomized phase 3 trials or the MCCD. Trials included were: IBR plus bendamustine-rituximab (BR) vs placebo plus BR (HELIOS: NCT01611090), IBR vs ofatumumab (RESONATE: NCT01578707), IDELA plus BR vs placebo plus BR (Study 115: NCT01569295); IDELA plus rituximab vs placebo plus rituximab (Study 116: NCT01539512); IDELA plus ofatumumab vs ofatumumab (Study 119: NCT01659021); VEN plus rituximab vs BR (MURANO: NCT02005471). All pts had R/R CLL and required treatment by iwCLL criteria. The model-building dataset (n=969) included pts from HELIOS and RESONATE, and was randomly assigned to the IBR/chemoimmunotherapy (CIT) training dataset (n=727) and IBR/CIT internal-validation dataset(n=242). Three independent external validation datasets included IDELA/CIT (n=897), VEN/CIT (n=389), and MCCD (n=220). We applied univariate and multivariate analyses (MVA) to 28 candidate clinical/laboratory and genetic prognostic factors to derive the risk model in the training dataset. The primary endpoint was OS. We assessed the need for separate models for targeted agents by interactions with treatment in univariate analyses. We proceeded to develop a single model for all pts with R/R CLL, as only one candidate factor (del(13q), interaction p value We evaluated cutoffs for dichotomized covariates and for definition of risk groups after the final factors were selected. We fit a Cox regression on the training and internal/external validation datasets using the risk categories as the covariate to test the difference among the groups, and calculated the C-statistic as a measure of discrimination. Results: Of 11 selected factors with a significant univariate effect on OS (p We excluded number of prior therapies from the model, reasoning that its optimal cutoff might change with advances in CLL therapies. IGHV did not remain significant (p=0.0592) in MVA of 5 remaining prognostic factors. Notably, del(17p) was not independently prognostic for OS. The final risk model consisted of 4 prognostic factors: B2M ≥5 mg/L, LDH elevated, HGB Our risk model was prognostic for OS in the IBR/CIT training dataset (C-statistic 0.74 [95% CI 0.60-0.85]; log-rank p Conclusions: We present the first validated risk model for OS in R/R CLL in the era of targeted therapies. Our model consists of 4 readily available factors (B2M ≥5 mg/L, LDH elevated, HGB Figure. Figure. Disclosures Darif: Jannsen: Employment. Londhe:Jannsen: Employment. Xing:Gilead Sciences, Inc.: Employment. Mun:Genentech: Employment, Equity Ownership. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Furman:Loxo Oncology: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Other: DSMB; Acerta: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Hillmen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Novartis: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Seymour:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding. Jones:Celgene: Employment, Equity Ownership. Ferrante:Jannsen: Employment. Dreiling:Gilead: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Stark:Genentech: Employment. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Howes:Janssen: Employment. James:Pharmacyclics: Employment. Bhargava:Gilead: Employment. Zelenetz:Novartis/Sandoz: Consultancy; Abbvie: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding.

Introduction FL is characterized by the translocation t(14;18), resulting in constitutive overexpression of the key anti-apoptotic protein BCL2. Ven, a selective, potent oral inhibitor of BCL2, has shown profound efficacy combined with anti-CD20 antibodies in chronic lymphocytic leukemia and is in development for treating other hematologic malignancies, including non-Hodgkin lymphoma (NHL). Preclinical and early clinical data in indolent NHL suggest addition of Ven to R or chemo may improve efficacy. The open-label CONTRALTO study (NCT02187861) assessed efficacy and safety of a chemo-free regimen with Ven+R or randomized Ven + standard chemoimmunotherapy regimen BR vs BR for treatment of R/R FL. Methods Pts ≥18 yrs, with confirmed grade (Gr) 1-3a R/R FL, ≥1 line of prior therapy for lymphoma, and adequate hematologic and organ function with no history of B-refractory disease (chemo arms), were assigned at investigators' discretion to receive Ven+R or be randomized to BR +/- Ven, with stratification by 1 vs 0 GELF criteria and ≥ vs Results 163 pts were enrolled; 52 received Ven+R, 9 in the safety run-in, 51 Ven+BR, 51 BR (Table 1). Median lines of prior treatment: 3 (1-6) in both Ven-treated arms and 2 (1-4) in BR arm. Ann Arbor stages III/IV: 88%, 73.5%, and 72.5% of pts in Ven+R, Ven+BR and BR arms, respectively. BCL2 expression by IHC and BCL2 translocations were observed in most pts (88% and 81% respectively); expression of MCL1 (1%) and BCLxL (29%) were low. 44 pts (90%) in Ven+BR arm required dose interruptions/modifications of any therapy compared with 21 (42%) in BR and 30 (58%) in Ven+R; most were of Ven: 20 (38.5%) in Ven+R arm and 43 (88%) in Ven+BR. 17 pts (35%) in Ven+BR arm and 2 (4%) in Ven+R discontinued Ven early. 30 pts (61%) in Ven+BR arm required dose interruption/modification of B versus 20 (40%) in BR; 10 pts (20%) in Ven+BR and 2 (4%) in BR discontinued B. Neutropenia and thrombocytopenia were the most common Gr 3-4 adverse events (AEs) overall (Table 2B), and led to dose interruptions/modifications. They were highest in Ven+BR arm (59% neutropenia, 45% thrombocytopenia). Serious AEs were seen more frequently with Ven+BR (Table 2A) than Ven+R or BR; most were infection/infestation events: 22% Ven+BR, 11.5% Ven+R, 8% BR. In Ven+R arm, 17% of pts reached CMR at 6 mo; 25% achieved CMR as best overall response (BOR), of whom all achieved minimal residual disease (MRD) negativity at mid-induction. A population of pts who were non-refractory to prior therapy had improved response (54% overall response rate, 35% CMR as BOR). Six-mo CMR rates were 74% and 68% with Ven+BR and BR, respectively, and were equal at 1 yr (Table 3). PFS analysis did not show a difference between these arms (adjusted HR, 0.69; p=0.2088). Although only 61.2% of pts in Ven+BR arm had ≥90% B dose intensity vs 95.8% in BR arm, efficacy in the 2 arms was comparable in CMR and PFS. Of note, pts maintaining all cycles of Ven+BR had a 6-mo CMR of 100%. Efficacy was comparable in biomarker subgroups, and did not identify clear predictors of response. Conclusion Ven+R had an acceptable toxicity in the population studied; this arm included a high number of pts with refractory status and shorter DOR to prior treatments, potentially leading to modest overall efficacy. Improved response rates and MRD negativity, and longer PFS were observed in a subgroup of pts with non-refractory FL, showing efficacy of Ven+R in FL. Addition of Ven to BR at the dose and schedule studied resulted in increased toxicity (Gr 3-4 cytopenias and gastrointestinal events), leading to dose interruptions/discontinuations, with consequent limitation of overall tolerability. However, despite lower dose intensity of BR in Ven+BR arm, efficacy remained the same between the 2 chemo-containing arms, mandating optimal dose delivery for improved efficacy in combination with chemo in future studies. Disclosures Zinzani: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Flinn:Portola: Research Funding; Curis: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Verastem: Consultancy, Research Funding; Forty Seven: Research Funding; Forma: Research Funding; Novartis: Research Funding; Kite: Research Funding; Celgene: Research Funding; ArQule: Research Funding; BeiGene: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Calithera: Research Funding; Agios: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Janssen: Research Funding. Yuen:Seattle Genetics: Research Funding. Topp:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Rusconi:Celgene: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria. Fleury:Novartis Pharmaceuticals Corporation: Consultancy; Merck: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Lundbeck: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy. Pro:Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; kiowa: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; portola: Honoraria. Gritti:Autolus: Consultancy. Crump:F. Hoffmann-La Roche Ltd: Consultancy; Servier Canada: Consultancy; Jansen-Ortho: Consultancy. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Danesi:F. Hoffmann-La Roche Ltd: Employment. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Anti-apoptotic protein BCL2 is overexpressed in hematologic malignancies such as CLL. BCL2 inhibitor VEN has shown profound efficacy when combined with B and anti-CD20 antibodies G and R, all of which are established components of CLL therapy. Pre-clinical and early clinical data in R/R CLL suggest addition of VEN to BR or BG may improve efficacy. Here we present data from a Phase Ib study of VEN in combination with BR/BG evaluated for first line (1L) CLL patients (pts). Methods This single-arm, open-label study had dose-finding (3 + 3 design) and subsequent safety-expansion stages. 1L CLL pts with ECOG PS ≤1, adequate marrow and organ function, who were in need of treatment, were first enrolled to BR-VEN, then safety data were reviewed before initiation of the BG-VEN cohort and expansions. In dose finding, 2 dosing schedules were assessed: a) Cycle 1: VEN ramp up introduced before BR/BG or b) Cycle 1: BR/BG loading dose introduced before VEN ramp up, with 1 schedule to be chosen for expansion. Pts were to receive 6 (28-day) cycles of BR/BG-VEN followed by 6 mo of VEN single agent for an overall treatment duration of 1 yr. VEN single agent could be extended upon request of the treating physician if pts were bone marrow (BM) minimal residual disease (MRD) positive and/or had partial response. Objectives were maximum tolerated dose of BR/BG-VEN, safety/tolerability of the combinations and efficacy, including undetectable MRD ( Results During dose finding, no dose-limiting toxicities were observed; schedule b (BR/BG before VEN) and VEN 400mg were recommended for safety expansion. As of June 1 2018, 50 pts were enrolled overall (baseline characteristics in Table 1): 49 pts received ≥1 dose of any study drug (27 BR-VEN, 22 BG-VEN), and 45 (26 BR-VEN, 19 BG-VEN) were evaluable for efficacy. 41% pts (11/27 BR-VEN, 9/22 BG-VEN) completed 6 combination cycles. Median B cycles: 5 (1-6) in both cohorts. Median VEN duration: 371 days (4-1082) BR-VEN, 336 days (11-543) BG-VEN. 8 pts in each cohort had VEN beyond planned 1 yr (14 still on VEN, 2 stopped as of cut-off date). Median time on study: 26 mo (3-43) BR-VEN and 18 mo (1-33) BG-VEN. VEN dose reductions/interruptions occurred in 82% pts (22/27 BR-VEN, 18/22 BG-VEN). 14 pts (8 BR-VEN, 6 BG-VEN) discontinued VEN due to AEs. All pts experienced ≥1 AE. Most common Gr 3-4 AEs: neutropenia (85% BR-VEN, 55% BG-VEN) and thrombocytopenia (37% BR-VEN, 50% BG-VEN; Table 2). No clinical tumor lysis syndrome (TLS) was observed; laboratory TLS was seen in 1 pt with BG before any VEN was given. 1 fatal AE occurred (hemorrhagic transformation after stroke in BR-VEN cohort, onset on Day 82). Infections (all-Gr/Gr 3-4) were observed in 70/0% with BR-VEN and 73/27% with BG-VEN. All pts responded to treatment; objective rates were consistent among pts with del(17p) and/or TP53 mutation (mut) and IGHV unmut status or number of B cycles received (6 vs Conclusion VEN 400mg daily combined with BR or BG in 1L CLL treatment was associated with toxicity leading to treatment interruptions and discontinuations; the most frequently reported toxicities were hematologic. However, despite dose modifications, all pts responded to treatment, independently of subgroups. 50% of pts achieved a CR/CRi; higher than previously reported with BG or BR alone (Brown et al. Blood 2015; Michallet et al. Haematologica 2018). Responses were durable and preliminary PFS data are encouraging. Response rates were similar, irrespective of whether pts received planned 6 or fewer cycles of B; the optimal number of B cycles and general benefit of B in combination with R-VEN or G-VEN should be examined further with longer follow-up. No marked differences in quality of clinical responses were observed when VEN was combined with BR or BG. Updated MRD data will provide a better understanding of the efficacy of these combination regimens compared with backbone chemo-free regimens. Disclosures Stilgenbauer: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morschhauser:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees. Wendtner:Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Hallek:Abbvie: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Kozloff:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lozanski:Novartis: Research Funding; BI: Research Funding; Stem Line: Research Funding; Beckman: Research Funding; Coulter: Research Funding; Genentech: Research Funding. Jiang:Genentech Inc: Employment, Equity Ownership. Huang:F. Hoffmann La Roche: Employment. Pignataro:Roche Products Limited: Employment. Schary:AbbVie: Employment. Humphrey:Roche Products Limited: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Salles:Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Morphosys: Honoraria; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria.

Introduction: BCL2 overexpression leading to evasion of apoptosis is common in hematologic malignancies. In DLBCL, 50% of patients (pts) overexpress BCL2 protein, 30% overexpress BCL2 and MYC (double-expressor [DE]) and 5-10% have translocations of BCL2 and MYC (double-hit [DH]), all of which are associated with a poor prognosis. We hypothesized that combination of the BCL2 inhibitor venetoclax (Ven) with chemotherapy would improve DLBCL outcomes based on pre-clinical and early clinical data. The Phase Ib part of the CAVALLI (NCT02055820) study assessed the maximum tolerated dose (MTD) of CHOP + rituximab (R) or obinutuzumab (G) with Ven (200-800mg) in non-Hodgkin lymphoma, recommending 800mg of Ven + R-CHOP for Phase II. The single-arm, multicenter Phase II part of CAVALLI investigated the efficacy of Ven + R-CHOP in all first-line (1L) DLBCL pts, by BCL2 immunohistochemistry (IHC) status within cell-of-origin (COO) subtypes, by BCL2 fluorescence in situ hybridization (FISH) and in DE and DH pts, with the intent to compare against a matched pt population in the R-CHOP arm of the GOYA Phase III study. Here we report the first safety, efficacy and biomarker analyses in all pts from this ongoing Phase II study. Methods: Eligible pts (age ≥18 yrs; Eastern Cooperative Oncology Group performance status ≤2; 1L DLBCL; International Prognostic Index score 2-5; ≥1 measurable lesion >1.5cm) were assigned to receive six 3-weekly cycles of R-CHOP + 800mg Ven daily for 10 days (Days 1-10, except Cycle 1: Days 4-10), followed by two 3-weekly cycles of 800mg Ven on Days 1-10 + R on Day 1. The primary endpoint was PET-CT response 6-8 weeks after the last R dose (EoT), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival (PFS) and safety. Biomarker analyses in CAVALLI and GOYA were performed in pre-treatment tumor samples including a BCL2 IHC assay (cutoff: 50% medium/high expression), MYC IHC assay (cutoff 40% signal), BCL2 and MYC FISH, and COO assay (Nanostring). Results: 211 pts were enrolled; 208 received any treatment and were included in efficacy and safety analyses. Overall, pt characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more Ann Arbor Stage IV (65.4% vs 47.1%) and BCL2 IHC-positive pts (57.7% vs 50.0%). The EoT complete response rate in all pts did not differ significantly between CAVALLI and GOYA (69.2% vs 62.8%, respectively; Table 1), but was improved in BCL2-positive subgroups, specifically in BCL2 FISH-positive (70.0% vs 47.5%) and DH (71.4% vs 25.0%) pts. With 20 months' median follow-up in CAVALLI, disease progression and death had occurred in 29 and 6 pts, respectively. When compared with GOYA and adjusted for baseline covariates by Cox methodology, PFS improvement was observed in BCL2 IHC-positive pts (HR, 0.53; 95% CI: 0.30-0.93), including within both activated B-cell (ABC; HR, 0.43; 95% CI: 0.19-0.94) and germinal center B-cell (GCB; HR, 0.41; 95% CI: 0.17-0.95) COO subgroups. No PFS benefit was observed in BCL2 IHC-negative GCB pts; the BCL2 IHC-negative ABC subgroup was too small for evaluation (Figure 1). Grade 3-4 adverse events (AEs) occurred in 85% (176/208) of pts in CAVALLI versus 66% (373/574) in GOYA; the majority were cytopenias, infections and febrile neutropenia (Table 2). In CAVALLI, 1% (3/208) of AEs were fatal versus 5% (30/564) in GOYA but follow-up was longer in GOYA (57 vs 20 months). The higher rate of AEs in CAVALLI led to dose interruptions/discontinuations of both Ven and R-CHOP; 61% of pts had >90% relative dose intensity (RDI) of Ven; 73.2% of CAVALLI pts had >90% RDI of each of doxorubicin and cyclophosphamide versus 76.4% for doxorubicin and 77.6% for cyclophosphamide in GOYA. There were no major differences in grade 3-4 AEs or the RDI of R-CHOP across intention-to-treat and BCL2-positive subgroups. GCSF prophylaxis was recommended, but not uniformly delivered. Conclusions: The addition of Ven to R-CHOP in 1L DLBCL treatment resulted in improved efficacy in BCL2 IHC-positive pts compared with matched GOYA controls. Higher rates of cytopenia, infection and febrile neutropenia were observed in CAVALLI versus the R-CHOP arm in GOYA. These data further support exploration of Ven + R-CHOP in a high-risk population of BCL2-positive 1L DLBCL, including DH pts. Disclosures Morschhauser: Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feugier:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Agios: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Curis: Research Funding; Genentech: Research Funding; Forma: Research Funding; Novartis: Research Funding; BeiGene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; TG Therapeutics: Research Funding; Portola: Research Funding; Calithera: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; Trillium: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Janssen: Research Funding; Kite: Research Funding; Takeda: Research Funding. Gasiorowski:Novartis: Honoraria; MSD: Honoraria. Greil:Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Johnson:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Honoraria; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding. Lugtenburg:Genmab: Consultancy; Squibb: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Sandoz: Consultancy; Bristol-Meyers: Consultancy; Servier: Consultancy, Research Funding; Roche: Consultancy. Salles:BMS: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Mir:F. Hoffmann-La Roche: Employment. Kornacker:F. Hoffmann-La Roche Ltd: Employment. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Samineni:Genentech Inc: Employment, Other: Ownership interests non-PLC. Szafer-Glusman:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Petrich:Abbvie: Employment, Other: Ownership interests PLC. Sinha:F. Hoffmann-La Roche Ltd: Employment. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Zelenetz:Celgene: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis/Sandoz: Consultancy; Amgen: Consultancy.

Introduction Although CLL minimal residual disease (MRD) status is used in contemporary clinical trials aimed at maximizing response or determining treatment duration, its role as a predictive factor for PFS has only been established following chemoimmunotherapy. In contrast, whether MRD is a valuable tool for treatment choice in the era of novel targeted agents for CLL is unknown. Unlike kinase inhibitors, the BCL2 inhibitor venetoclax does result in undetectable MRD (uMRD). MURANO demonstrated significant PFS benefit for venetoclax + rituximab (VenR) given for a fixed duration vs bendamustine + rituximab (BR) in relapsed/refractory (R/R) CLL. Here we present analysis of peripheral blood (PB) MRD kinetics in relation to PFS in MURANO with long follow up, when all pts have completed therapy. Methods Pts were randomized to VenR (Ven 400mg/d for 2 yrs + R for first 6 mo) or BR (6 mo). Response was assessed clinically using complete blood count and physical exam at follow-up visits. PB MRD was analysed centrally by ASO-PCR and/or flow cytometry at Cycle 4, end of combination therapy (EOCT; mo 9) and every 3 mo thereafter until 3 yrs, then every 6 mo. As strong concordance between PB and bone marrow (BM) MRD with VenR was previously shown (Hillmen et al. ASCO 2018), we focus on PB MRD. Pts were categorized into uMRD ( Results As of May 8 2018, median follow-up was 36.0 mo. VenR pts achieved high PB uMRD rates at EOCT (62% vs 13% for BR). The same pattern was observed through mo 24, when Ven single-agent treatment was scheduled to cease: 48% uMRD in VenR vs 2% in BR, and 16% int-MRD+ in VenR vs 7% in BR (Table 1). By then, 18% pts in the VenR arm had progressed/died/withdrew from study vs 66% in BR. Consistently high uMRD rates were observed in all VenR subgroups, including pts with high-risk cytogenetics and molecular factors: del(17p) and/or TP53 mutated: 57% at EOCT and 36% at mo 24; IGHV unmutated: 61% at EOCT and 51% at mo 24. Landmark analysis of PFS by MRD status in PB at the EOCT response visit showed that, regardless of treatment arm, uMRD status was associated with longer PFS. Within MRD+ pts, the int-MRD+ group had improved PFS over high-MRD+ pts (Fig 1). Due to the very low rate of uMRD in the BR arm, all further analyses were performed in VenR pts; PFS curves overlapped for pts with uMRD, regardless of whether in CR or PR by investigator assessment, while inferior PFS for MRD+ PR/nPR pts becomes manifest from mo 18 after EOCT (Fig 2). MRD+ pts in CR (all int-MRD+) did as well as uMRD, but numbers are very small. 130 pts in VenR arm completed 2 yrs Ven treatment without PD; among them: 83 (64%) were uMRD, 23 (18%) were int-MRD+, 14 (10%) were high-MRD+ and 10 (8%) had missing data at mo 24. With 9.9 mo median follow-up from Ven completion, amongst uMRD pts at mo 24, the majority remained uMRD (57/83, 69%) and 26/83 (31%) converted to confirmed MRD+ (2 serial assay positive). Conversions were mainly to int-MRD+ (21/26, 81%), all of whom remain PFS event-free; 19% (5/26) converted to high-MRD+, 2 had PD per iwCLL criteria (Fig 3). Of pts converting from uMRD to MRD+ after cessation of Ven at mo 24, 40% (10/25) carried del(17p) and/or TP53 mutation, vs 23% (12/53) among those who did not convert. Of int-MRD+ pts at mo 24, 9/23 (39%) became high-MRD+ (2 had PD); there was 1 PD among the remaining 14. PD was seen in 11/14 (79%) of pts who were high-MRD+ at mo 24. Conclusion The higher PB uMRD rate observed at EOCT in the VenR arm vs BR arm was maintained at completion of Ven treatment, including in high-risk subgroups, consistent with maintained PFS benefit seen with longer follow up. VenR pts who achieved uMRD or int-MRD+ had durable PFS. MRD status powerfully identified distinct outcomes for pts with PR/nPR; longer follow-up is needed to determine the impact of MRD status among CR/CRi. In the first yr post-completion of fixed-duration VenR treatment, majority of uMRD pts remained uMRD; reemergence of MRD+, mainly at int levels, is seen in a minority of pts, and has shown a low rate of progression to clinical PD to date. These data are the first to demonstrate the value of PB MRD as a predictive marker of clinical outcome for the fixed-duration chemotherapy-free regimen, VenR. Our data corroborate that uMRD and int-MRD+ rate is a meaningful endpoint and desirable goal of CLL therapies, including targeted agents. Disclosures Kater: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hillmen:F. Hoffmann-La Roche Ltd: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Pharmacyclics: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Langerak:F. Hoffmann-La Roche Ltd: Research Funding; • InVivoScribe Technologies: Patents & Royalties. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Genentech Inc: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Owen:Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Research Funding; Merck: Honoraria; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Teva: Honoraria; Celgene: Research Funding. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Punnoose:Genentech Inc: Employment; Roche: Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Chyla:AbbVie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Wu:Genentech Inc: Employment. Jiang:Genentech Inc: Employment, Equity Ownership. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Seymour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction The measurement, analysis, and communication of treatment-related symptoms and their impact on the functioning of individuals in clinical trials is an area of interest to the medical community, the Food and Drug Administration and other regulatory agencies. Inclusion of GAs and PROs in early phase trials can characterize the heterogeneity of aging and guide development of therapies to benefit older adults. Despite evidence that GAs and PROs are feasible and predictive of outcome, few early phase trials have integrated them to inform on treatment tolerance. The aim of this analysis is to describe changes in GAs and PROs among older adults with R/R AML in a Phase 1b trial of BCL2 inhibitor venetoclax (Ven) with either MEK inhibitor cobimetinib (cobi) or MDM2 antagonist idasanutlin (idasa) (NCT02670044). Methods Patients (pts) aged ≥60 yrs who were ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled in this open-label, multicenter study, designed to evaluate the safety, tolerability, and efficacy of Ven+cobi/idasa in R/R or secondary AML. GA measures were Short Physical Performance Battery (SPPB; gait speed, balance tests, chair stands), Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) and Short Blessed Orientation Test (SBOT). Treatment-related symptoms were assessed via the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), administered electronically throughout treatment. GAs were administered at screening, Cycle (C) 2 Day (D) 1, C3D1, and C7D1; PRO-CTCAE was administered at C1D1, weekly during C1, for the first 3 weeks of C2 and C3, and monthly starting at C4D1. Mean GA scores were calculated over time for each treatment arm and pt-level heatmaps were created. The 'frequency', 'severity', 'interference', and 'presence' of PRO-CTCAE symptoms were reported at each assessment, with a longitudinal analysis to understand how symptoms changed over the course of treatment. Results As of April 6 2018, 64 pts had been treated with either Ven+cobi or Ven+idasa. Baseline characteristics were comparable between arms; respectively: median age, 72, 74 yrs; ECOG performance status 0-1, 83%, 82%; refractory disease, 63%, 56%. GA and PRO data were available in 52 and 38 pts, respectively. Screening of GAs identified a physically frail (mean SPPB score 70% of pts 'never' or 'rarely' experienced nausea, vomiting or diarrhea; >75% and >50% reported 'none' or 'mild' decreased appetite and fatigue, respectively. In both arms, pt numbers reduced over C1-3, with 8 pts in the Ven+cobi and 6 pts in the Ven+idasa arms providing data at C3D1; this was largely due to attrition on study. Pts reported that their worst post-baseline symptom was 'frequent' or 'almost constant' symptoms of nausea (55%), diarrhea (71%), and vomiting (5%) at some point, and 'severe' or 'very severe' decreased appetite (55%) or fatigue (55%). Variations in the worst post-baseline symptoms were observed between treatment arms, although this was not statistically tested. Symptoms tended to increase and decrease with the start and end of each treatment cycle and appeared worse during C1 for Ven+cobi (Figure 1). Despite differences in symptoms during the cycle, there did not appear to be changes in mean SPPB scores from baseline to C2, no cognitive impairment during treatment, and little to no increase in comorbidity burden. These results may be influenced by a reduction in pt numbers in each treatment arm over subsequent assessments. Conclusion PROs from this Phase 1b study indicate an increased frequency of treatment-related symptoms, in particular, nausea, diarrhea, vomiting, decreased appetite and fatigue, in older AML pts treated with Ven+cobi or Ven+idasa compared with pre-treatment. PROs and GAs can provide additional complementary insight into the older pt's treatment experience on early phase clinical trials that can inform design of later-phase studies. However, strategies to address missing data will be important for maximizing value gained. Disclosures Klepin: Genentech Inc: Consultancy. Campinha-Bacote:Genentech Inc: Employment. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Trask:Genentech Inc: Employment; F. Hoffmann-La Roche: Employment.

Venetoclax, a potent, orally bioavailable inhibitor that selectively targets BCL-2 and induces intrinsic apoptosis, is currently approved for the treatment of relapsed/refractory chronic lymphocytic leukemia with 17p deletion (R/R 17p del CLL) and also has profound efficacy in broad R/R CLL as a single agent or in combination with obinutuzumab (anti-CD20 antibody). However, evidence of robust efficacy by venetoclax as a single agent in certain subtypes of non-Hodgkin lymphoma (NHL) has been limited. For example, diffuse large B-Cell lymphoma (DLBCL) is the most common sub-type of NHL, yet the overall response rate of DLBCL patients to venetoclax was 18% in contrast to 61% in other NHL sub-types. It has been proposed that expression of other pro-survival BCL-2 family members may limit single-agent venetoclax efficacy and is thus considered a potential major resistance factor. To this end, we have observed that low sensitivity to venetoclax monotherapy is correlated with MCL-1 expression in NHL cell lines. We have previously reported that anti-tubulin agents promote MCL-1 degradation. Given that polatuzumab vedotin is a novel antibody drug conjugate targeted to CD79b and delivers an auristatin anti-tubulin agent, we hypothesized that combining polatuzumab with venetoclax presents a mechanism-driven combination strategy for maximizing anti-tumor responses in NHL. In NHL patients, both polatuzumab vedotin and venetoclax have acceptable and non-overlapping toxicities and the combination of both drugs may provide an improved therapeutic index relative to conventional chemotherapy. Here, we demonstrate that polatuzumab vedotin synergizes with venetoclax both in vitro and in vivo. Mechanistically, the combination of both drugs promotes apoptosis in NHL cell lines as indicated by caspase 3/7 activation and dependence on BAX/BAK expression, and decreases MCL-1 protein levels. Furthermore, the combination of venetoclax with polatuzumab vedotin is more efficacious in vitro than the combination of venetoclax with a selective MCL-1 small molecule inhibitor (AMG 176). The combination of polatuzumab vedotin with venetoclax results in durable tumor regressions in diffuse large B-cell and mantle cell lymphoma xenograft models at tolerated doses and is more efficacious than the combination of venetoclax plus bendamustine, a standard chemotherapeutic agent. Based on our pre-clinical data and the strong mechanistic rationale, a drug combination regimen of venetoclax with polatuzumab vedotin and obinutuzumab is currently being evaluated in Phase1b clinical trials in R/R FL and DLBCL (ClinicalTrials.gov identifier NCT02611323). Citation Format: Dhara N. Amin, Jason Oeh, Anuradha Zindal, Lisa Musick, Jamie Hirata, Mehrdad Mobasher, Andy Polson, Deepak Sampath, Ingrid E. Wertz. Anti-tubulin antibody drug conjugates potentiate venetoclax activity in non-Hodgkin lymphoma by targeting MCL-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 880.

7526Background: VEN can cause rapid tumor debulking in patients (pts) with relapsed/refractory CLL. Current VEN dosing schedule with TLS prophylaxis/monitoring averts overt TLS, but further data on...

e22040Background: Novel therapies are needed for older patients (pts) with acute myeloid leukemia (AML). Functional impairments and age-related comorbidities can limit treatment (tx) tolerance. Con...

Introduction: Effective treatment options for patients (pts) with R/R AML are limited and novel therapies are needed. Previous pre-clinical data have shown that venetoclax (VEN) plus cobimetinib (cobi) or idasanutlin (idasa) may be synergistic. MEK and MDM2 inhibition have been shown to down-regulate MCL-1, overcoming a resistance pathway to BCL-2 inhibition in AML (Han, ASH 2016; Pan, ASH 2014). We report preliminary results from a dose-escalation study evaluating VEN plus cobi or idasa in pts with R/R AML. This is the first study evaluating novel-novel oral combinations with VEN in pts with AML. Methods: This open-label, multicenter study evaluates the safety, tolerability and efficacy of VEN + cobi or idasa in pts ≥60 yrs old with R/R or secondary AML who have received therapy for a prior antecedent hematological disease and are not eligible for cytotoxic therapy (NCT02670044). Two-dimensional dose escalation is being used to establish the maximum tolerated dose (MTD) for each combination. Pts on Arm A received VEN PO daily + cobi PO on Days 1-21, and pts on Arm B received VEN PO daily + idasa PO on Days 1-5 in 28-day cycles. Dose limiting toxicities (DLTs) were assessed for the first cycle. Results: As of 25 April 2017, 42 pts were treated in the dose-escalation stage. Arm A included 4 cohorts: VEN 400 mg + cobi 40 mg (n=4), VEN 600 mg + cobi 40 mg (n=7), VEN 800 mg + cobi 40 mg (n=4) and VEN 400 mg + cobi 60 mg (n=7); Arm B included 3 cohorts: VEN 400 mg + idasa 200 mg (n=3), VEN 600 mg + idasa 200 mg (n=8) and VEN 400 mg + idasa 400 mg (n=9). Median age was 72 (range 60-93) yrs and median number of prior therapies was 2 (range 1-10). 19% (8/42) were ECOG 2, 62% (26/42) of pts were refractory to last therapy and 48% (20/42) of pts had secondary AML. According to ELN risk classification, 29% were intermediate-I, 34% intermediate-II and 34% were adverse risk. Most common AEs in both arms are summarized in Table 1. In the VEN + cobi arm, the majority of deaths on study were due to progressive disease (PD); 3 deaths were due to AEs of sepsis, pneumonia and respiratory failure. Three DLTs were reported: 1 diarrhea (Gr 3) in VEN 600 mg + cobi 40 mg and 1 diarrhea (Gr 3) and 1 decrease in ejection fraction (EF) (Gr 3) in VEN 400 mg + cobi 60 mg. The Gr 3 decrease in EF occurred in the setting of sepsis and was subsequently not considered related to study treatment. Due to the higher rates of Gr ≥3 diarrhea (57%) in VEN 400 mg + cobi 60 mg, this dose level will no longer be evaluated in this study. The VEN 800 mg + cobi 40 mg cohort is ongoing. In the VEN + idasa arm, the most common cause of death was PD; 1 death was due to an AE of sepsis. Four DLTs were reported: 1 generalized muscle weakness (Gr 3) and 1 diarrhea (Gr 3) in VEN 600 + idasa 200 mg and 1 acute coronary syndrome (Gr 3) and 1 elevated bilirubin (Gr 4) in VEN 400 mg + idasa 400 mg. Additional dose cohorts evaluating VEN + idasa are ongoing. When compared to monotherapy data at the same dose, preliminary PK analyses suggest that VEN exposure is slightly lower, while cobi and idasa exposures are similar. Preliminary efficacy for the VEN + cobi arm showed 2 CRs (9%), 1 CRp (4.5%) and 1 CRi (4.5%) for an overall response rate (ORR) of 18% (4/22); duration of response (DOR) ranged from 1 to 5 mo, with 1 response ongoing at data cut-off. For the VEN + idasa arm, 1 CR (5%), 1 CRp (5%), 1 CRi (5%) and 1 PR (5%) were achieved for an ORR of 20% (4/20); DOR ranged from 1.3 to 6.7 mo, with 1 response ongoing at data cut-off. In the VEN 600 mg + idasa 200 mg cohort, the ORR was 38% (3/8) with 1 CR, 1 CRp, and 1 CRi. Of the pts who did not achieve a response by IWG criteria, anti-leukemic activity was seen in an additional 7 pts who achieved ≥ 50% bone marrow blast reduction from baseline (3/22 [14%] pts on VEN + cobi and 4/20 [20%] pts on VEN + idasa). Baseline mutation profiling was available in 32 of 42 pts and is summarized for responders in Table 2. Of the 9 pts who had an IDH1/2 mutation at baseline, 44% (4/9) achieved a response (1 on VEN + cobi and 3 on VEN + idasa). Of the 3 pts with known p53 mutations on the VEN + idasa cohorts, none achieved a response. Conclusions: Preliminary results show that VEN plus cobi or idasa can be administered with appropriate risk mitigation measures for GI toxicity and early evidence of clinical activity in R/R AML pts. Dose finding is ongoing and the MTD for both combinations has not yet been determined. Preliminary ORR for the VEN 600 mg + idasa 200 mg cohort was encouraging at 38%. Safety, PK and efficacy data will be updated at the time of presentation. Disclosures Daver: Novartis Pharmaceuticals Corporation: Consultancy; Pfizer Inc.: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Yee: Oncoethix: Research Funding; Novartis Canada: Honoraria; Astex: Research Funding; Karyopharm: Research Funding; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kelly: Abbvie: Honoraria; Pharmacyclics: Honoraria; Amgen: Honoraria; Jannsen: Honoraria. Roboz: Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Kshirsagar: Genentech, Inc: Other: Services via contractor. Dail: Genentech, Inc.: Employment. Wang: Genentech: Employment. Mobasher: Roche: Equity Ownership; Genentech: Employment. Chen: 4. F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hong: Genentech: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership.

Introduction Venetoclax (V), an orally administered, highly selective, potent BCL-2 inhibitor, induces high ORR when given as monotherapy to pts with relapsed/refractory (R/R) CLL, including high-risk populations, e.g. del(17p). V is also well tolerated when combined with rituximab (R) and achieves improved CR rates and minimal residual disease negativity (MRD-). Here, we provide first released data from the primary analysis of MURANO (NCT02005471), the first Phase 3 study of V in pts with R/R CLL, which assessed efficacy/safety of VR vs standard chemoimmunotherapy, bendamustine (B) + rituximab (BR). Methods Eligibility for this open-label, randomized, Phase 3 study included R/R CLL requiring treatment (iwCLL guidelines), 1-3 prior lines of therapy (including ≥1 chemo-containing) and ECOG PS ≤1. Prior B was allowed provided response duration was ≥24 mo. Pts were randomized (1:1) to VR or BR. Stratification factors were del(17p), responsiveness to prior therapy and geographic region. In the VR arm, a 4- or 5-wk graduated dose ramp-up of V from 20-400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk. Beginning at Wk 6, R was then given monthly for six 28-day cycles (IV 375 mg/m2 first dose, then 500 mg/m2) in combination with V daily. Pts continued with V 400 mg for a maximum of 2 yr or until disease progression (whichever first). In the BR arm, pts were given B (IV 70 mg/m2) on Days 1 and 2 of each of six 28-day cycles in combination with R using same R dosing schedule. MRD was centrally assessed by ASO-PCR and/or flow cytometry in peripheral blood at screening, Mo. 4 and 9, and 3-monthly follow-up visits. The primary endpoint was investigator (INV)-assessed PFS. An interim analysis was preplanned at ~140 INV-assessed PFS events. On data review, an Independent Data Monitoring Committee recommended study arms to be unblinded to the sponsor as pre-specified statistical boundaries for early stopping were crossed for PFS in favor of VR. Results 389 pts were enrolled in VR (n=194) and BR (n=195) arms, which were well balanced: median (range) age, 64.5 (28-83) vs 66.0 (22-85) yr; 1 prior therapy, 57.2% vs 60.0%; fludarabine refractory, 14.1% vs 15.5%; del(17p), 26.6% vs 27.2%. At data cut-off (8 May 2017; median follow-up, 23.8 mo. [range 0.0-37.4]), INV-assessed PFS was superior for VR vs BR with HR 0.17, 95% CI 0.11-0.25, P Consistent with known safety profiles of the regimens, Grade 3-4 neutropenia was higher in VR arm but there was no increase in febrile neutropenia or Grade 3-4 infection (Table 2). There were 6 (3.1 %) and 2 (1.1%) Grade ≥3 AEs of TLS reported for VR and BR, respectively; one clinical TLS event in each arm (a Grade 4 acute renal failure in BR, transient increase in creatinine in VR; VR event occurred on an earlier 4-week ramp-up schedule). Richter transformation was confirmed in 6 pts and 5 pts for VR vs BR, respectively. AEs leading to death were seen in 5.2% vs 5.9% of pts. Median relative V dose intensity was 97% of protocol-specified drug exposure. Conclusion The primary analysis of MURANO, the first Phase 3 study of V in R/R CLL, shows a profound improvement in PFS vs standard BR chemoimmunotherapy, with consistent effects in all-risk subsets. Key secondary endpoints, including OS, ORR and CR rate, also showed consistent improvements with remarkable rates of peripheral blood MRD- that exceed those previously attained in treatment of R/R CLL. This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for pts with R/R CLL. Disclosures Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Celgene: Consultancy; Oncternal: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Eichhorst:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Hillmen:Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. D'Rozario:Roche: Consultancy. Assouline:Lundbeck: Other: Advisory Board; Paladin: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myer Squibb: Speakers Bureau; Roche Canada: Consultancy. Owen:AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Merck: Honoraria. Gerecitano:Merck: Consultancy; Mass Medical International: Consultancy; Incyte: Consultancy; Arcus Medica: Consultancy; Aratana: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Samus Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Orexo: Consultancy. Robak:AbbVie: Honoraria, Research Funding; Akari Therapeutics Plc: Honoraria, Research Funding; Roche: Honoraria, Research Funding. De la Serna:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria; AOP Orphan: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; GSK: Honoraria; Infinity: Honoraria; Millennium: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding. Cartron:Gilead: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Novartis: Honoraria; Roche: Research Funding; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Humerickhouse:AbbVie: Employment, Equity Ownership. Punnoose:Genentech: Employment. Li:Genentech: Employment. Boyer:Roche: Employment. Humphrey:F-Hoffmann-La Roche: Employment, Equity Ownership. Mobasher:Roche: Equity Ownership; Genentech: Employment. Kater:Roche: Consultancy; Acerta/Astra Zeneca: Consultancy, Research Funding; Roche/Genentech: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Research Funding; Sandoz: Consultancy.