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Purpose: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors. Patients and Methods: We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies. Results: Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0–15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0–56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression. Conclusions: Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. Clin Cancer Res; 24(18); 4371–9. ©2018 AACR.

Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.

We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features. Significance: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106–17. ©2016 AACR. See related commentary by Pullarkat and Newman, p. 1082. This article is highlighted in the In This Issue feature, p. 1069

Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1–3 and 8–10,; and gemcitabine 1,000 mg/m2 on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1–3, 8–10, and 15–17; and gemcitabine 1,000 mg/m2 on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m2 for the 21-day schedule. No clinically significant pharmacokinetic drug–drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m2 was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.

Background: Venetoclax (VEN) is a potent, highly selective, orally bioavailable small-molecular BCL2 inhibitor that is FDA-approved for patients (pts) with chronic lymphocytic leukemia (CLL) that harbors del(17p) and who have received ≥1 prior therapy. VEN monotherapy induces objective response in ~80% of pts (16-20% complete remission by investigator) with relapsed/refractory (R/R) CLL, including del(17p) CLL (Roberts et al, 2016; Stilgenbauer et al, 2016). Safety of VEN monotherapy was evaluated using an integrated dataset from pts with CLL. Methods: Pts were included if they received at least one dose of 400 mg VEN as target dose in the M12-175 (first in human), M13-982 (del[17p] CLL), or M14-032 (prior ibrutinib or idelalisib) Phase I or II studies. All started with weekly dose ramp up to 400 mg daily over 4-5 weeks and continued VEN until disease progression/discontinuation. Results: Overall, 296 pts were included in the analysis: median age was 66 years (range: 29-85), 94% had ECOG score 0-1, 53% had Binet stage A, 27% B, and 19% C. 66% had del(17p) CLL, 77% had unmutated IGHV, and 69% had β-2 microglobulin >3 mg/L. Pts had received a median of 3 prior therapies (range: 0-12) and 94 (32%) had received prior ibrutinib or idelalisib. A history of cytopenias was common, with neutropenia in 52 (18%) pts, anemia in 118 (40%), and thrombocytopenia in 80 (27%). Forty-six (16%) pts were on G-CSF support prior to enrollment. At the time of analysis, median duration on VEN was 13 months (range: 0-50), with 55% pts receiving VEN daily for >1 year. Common AEs (any grade) were neutropenia (41%), diarrhea (39%), nausea (36%), anemia (29%), fatigue (26%), and upper respiratory tract infection (23%). The most common Grade 3/4 AEs were neutropenia (37%), anemia (15%), and thrombocytopenia (14%). Grade 3/4 infections were reported for 19% of pts. Common serious AEs were pneumonia and febrile neutropenia (5% each); most serious AEs occurred within the first 3 months on VEN. Twenty-five deaths were reported: 13 due to disease progression and 12 were treatment-emergent AEs due to complications related to underlying CLL (most common were infections [4]); none were attributed by the investigator to VEN. The safety profile was similar when analyzed by subgroups, including age, sex, race, or prior ibrutinib/idelalisib. Four pts had AEs of TLS, though only one met Howard criteria for laboratory TLS (decreased calcium and increased phosphate). No clinical TLS was observed. All events occurred during the 5-week dose ramp up and pts interrupted VEN dosing for median of 3 days (range: 1-5), though all restarted VEN to reach 400 mg. Events were managed by IV hydration and standard of care for laboratory abnormalities. A major reason for VEN interruptions/reductions was neutropenia, with most dose adjustments occuring within the first 3 months on study. Neutropenia was managed by standard supportive care measures, including G-CSF support for 136 (46%) pts during this time. Time of first onset for most hematologic toxicities (any grade) occurred during dose ramp up (Figure). First onset of new AEs within or after 3 months on VEN (shown as within/after 3 months) was 34%/7% for neutropenia, 27%/3% anemia, and 14%/5% thrombocytopenia. This temporal pattern is likely due to improving CLL disease control though for some pts this may be the result of increasing time off prior myelosuppresive chemotherapy. Grade 4 neutropenia was reported in 71 (24%) pts and median time to event was 28 days (range: 2-416); 48/71 (67%) had Binet C at screening and median time to event was 23 days (range: 2-415). Grade 4 neutropenia required dose reductions for 21% of pts, 80% received G-CSF support, and 1 event led to study discontinuation. Grade 4 thrombocytopenia occurred in 32 (11%) pts (23 had Binet C) and Grade 4 anemia in 2 (2%) pts (both Binet C). Gastrointestinal toxicities were mainly Grade 1/2, with 60% new events reported in the first 3 months vs 11% reported > 3 months (Figure). No late toxicity signal has been observed in pts receiving >1 year of therapy. Conclusions: The safety profile of 400 mg VEN daily was consistent across pts with CLL pooled from 3 studies and remains acceptable with longer follow up in this larger population. No clinical TLS was observed and one event of laboratory TLS was manageable. The majority of AEs, including cytopenias (most common Grade 3/4 AEs), occurred during the first months of VEN and onset of AEs decreased over time in pts with emergent toxicities. Figure Figure. Disclosures Seymour: AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: 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, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Infinity: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Roberts:AbbVie: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; Janssen: Research Funding; Servier: Research Funding. Hallek:GSK: Research Funding; Mundipharma: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Gilead: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria. Wierda:Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Gerecitano:Samus: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Cerri:AbbVie: Employment. Potluri:AbbVie: Employment. Kim:AbbVie: Employment. Busman:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Humerickhouse:AbbVie: Employment. Best:AbbVie: Employment. Desai:AbbVie: Employment. Stilgenbauer:Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding.

Introduction: The overall outcome of patients (pts) with chronic lymphocytic leukemia (CLL) who relapse after or become refractory to treatment with B-cell receptor (BCR) signaling antagonists, including ibrutinib (IBR) or idelalisib (IDE), is recently being appreciated and appears quite poor. To date, no phase 2 studies have reported efficacy in this population. Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor with a BCR-independent mechanism of action and substantial activity in pts with heavily pretreated relapsed or refractory CLL. We report preliminary results from an ongoing phase 2, open-label study evaluating venetoclax monotherapy in CLL pts relapsed after or refractory to IBR or IDE (NCT02141282). Methods: Pts with CLL relapsed after or refractory to IBR (Arm A) or IDE (Arm B) receive venetoclax monotherapy starting at 20 mg followed by a 5-step weekly ramp-up to a final daily dose of 400 mg. Pts with Richter's transformation (RT) suspected by screening PET CT or confirmed by lymph node biopsy are ineligible. The primary objectives are to assess the efficacy (investigator assessed overall response rate, ORR) and safety of venetoclax. Disease and response assessment was performed using iwCLL criteria at weeks 8, 24 and every 12 weeks thereafter. Adverse events (AEs) are monitored throughout the study. Results: As of April 30, 2015, 28 pts were enrolled in the study. Three screened pts were ineligible due to RT. Pt demographics are summarized by treatment arm in the table. Twenty-two entered into Arm A after a median duration on IBR of 15.5 months (range: 1-56). Investigator-reported best responses while on IBR prior to starting venetoclax were 14 partial response (PR), 4 stable disease (SD) and 3 progressive disease (PD); best response for 1 pt is unknown. Six entered into Arm B after a median duration on IDE of 9.7 months (range: 1-34). Investigator-reported best responses while on IDE prior to starting venetoclax were 1 complete response (CR), 3 PR and 2 SD. At last follow-up, the median time on venetoclax was 2.4 months (range: 0.1- 7) for Arm A and 1.7 months (range: 1.2-4.5) for Arm B. Venetoclax discontinuation occurred in 4 pts in Arm A (1 each due to respiratory failure, multi-organ failure, PD of RT, death of unknown cause) and in 1 pt in Arm B (PD prior to first assessment). Fifteen pts in Arm A and 3 in Arm B underwent Week 8 response assessment. In Arm A, 8/15 (53%) achieved a PR, 6/15 (40%) had SD, and 1/15 was inevaluable. In Arm B, 2/4 achieved a PR, 1/4 had SD, and 1/4 had PD prior to first assessment. Pts with SD had evidence of ongoing disease reduction, measured by decreasing circulating lymphocytes and lymph nodes. As of the cutoff date, 23 pts remain on venetoclax therapy. Compared to prior venetoclax monotherapy studies, no new safety signals for venetoclax were observed in either treatment arm. Treatment-emergent AEs (all grades) in >25% of the overall population were neutropenia (57%), anemia (35%), diarrhea (32%) and nausea (32%). Treatment-emergent grade 3/4 AEs in >10% of the overall population were neutropenia (43%; 3/12 of the neutropenic pts developed febrile neutropenia), anemia (29%), thrombocytopenia (18%), hypophosphatemia, hypoxia, leukopenia, and pneumonia (each 11%). Serious AEs in ≥2 pts overall were febrile neutropenia, increased blood potassium, multi-organ failure, and pneumonia (each 7%). Prior to study entry, 7/22 (32%) in Arm A received G-CSF support. One pt with high disease burden developed laboratory TLS in week 4, upon escalating to the 200 mg daily venetoclax dose, evident by hyperuricemia and hyperphosphatemia. Electrolytes returned to normal levels after a dose interruption and intervention. No pts experienced clinical TLS; laboratory changes were not clinically significant. Conclusions: In this group of pts with aggressive disease relapsed after or refractory to BCR-targeted agents, venetoclax monotherapy demonstrated early activity at the 8 week assessment, which occurred within 3 weeks of reaching the target 400 mg daily dose. The majority of evaluable pts achieved PR or SD. Venetoclax monotherapy exhibited a tolerable safety profile without events of clinical TLS. This is the first phase 2 study to show activity in a relatively uniform population of pts previously treated with BCR kinase inhibitors; the data suggests that venetoclax is active in these pts. Enrollment in both arms was ongoing as of the data cut. Figure 1. Figure 1. Disclosures Jones: Genentech, Pharmacyclics; institutional research funding from Abbvie, Pharmacyclics, Genentech, and Gilead: Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Mato:AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Coutre:AbbVie: Research Funding. Wierda:Genentech: Consultancy; AbbVie and Genentech: Research Funding. Choi:AbbVie and Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; AbbVie: Research Funding. Davids:AbbVie and Janssen: Consultancy; Genentech and Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, TG Therapeutics, and Infinity: Research Funding. Lamanna:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barr:Pharmacyclics: Research Funding; AbbVie and Pharmacyclics: Consultancy. Burns:AbbVie: Employment, Equity Ownership. Montalvo:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Busman:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Byrd:Pharmacyclics: Research Funding; Genenttech, AbbVie, Acerta, Pharmacyclics: Other: Unpaid consultant.