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Supplementary Table S1. Overall activity and predictors of treatment failure (PD or less than partial response by IWG criteria). Supplementary Figure S1. BCL-2 family protein index at screening. Supplementary Figure S2. Mean (+ SD) venetoclax plasma concentration-time profile at week 6 day 1 (800 mg). Supplementary Figure S3. Study design.

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.

Supplementary Data

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

Background: Clarithromycin has established efficacy and safety in the treatment of respiratory infections. Objective: This study examined the efficacy and safety of a new extended-release formulation of clarithromycin compared with amoxicillin/clavulanate in the treatment of acute exacerbation of chronic bronchitis (AECB). Methods: This phase IIIB, multicenter, randomized, parallel-group, investigator-blinded study in patients with AECB and productive cough with purulent sputum compared treatment with extended-release clarithromycin (two 500-mg tablets once daily for 7 days) and amoxicillin/clavulanate (one 875-mg tablet twice daily for 10 days). Assessments were performed before treatment, between study days 10 and 12 (or within 48 hours after premature discontinuation), and between study days 17 and 21 (test of cure). Results: Of 287 patients randomized and treated, 270 were clinically evaluable (137 clarithromycin, 133 amoxicillin/clavulanate). Treatment groups were well matched in terms of demographic characteristics, medical condition, and history. Among clinically evaluable patients at test of cure, 85% and 87% of clarithromycin- and amoxicillin/clavulanate-treated patients, respectively, demonstrated clinical cure (as defined in 1998 draft US Food and Drug Administration guidelines); among clinically and bacteriologically evaluable patients, 92% versus 89%, respectively, demonstrated bacteriologic cure. Overall pathogen eradication rates were similar in the 2 groups (88% clarithromycin, 89% amoxicillin/clavulanate). Rates of premature discontinuation of study drug for any reason differed between treatments: 3% ( 4 142 ) of clarithromycin-treated patients versus 12% ( 17 145 ) of amoxicillin/clavulanate-treated patients (P = 0.005). One percent ( 2 142 ) and 6% ( 8 145 ) of the respective treatment groups discontinued study drug because of adverse events. Adverse events generally occurred with a similar frequency in the 2 groups; however, taste alteration was more common with clarithromycin ( 9 142 [6%]) than with amoxicillin/clavulanate ( 1 145 [1%]; P = 0.01). Mean severity scores for gastrointestinal adverse events showed a significant difference between groups (1.16 for clarithromycin-treated patients and 1.58 for amoxicillin/clavulanate-treated patients; P = 0.016). Conclusions: The results of this study demonstrate the clinical and bacteriologic equivalence and improved gastrointestinal tolerability of a 7-day course of once-daily extended-release clarithromycin relative to a 10-day course of twice-daily amoxicillin/clavulanate in the treatment of AECB.

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.

Introduction: BCL-2 has been implicated in hematologic malignancies and associated with drug resistance and poor prognosis in acute myelogenous leukemia (AML). Patients (pts) with relapsed/refractory (R/R) AML have poor prognosis with limited overall survival. ABT-199 is a selective, potent, orally bioavailable small molecule BCL-2 inhibitor. ABT-199 has demonstrated pre-clinical efficacy inhibiting the growth of AML cell lines or AML-pt derived primary cells systemically engrafted into immunocompromised mice. The current study evaluates ABT-199 monotherapy in pts with high-risk R/R AML and those unfit for chemotherapy. Methods: The primary objective of this phase 2, open-label, multicenter trial was to evaluate preliminary efficacy of ABT-199 in R/R AML or as frontline therapy for pts unfit for intensive therapy. Secondary objectives included safety and phamacodynamic assessments. An intra-pt dose escalation was implemented in which pts received 20 mg ABT-199 on Week (Wk) 1 Day 1, with daily escalation to a final target dose of 800 mg on Day 6 and daily thereafter. Pts without a complete response (CR) or complete response with incomplete blood count recovery (CRi) at first scheduled assessment (end of Wk 4) were able to escalate to 1200 mg. Safety analyses were performed for all pts. Adverse events (AEs) were reported according to the NCI-CTCAE version 4.0. Responses were evaluated using the revised guidelines by the International Working Group for AML. Samples were collected over 24 hours at Wk 6 to evaluate ABT-199 pharmacokinetics. Results: As of July 8, 2014, 32 pts enrolled with a median time on study of 81 (range 13-187) days. The median age was 71 (range 19–84) years and 16 (50%) were male. Thirty (93.8%) pts had R/R disease. Twelve (37.5%) had a history of myelodysplastic syndrome and 2 (6%) had a history of myeloproliferative neoplasms. Fourteen (44%) had received more than three prior treatments and 22 (69%) had received one or both hypomethylating agents. Isocitrate dehydrogenase (IDH) 1 and 2 mutations (mt) were reported in 2 (6%) and 9 (28%) pts, respectively. In addition, 6 (19%) were shown to have FLT3-ITD mt (2 of these also had IDH2 mt). The most common treatment-emergent AEs (in ≥25% of pts) were nausea (14/32, 44%), diarrhea (12/32, 38%), fatigue (9/32, 28%), neutropenia and vomiting (each 8/32, 25%). Grade 3/4 AEs (in ≥3 pts) were febrile neutropenia (8/32, 25%), anemia and pneumonia (each 3/32, 9%). There were no reported events of clinical or laboratory tumor lysis syndrome. There were no AEs leading to death. The median bone marrow blast count was 50% (range 5–97; n=25) at baseline. Twenty eight pts were evaluable at first assessment and the median bone marrow blast count decreased to 21% (range 1–87.5; n=25; 1 patient had marrow aplasia, 1 had hemodilute aspirate and another had clinical progression), a 36% decrease from baseline. One pt had a CR (3%) and 4 (12.5%) had a CRi at first assessment. Of the 4 CRi, 1 achieved CR by Wk 20. Of the pts with CR/CRi, 3 had IDH mt; two pts with IDH2 mt were MRD negative by flow cytometry and the third with IDH1 mt remained MRD positive. Three more pts with IDH mt experienced anti-leukemic activity that did not meet IWG response criteria due to lack of hematologic recovery. Six of 32 (19%) pts had at least 50% bone marrow blast reduction at first assessment. Ten progressed before the first assessment. Two pts with coexisting IDH2 and FLT3 mt had no evidence of antileukemic activity. The overall response rate (CR/CRi by IWG response criteria) was 15.5% (5/32). All 3 pts with IDH mt relapsed before Wk 12. Two IDH wild type (WT) pts remain in CR/CRi, respectively, and 2 additional IDH WT pts continue to show hematologic improvement without meeting IWG response criteria. Mean (CV%) ABT-199 peak concentration and AUC24 for 15 pts on 800 mg dose at Wk 6 was 3.62 (49) µg/mL and 56.7 (73) µg•h/mL, respectively, which is similar to that seen in pts with lymphoid malignancies. Conclusions: These preliminary data indicate that ABT-199 employed as a single agent has considerable clinical activity in pts with poor prognosis R/R AML and that pts with IDH mt may be particularly sensitive. ABT-199 monotherapy demonstrated an acceptable safety profile in these pts. ABT-199 demonstrates promising clinical activity in R/R AML pts who have limited available treatment options. This agent is being actively developed and evaluated in AML. Disclosures Konopleva: AbbVie, Inc: Research Funding; Genentech: Research Funding. Potluri:AbbVie, Inc: Employment. Chyla:AbbVie, Inc: Employment. Busman:AbbVie, Inc: Employment. McKeegan:AbbVie, Inc: Employment. Salem:AbbVie, Inc: Employment. Zhu:AbbVie, Inc: Employment. Ricker:AbbVie, Inc: Employment. Blum:Genentech: Consultancy. Dunbar:AbbVie, Inc: Employment. Kirby:AbbVie, Inc: Employment. Falotico:AbbVie, Inc: Employment. Leverson:abbvie: Employment, Equity Ownership. Humerickhouse:AbbVie, Inc: Employment. Mabry:AbbVie, Inc: Employment. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Letai:AbbVie, Inc: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

Abstract 2455 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50 ≤ 1μM) against T and B lymphoid malignancies that over-express Bcl-2. A phase 1 trial demonstrated oral navitoclax monotherapy to be well-tolerated and to have anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). However, thrombocytopenia (TCP) was the dose-limiting toxicity (DLT). Phase 3 studies showed improved outcomes in CLL pts with the fludarabine/cyclophosphamide/rituximab (FCR) combination, and a phase 2 trial showed bendamustine/rituximab (BR) to be effective for pts with relapsed or refractory CLL. Navitoclax enhanced R (monotherapy and in combination with chemotherapy) efficacy in preclinical models of B-cell lymphoma. Methods: This is an ongoing, international, phase 1 dose-escalation study to evaluate the safety and pharmacokinetics (PK) of oral navitoclax in combination with FCR (Arm A) or BR (Arm B) in pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥100/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. After obtaining informed consent, pts were assigned to Arm A or Arm B based on physician preference, each consisting of 28-day dose-escalation cycles with once-daily, pre-infusion, navitoclax treatment on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Navitoclax starting dose was 110 mg daily. Dose escalation to the next cohort (200 mg) was according to a continuous reassessment model. Tumor responses were evaluated using NCI-WG 1996 criteria. Pts could continue on navitoclax therapy for 1 yr in the absence of progressive disease or significant toxicity. Results: As of July 2010, 7 pts enrolled in the initially prioritized Arm B (BR+navitoclax); all completed the first cohort of 110 mg (median age 60 yr [range 55–72]). Study sites are currently enrolling pts in Arm A (FCR+navitoclax); 2 pts have enrolled to date. The median number of prior therapies was 2 (range 1–7). One pt had a DLT of elevated AST (Arm B, 110 mg cohort) and 1 pt had a DLT of neutropenic fever (Arm A, 110 mg cohort). In Arm B, neither TCP nor neutropenia have been DLTs. For the 7 pts with navitoclax-related AEs, the most common were diarrhea (3 pts), nausea (5 pts), and fatigue (3 pts). Seven pts remain on study; 2 pts discontinued due to disease progression and 2 withdrew per physician preference. In Arm B, preliminary antitumor best responses were assessable in 4 pts who received 2 cycles; 1 CRi in a pt with del17p- (based on lymph node [LN] response and no morphologic evidence of CLL in the bone marrow), 2 unconfirmed CRs (based on LN response and no bone marrow at this time), and 1 PR in a pt with del17p- (this pt subsequently received an allogeneic stem cell transplant). Preliminary PK results for the Arm B 110 mg cohort indicated that navitoclax PK was similar in Cycle 1 (navitoclax+BR) and Cycle 2 (navitoclax alone), and appeared comparable to PK in the navitoclax monotherapy study. Conclusions: Early results show that the combination of navitoclax with BR is well-tolerated, without DLTs of TCP or neutropenia, and show evidence of anti-tumor activity. Data are limited in the FCR portion of the study. The maximum tolerated dose of navitoclax has not been reached. Accrual is ongoing and following completion of the dose-escalation components of this study, expanded cohorts of pts will be assessed using the recommended phase 2 dose of navitoclax to further assess the tolerability and dose, and to continue to explore for efficacy signals in combinations. Preliminary data in combination with BR are encouraging. Disclosures: Kipps: Abbott Laboratories: Research Funding; Genentech/Roche: Research Funding. Wierda: Abbott: Research Funding; Genentech: Honoraria, Speakers Bureau. Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Swinnen: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yang: Abbott: Employment. Cui: Abbott: Employment. Busman: Abbott: Employment. Krivoshik: Abbott: Employment. Enschede: Abbott: Employment. Humerickhouse: Abbott: Employment.

Abstract 883 ABT-263, a novel orally bioavailable BH3 mimetic, binds with high affinity (Ki ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. In vitro, ABT-263 potently induces apoptosis (EC50 ≤ 1μM) in Bcl-2 overexpressing human lymphoma cell lines and primary CLL cells. Preclinical mechanism-based toxicities include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, reflecting inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-873 is a phase 1/2a dose-escalation trial employing a continuous reassessment method (CRM) to evaluate ABT-263 PK, safety and antitumor activity of two dosing schedules in pts with relapsed or refractory CLL. Tumor responses were evaluated by the NCI-WG criteria. Pts were initially dosed on d1-14 of a 21d cycle with 10-250 mg ABT-263. To ameliorate the impact of thrombocytopenia (TCP) due to on-target Bcl-XL inhibition-induced platelet apoptosis, a 100 mg lead-in dose for 7d followed by continuous 21/21d dosing (up to 300mg/d) was investigated. This study has completed enrollment at 300 mg with 29 pts (15 on a 14/21d; 14 on a 21/21d schedule) as of June 2009. The PK exposure of ABT-263 was approximately dose-proportional from 10-300 mg with a terminal half-life of 11 h. Platelet nadirs were transient, occurring on d3-5 followed by partial recovery due to compensatory increased megakaryopoiesis during continued dosing. Lead-in dosing reduced the early platelet nadir, and minimized fluctuations in platelet count observed with intermittent dosing. Circulating platelet count dropped maximally during cycle 1 by an average 12%, 57%, 68% and 70% from baseline at 10 mg, 110 mg, 200 and 250 mg for the 14/21d schedule, and an average of 52%, 63%, 63% and 68% from baseline at 125 mg, 200 mg, 250 mg and 300 mg for the 21/21d schedule. Of the 21 evaluable pts, 2 had radiographically confirmed partial responses (99% and 79% reductions) and 3 had as yet unconfirmed nodal regression (100%, 71% and 55%). 7 pts maintained a ≥50% decrease in circulating absolute lymphocyte count for ≥ 2 months with 2 pts having PR by physical examination; the overall response rate was 33%. Stable disease was noted in 8 pts and 2 pts had progressive disease. Responses tend to be durable, with the median PFS not yet reached while the median time on study is 9 mos (range 0.63 - 18.4 mos). The most common adverse events (AE) were diarrhea (52%), nausea (44%), vomiting (24%), fatigue (24%) thrombocytopenia (TCP; 20%) and neutropenia (12%). Dose limiting toxicities (DLT) were observed in 3 pts on the 14/21d schedule; 2 at 110mg (hospitalization & Grade 4 TCP) and 1 at 250 mg (Grade 4 TCP). Among the 14 pts on the 21/21d schedule, 3 pts experienced DLT; 1 at 200 mg (Grade 4 TCP); 1 at 250 mg (Grade 2 nausea) and 1 at 300 mg (Grade 4 TCP). ABT-263 was well-tolerated and had favorable PK and acceptable safety profiles. One week 100mg/d lead-in followed by continuous dosing minimizes platelet nadir and cycle variability. Based on the 21/21d continuous dosing data, the CRM model projection for MTD converged. The recommended phase 2 dose is 100 mg 7-d lead-in followed by 250 mg/d continuous dosing. Disclosures: Roberts: Abbott : Research Funding; Genentech: Research Funding. Off Label Use: ABT-263 is an experimental drug that is not yet registered. It is designed to induce apoptosis in tumor cells.. Brown:Celgene: Research Funding; Genzyme: Research Funding. Wierda:GSK: Consultancy; Ligand: Consultancy; Genentech: Consultancy; MEDIMMUNE: Consultancy; ABBOTT: Consultancy; TRUBION: Consultancy; BAYER, SANOFI-AVENTIS, MEMGEN, GENITOPE, GENMAB, SUNESIS, ABBOTT, GSK: Research Funding; GENENTECH: Honoraria; CELGENE: Speakers Bureau. Xiong:Abbott: Employment. Cui:Abbott: Employment. Busman:Abbott: Employment. Enschede:Abbott: Employment. Krivoshik:Abbott: Employment. Humerickhouse:Abbott: Employment.