Abstract: Abstract 304 Background: BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki 〈 0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods: This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3] , 400 mg [n=4], and 600 mg [n=7] . Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results: To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy ( 〉 5cm). Most common AEs (experienced by 〉 2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in 〉 1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of 〉 50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions: ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures: Roberts: Abbott: Research Funding; Genentech: Research Funding. Anderson:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kahl:Genentech: Consultancy, Research Funding; Abbott: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Yang:Abbott: Employment, own Abbott stock Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Seymour:Roche: Advisory board member, Advisory board member Other, Consultancy; Genentech: Advisory board member, Advisory board member Other, Consultancy.

Abstract: B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Abstract: Introduction: BCL-2 is an anti-apoptotic protein that is commonly overexpressed in hematologic malignancies, including Non-Hodgkin Lymphoma (NHL). Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor. Patients (pts) with relapsed/refractory (R/R) NHL were enrolled in a phase 1, open-label, dose-escalation, multicenter study to determine the safety, pharmacokinetics, and efficacy of venetoclax monotherapy. We present updated data on the safety profile and efficacy as of June 10, 2015. Methods: Venetoclax was administered once-daily until progressive disease or unacceptable toxicity. To mitigate the risk of tumor lysis syndrome (TLS), a 3-week period with a stepwise, intrapatient dose ramp-up was used, starting at 200 mg and reaching a maximum dose level of 1,200 mg in the dose escalation cohorts. In a safety expansion cohort, stepwise escalation from 400 mg to 800 mg to 1200 mg was evaluated. Adverse events (AEs) were graded according to NCI-CTCAE version 4.0. Responses were assessed using 2007 Cheson IWG response criteria including CT scans beginning at week 6. Results: Accrual is complete with 106 pts enrolled. NHL subtypes included in the dose escalation cohorts (200-1200 mg/day) were diffuse large B-cell lymphoma (DLBCL, n=20), follicular lymphoma (FL, n=14), mantle cell lymphoma (n=28), Waldenström macroglobulinemia (n=4), marginal zone lymphoma (n=3), and multiple myeloma (n=1). NHL subtypes enrolled in the safety expansion cohort (1200 mg/day) were DLBCL (n=21) and FL (n=15). The current analysis focuses on pts with DLBCL and FL from the dose escalation and safety expansion cohorts. Data on other subtypes will be presented at the meeting. In total, 57/70 pts with DLBCL and FL have discontinued (n=49 due to PD, n=3 due to AE, n=2 withdrew consent, n=2 proceeded to transplant and n=1 due to non-compliance). Treatment emergent-AEs of any grade in ≥20% of the 70 pts with DLBCL or FL were diarrhea and fatigue (each 44%), nausea (33%) and vomiting (23%). Treatment-emergent grade 3/4 AEs in ≥5 pts, were anemia (14%), fatigue (9%) and thrombocytopenia (7%). Serious adverse events in ≥2 pts were hyponatremia (4%), and dehydration, diarrhea, and febrile neutropenia (each 3%). Two events of laboratory TLS were previously reported. There were no new events of laboratory TLS and no pts had clinical TLS. Among 41 pts with DLBCL, 7 were DLBCL-Richter's transformation (RT) and 2 had primary mediastinal large B-cell lymphoma (PMBCL). The median age was 68 (range: 25-86). The median number of prior therapies was 3 (range: 1-8). Five (12%) had rituximab-refractory disease. The median time on venetoclax for pts with DLBCL was 5 months (range: 0.4-9). The overall response rate (ORR) was 15% [3 (9%) CR and 2 (6%) PR] for pts with DLBCL (n=34). The median duration of response for DLBCL was 3.3 months (range: 2-4) with no responses ongoing and the median duration of SD was 2.3 months (range: 1-15). One pt with SD remains on study at 9 months of venetoclax. Two responders (1 with DLBCL who achieved CR and 1 with PMBCL who achieved PR) proceeded to allogeneic hematopoietic stem cell transplant. The ORR was 43% (3 PR) for pts with DLBCL-RT (n=7). One pt with PR remains on study at 18 months of venetoclax. Among 29 pts with FL, the median age was 64 (range: 46-75). The median number of prior therapies was 3 (range: 1-10). Eight (28%) had rituximab-refractory disease. The median time on venetoclax was 7 months (range: 1-19). The ORR was 34% [3 (10%) CR and 7 (24%) PR] for pts with FL (n=29). All 3 patients with CR were enrolled in the dose escalation cohorts. The median duration of response was 10 months (range: 1-30) and the median duration of SD was 4.2 months (range: 2-18). Eleven patients remain on study. Response rates are summarized in the table. Conclusions: Venetoclax monotherapy demonstrated a tolerable safety profile in pts with R/R NHL. Several pts with DLBCL had an initial response to venetoclax, but this response was not sustained. In FL, venetoclax monotherapy achieved an ORR of 34% indicating clinical benefit, as evidenced by long durations on therapy. These results suggest that the optimal role of venetoclax for treatment of DLBCL and FL will be in combination therapies. Venetoclax is currently being evaluated in combination with bendamustine and rituximab and in combination with R or obinutuzumab plus CHOP in phase 2 studies of pts with FL. Table 1. Table 1. Disclosures Gerecitano: Genentech: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Roberts:Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax: Employment; AbbVie and Genentech: Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: 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, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, 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, Other: Travel support, Research Funding, Speakers Bureau; Takeda: 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. Wierda:Consultant and speaker bureau for Genentech: Consultancy; AbbVie and Genentech: Research Funding. Kahl:Genentech: Consultancy; AbbVie: Research Funding; Teva: Consultancy. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Puvvada:AbbVie and Genentech: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Gressick:AbbVie: Employment, Equity Ownership. Wagner:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Heitner Enschende:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Abstract: New treatment options are needed for patients (pts) with R/R NHL, particularly in MCL where there are no curative options. Dysregulation of the anti-apoptotic protein Bcl-2 is a hallmark of NHL pathogenesis and contributes to chemotherapy resistance. ABT-199 is a selective, potent, orally bioavailable small molecule Bcl-2 inhibitor that is a promising agent for the treatment of pts with NHL. Methods The primary objectives of this phase I, dose-escalation study were to evaluate the safety and pharmacokinetics (PK), and to determine a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ABT-199. Secondary objectives were to assess the efficacy of ABT-199 and to explore biomarkers for response. Adult pts requiring therapy, with ECOG performance status ≤1 and adequate marrow function (ANC ≥1.0 x 109/L, Plt ≥50 x 109/L) received ABT-199 on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise escalation starting with lower doses to final cohort doses of 200, 300, 400, 600, and 900 mg was implemented. Evaluations include adverse events (AE; NCI-CTCAE-V4), PK parameters and disease responses (IWG 2007 criteria). Results As of July 4, 2013, 32 pts were enrolled, 11 (34%) with follicular (FL), 8 (25%) with MCL, 8 (25%) with diffuse large B-cell (DLBCL), 1 (3%) with marginal zone (MZL), 3 (9%) with Waldenström macroglobulinemia (WM), and 1 (3%) multiple myeloma (MM). The median age was 68 (range 35-85), 63% were male with a median of 3.5 prior therapies (range 1-7), and the median time on study was 6.0 months (range 0.5-15.0). 44% of the pts had bulky disease ≥5 cm, including ≥10 cm in 16%. 22 pts have discontinued (D/C) drug: 18 due to progressive disease, 2 due to AEs, and 2 who proceeded to stem cell transplant in ongoing response. The most common AEs of any grade (G) occurring in ≥20% of pts were nausea (41%), diarrhea (31%), vomiting (22%), fatigue (22%), and upper respiratory tract infection (22%). G 3/4 AEs occurring in 〉 3 pts were anemia (15%), neutropenia (13%), and thrombocytopenia (13%). G 3/4 thrombocytopenia was not dose-dependent or dose-limiting. Two of 10 pts in cohort 5 experienced a DLT (G3 febrile neutropenia and G4 neutropenia) at the target dose of 600 mg. G3 laboratory tumor lysis syndrome was seen after the initial dose in 1 pt with bulky MCL (elevations in phosphate and potassium only) and 1 pt with DLBCL (elevations in phosphate and uric acid only). After a single dose with food, ABT-199 had Tmax and T1/2 of approximately 8 and 15 hours, respectively. Food increased ABT-199 bioavailability by 3-4 fold. Preliminary efficacy data are summarized in the table. Conclusions ABT-199 showed anti-tumor activity as monotherapy for several NHL subtypes, with an overall response rate of 53% in this R/R population. Anti-tumor activity was seen in all MCL and WM pts treated across the range of ABT-199 cohort doses, and responses in DLBCL and FL pts were observed at doses ≥600 mg. Dose escalation is continuing to determine the MTD and RP2D. Biomarker studies are also underway in various NHL subtypes to explore a potential correlation with response. Disclosures: Seymour: Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Gerecitano:AbbVie: Research Funding; Genentech: Research Funding. Kahl:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding. Wierda:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau. Anderson:Genentech: Research Funding; AbbVie, Inc.: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, which recieves commercial income related to ABT-199, Employee, which recieves commercial income related to ABT-199 Other. Rudersdorf:AbbVie, Inc.: Employment, Stock Other. Gressick:AbbVie, Inc: Employment, Stock Other. Montalvo:AbbVie, Inc.: Employment, Stock Other. Yang:AbbVie, Inc.: Employment, Stock Other. Busman:AbbVie, Inc.: Employment, Stock Other. Dunbar:AbbVie, Inc.: Employment, Stock Other. Cerri:AbbVie, Inc.: Employment, Stock Other. Enschede:AbbVie, Inc.: Employment, Stock Other. Humerickhouse:AbbVie, Inc.: Employment, Stock Other. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment.

Abstract: Background: The oral selective BCL-2 inhibitor, venetoclax, is FDA-approved for the treatment of Chronic Lymphocytic Leukemia (CLL) patients with 17p deletion [del(17p)] who have received at least one prior therapy.Multiple clinical trials investigating its activity in patients with relapsed or refractory CLL are ongoing, and longer term follow-up is now available since the original publications of the initial Phase 1 and 2 trials. In order to define the response rate and durability of response across a broader population than studied in any individual trial, we performed a pooled analysis of current data available from four ongoing studies. Methods: Data were analyzed from the following venetoclax trials - NCT01328626 (M12-175 study): phase 1, venetoclax monotherapy in patients with relapsed or refractory CLL (n=116, data as of 04APR2016,); NCT02141282 (M14-032 study): phase 2, venetoclax monotherapy for CLL patients who have progressed on ibrutinib or idelalisib (n=64, data as of 28JUN2016, and excludes safety expansion patients whose long term data are not available); NCT01889186 (M13-982 study): phase 2, venetoclax monotherapy in relapsed or refractory CLL patients with del(17p) (n=158, data as of 29MAR2016); NCT01682616 (M13-365 study): phase 1b, venetoclax plus rituximab in relapsed or refractory CLL (n=49; data as of 04MAR2016). Bone marrow minimal residual disease (MRD) status was determined using data from the M13-982 and M13-365 studies (n=207). MRD data for the M14-032 study is not yet available and MRD assessment was not systematically performed for the M12-175 study. Del(17p) status was assessed using fluorescence in situ hybridization and TP53 mutation status was determined by next generation sequencing. Descriptive statistics (median, range, proportion) were calculated for demographics, baseline characteristics, and overall response. All post-baseline data were included to determine the overall response and did not account for differences in the follow-up times between studies. Kaplan-Meier methodology was used to calculate 24-month estimates and associated 95% confidence interval (CI) for duration of response (DOR) and progression free survival (PFS). Results: A total of 387 patients were included in this analysis [median age: 66 years (range: 29 - 88)]. Bulky nodes (≥5 cm) were present in 194/386 (50%) patients and del(17p) was confirmed in 211/356 (59%) patients with available data; 207/387 (53%) patients had ≥3 prior therapies. Venetoclax doses ranged from 150 mg/day to 1200 mg/day; 299/387 (77%) patients received the recommended phase 2 dose (RPTD) of 400 mg/day. Across all four studies, the median duration on venetoclax was 15.3 (range: 0 - 51.8) months and the median time on study was 16.6 months (range: 0 - 51.8). 54% of the patients continue on venetoclax; 46% have discontinued due to: progressive disease (30%), adverse events (9%), stem cell transplant (3%), withdrew consent (3%), investigator request, lost to follow-up, non-compliance (n=1, 0.25% each). The overall response rate (ORR) in all patients was 77% (Table 1). The CR/CRi (complete remission/complete remission with incomplete marrow recovery) rate was 22% and the number increased over time on venetoclax [median time to CR/CRi = 8.3 (range: 2.6 - 28.6) months] ; MRD-negativity in the marrow was achieved by 21% (44/207) of patients, including 12% (19/157) of those with del(17p). The impact of clinical response, marrow MRD negativity, and del(17p) or TP53 status on DOR and PFS is summarized in Table 2. For all four studies combined, the median DOR was 29.2 months (95% CI=25.1, 40.1) and the median PFS was 27.9 months (95% CI=24.9, 30.5). The 24-month estimate for DOR in all patients was 64.3% (95% CI=55.5, 71.8) and that for PFS was 56.9% (95% CI=50.3, 63). Patients who achieved marrow MRD negativity had the highest 24-month DOR estimate of 96.6% (95% CI= 77.9, 99.5), followed by those with CR+CRi [89.8% (95% CI=73.5, 96.3)] and those without del(17p) or TP53 mutation [74.6 (95% CI=62.3, 83.4)] . Similar trends were seen for the 24-month PFS estimates. Conclusions: Pooled data from the four studies show that venetoclax induces deep (22% CR/CRi and 21% marrow MRD negativity rates) and durable responses in patients with relapsed/refractory CLL. DOR and PFS were the most favorable in patients who achieved marrow MRD negativity and CR/CRi and those without del(17p) or TP53 mutation. Disclosures Roberts: Servier: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding. Seymour:Takeda: Honoraria, 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, Research Funding, Speakers Bureau; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Eichhorst:Abbvie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding. Davids:Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Honoraria, Research Funding; Infinity: Honoraria, Research Funding. Gerecitano:AbbVie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Samus: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Popovic:AbbVie Inc.: Employment, Other: may own stock. Chyla:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Verdugo:AbbVie: Employment, Other: may own stock. Potluri:AbbVie Inc.: Employment, Other: may own stock. Lash:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie Inc.: Employment, Other: may own stock. Hallek:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Abstract: 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.

Abstract: 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.

Abstract: 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 & lt;0.0001; median not reached vs 17.0 mo. (Fig 1). 24-mo. PFS estimates were 84.9% vs 36.3%, respectively. Consistent treatment effects on PFS were observed in all subgroups assessed (Fig 2). With HR 0.19, 95% CI 0.13-0.28, P & lt;0.0001, Independent Review Committee-assessed PFS showed a similar magnitude of benefit. Key secondary efficacy endpoints showed consistent improvements for VR vs BR including a notable improvement in OS (HR 0.48, 95% CI 0.25-0.90). INV-assessed ORR was 93.3% with VR vs 67.7% with BR (Δ=25.6%, 95% CI 17.9-33.3%); CR/CRi was achieved in 26.8% vs 8.2% of pts, respectively (Table 1). Higher peripheral blood MRD- rates attained at any time were seen with VR vs BR (83.5% vs 23.1%; Δ=60.4%, 95% CI 52.3-68.6%) by ITT analysis. MRD negativity was more durable in the VR arm. 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.