Abstract: Background: Umbralisib is an oral, once-daily, novel, dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. U2 has been well-tolerated and demonstrated promising activity in heavily pre-treated CLL patients. Herein, results are presented for the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311), which evaluated U2 vs O+Chl in patients with TN and R/R CLL. Methods: Patients ≥18 years of age with treatment-naïve (TN) or relapsed/refractory (R/R) CLL requiring treatment per iwCLL criteria with adequate organ function and ECOG PS ≤2 were eligible. Stratification factors included treatment status (TN vs R/R) and del(17p) status. Patients were initially randomized 1:1:1:1 to receive U2, O+Chl, umbralisib monotherapy, or ublituximab monotherapy. Following establishment of contribution comparing U2 to the single agents, patients were randomized 1:1 to U2 or O+Chl. Umbralisib was given orally at 800 mg once-daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. O was given intravenously at 1000 mg on Days 1/2 [split 100/900] , 8, and 15 of Cycle 1, and Day 1 of Cycles 2 - 6. Chl was given orally at 0.5 mg/kg on Day 1 and 15 of Cycles 1 - 6. Each cycle was 28 days. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) of U2 vs O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response (CR), undetectable minimal residual disease (uMRD), duration of response (DOR), and safety (assessed from the first dose until 30 days after the last dose of study medication in each arm) as well as contribution of umbralisib and ublituximab to the U2 combination. Results: From Feb 2016 - Oct 2017, 421 pts were randomized to the U2 (n=210) or O+Chl (n=211) arms. The median age was 67 y (range, 36-91); 57% of patients (n=240) were treatment-naïve; 43% (n=181) had R/R CLL (median number of prior treatments = 1); 10% had del(17p), 20% del(11q), and 56% were IgHV unmutated. 66% were male. Demographics were well-balanced between treatment arms. At a median follow-up of 36.2 mos, U2 significantly prolonged PFS vs O+Chl (median 31.9 mos vs 17.9 mos; HR 0.546, 95% CI 0.413-0.720, P & lt;0.0001; Figure 1). Estimated 24-mo PFS rates with U2 and O+Chl were 60.8% and 40.4%, respectively. PFS improvement with U2 vs O+Chl was consistent across all subgroups examined including treatment naïve patients (median 38.5 mos vs 26.1 mos; HR [95% CI]; 0.482 [0.316-0.736] ); and relapsed/refractory patients (median 19.5 mos vs 12.9 mos; HR [95% CI]; 0.601 [0.415-0.869] ). IRC-assessed ORR was higher with U2 (83.3%; 95% CI, 78.1%-88.6%) vs O+Chl (68.7%; 95% CI, 62.2%-75.2%; P & lt;0.001). Among previously treated subjects, twenty-six (6%) received prior ibrutinib (14 on U2, 12 on O+Chl), with an ORR of 57% observed for U2 compared to 25% for O+Chl in this population. MRD data is currently being analyzed. The median treatment duration was 23 mos for U2 (range, 0.1 - 49 mos) and 5 mos (range, 0.1 - 7 mos) for O+Chl. G3/4 AEs of interest regardless of causality (U2 vs O+Chl) included neutropenia (30.6% vs 34.7%), thrombocytopenia (3.4% vs 13.1%), diarrhea (12.1% vs 2.5%), infusion related reaction (1.9% vs 3.5%), elevated AST/ALTs (8.3% vs 2%), colitis (3.4% vs 0%) and pneumonitis (2.9% vs 0%). AEs led to treatment discontinuation in 34 patients (16.5%) on U2 and 16 patients (7.6%) on O+Chl. Conclusions: UNITY-CLL is the first randomized Phase 3 study in CLL of a PI3Ki vs. chemoimmunotherapy, and the first randomized study of a PI3Ki in treatment-naive CLL. U2 exhibited a well-tolerated safety profile, and significantly improved PFS vs. standard of care chemoimmunotherapy in patients with treatment-naive and relapsed/refractory CLL. Figure Disclosures Gribben: Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Honoraria. Jurczak:Celgene: Research Funding; Afimed: Research Funding; Sandoz-Novartis: Consultancy; European Medicines Agency,: Consultancy; AstraZeneca: Consultancy; Takeda: Research Funding; Janssen China R & D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Research Funding; Acerta: Consultancy, Research Funding; Pharmacyclics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; MEI Pharma: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding; Epizyme: Consultancy; Roche: Research Funding; MorphoSys: Research Funding; TG Therapeutics, Inc.: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months. Jacobs:Sanofi Genzyme: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Verastem: Consultancy; Seattle Genetics: Consultancy; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding. Giannopoulos:BMS-Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Florida Cancer Specialists and Research Institute: Current Employment; Sarah Canon Research Institute: Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Danilov:Nurix: Consultancy; Celgene: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Gilead Sciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy; BeiGene: Consultancy; Takeda Oncology: Research Funding; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Rigel Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Research Funding; Bayer Oncology: Consultancy, Research Funding. Burke:Gilead: Consultancy; Epizyme: Consultancy; Adaptive: Consultancy; Kura: Consultancy; Astra Zeneca: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; Roche: Consultancy; Seattle Genetics: Speakers Bureau; Celgene: Consultancy. Goldschmidt:Bristol-Myers Squibb: Speakers Bureau; Amgen: Consultancy; Blue Ridge Cancer Care: Current Employment. Huntington:Genentech: Consultancy; Astrazeneca: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; DTRM: Research Funding. Pinilla Ibarz:AstraZeneca: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; Sunesis Pharmaceuticals: Consultancy; TG Therapeutics: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding. Siddiqi:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Brander:MEI Pharma: Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; NCCN: Other; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding. Kolibaba:TG Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other; Verastem: Honoraria; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; McKesson Life Sciences: Consultancy; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cell Therapeutics: Research Funding; Compass Oncology: Ended employment in the past 24 months. Ghosh:Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol-Myers Squibb: Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding. Sportelli:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor:Astex Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nomocan: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Mundipharma: Other: Consulting; Servier: Consultancy. Weiss:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Flinn:Iksuda Therapeutics: Consultancy; Curis: Research Funding; Infinity Pharmaceuticals: Research Funding; F. Hoffmann-La Roche: Research Funding; Vincera Pharma: Consultancy; Karyopharm Therapeutics: Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; ArQule: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; BeiGene: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding; Great Point Partners: Consultancy; IGM Biosciences: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Johnson & Johnson: Other; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Curio Science: Consultancy; Nurix Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Calithera Biosciences: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Agios: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Abstract: Introduction: Venetoclax is a potent BCL-2 inhibitor that is approved as monotherapy and in combination with rituximab for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) in the United States, and as a monotherapy for patients with 17p deletion or TP53 mutation in the European Union and other countries. Here we report the long-term efficacy and safety of the combination of venetoclax and rituximab from this phase 1b study with a median follow up of 〉 4 years, two years beyond when initially published. Methods: Patients received daily venetoclax (200 - 600mg) and 6 - 9 doses of rituximab over 6 months, then venetoclax monotherapy.(NCT01682616; Seymour, et al. Lancet Oncol. 2017; 18(2):230-240.) Minimal residual disease (MRD) was assessed in bone marrow (BM) using ≥4-color flow cytometry (min sensitivity: 0.01%). As amended in specific protocol versions, patients who achieved complete remission (CR) or BM MRD-negativity regardless of CR status (collectively considered as deep responses) could stop venetoclax and remain on study, retreating with venetoclax +/- rituximab at clinical disease progression (iwCLL criteria). Results: Forty-nine patients, with a median 2 (range: 1 - 5) prior therapies, were enrolled. As of June 4, 2018 (N=49), the median time on study was 4.1 years (range: 0 - 5.8) and the median time on venetoclax was 2.5 years (range: 0 - 5.8). The overall response rate (N=49) was 86%, CR rate was 51%, and BM MRD-negativity rate was 61%. The 48-month estimates (N=49) for overall survival was 89% (95% CI: 75%, 95%), progression free survival was 61% (95% CI: 45%, 74%), and duration of response was 64% (95% CI: 46%, 77%) (for patients with BM MRD-negativity, 88% [95% CI: 66%, 96%]). The adverse events of any grade occurring in 〉 15% of patients beyond 2 years of treatment were upper respiratory infection, neutropenia, and diarrhea (Table). Disease progression occurred in 17 patients, 14 while on continuous therapy: 5 with Richter transformation at a median of 5 months (range 1 - 8), 9 with CLL progression at a median of 29 months (range: 12 - 55). Three patients (2 MRD-positive CR and 1 MRD-negative CR with CLL cells detectable below the threshold of 10-4) progressed after stopping venetoclax (asymptomatic progression at 23, 24 and 38 months off venetoclax). All three have been re-treated with venetoclax plus rituximab, resulting in CR in one patient (duration of ongoing subsequent CR, 17 months), one partial response (PR) followed by progressive disease 18 months later, and results are pending for the third patient. Fifteen additional patients stopped venetoclax per protocol following the achievement of a deep response (median duration [range] of treatment 19 months (range: 8 - 40);13 MRD-negative CR, 2 MRD-negative PR) (Figure). Four have discontinued the study (withdrew consent [n=4] ) and 11 remain on study in long term follow up with a median duration of ongoing response of 49 months (range: 32 - 59), and a median of 33 months (range: 12 - 58) off venetoclax to date. Twelve patients who have received continuous venetoclax and remain on study, remain free of disease progression: 8 in CR (7 MRD-negative, 1 MRD-positive) and 4 in MRD-negative PR. Median duration of response on therapy is 51 months (range: 44 - 66). The 4 patients with PR do not meet CR criteria because of lack of BM biopsy results (n=2) and residual adenopathy (n=2; max node dimension; 17 and 23 mm). The other 5 patients have discontinued because of withdrawal of consent (n=2; 1 without response, 1 MRD-positive PR) and adverse events (n=3; tumor lysis syndrome, worsening peripheral neuropathy, both without response, and fatal ischemic heart disease considered unrelated to therapy in MRD-negative CR [n=1]). Conclusions: Venetoclax with rituximab induces deep and durable responses in patients with previously treated CLL, with 51% achieving CR and 61% achieving BM MRD-negativity. Those with a deep response can discontinue venetoclax and maintain prolonged treatment-free remission of more than three years, especially if MRD-negative. Disclosures Brander: Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Seymour:Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding. Ma:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Acerta: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Choi:Genentech: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Kipps:Genentech Inc: Consultancy, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Nandam:AbbVie, Inc: Employment, Equity Ownership. Kim:Abbvie: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Roberts:AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax.

Abstract: Abstract 1626 Background: Diffuse Large B-cell Lymphoma (DLBCL) patients with primary refractory or multiply relapsed disease have limited treatment options. Therefore it is imperative that novel drugs be tested to find new, effective approaches for these patients. With evidence demonstrating that increased vascularity and pro-angiogenic factors correlate with adverse prognosis in the hematologic malignancies, angiogenesis has emerged as a novel therapeutic target. PTK787/ZK222584 is an orally active amino-phthalazin that inhibits all known tyrosine kinase receptors of vascular endothelial growth factor (VEGF). The efficacy, safety and tolerability of PTK787/ZK222584 in patients with rel/ref DLBCL was evaluated in this non-randomized phase II study. Patients and Methods: Patients with relapsed or refractory DLBCL were eligible. Additional key inclusion criteria were negative proteinuria, and normal renal and liver function. Central nervous system disease, prior allogeneic transplant, recent chemotherapy, or previous anti-VEGF therapy excluded subjects from enrollment. All patients inititated PTK787/ZK222584 at a dose of 750mg by mouth (PO) daily on day 1 of a 28 day cycle. Drug dose was increased weekly, initially to a dose of 1000mg PO daily and then to a target dose of 1250mg daily unless a grade ≥2 toxicity (using NCI CTC V3.0) developed. Primary endpoint was response (complete response (CR) + partial response (PR)); secondary endpoints included safety and tolerability. Results: Twenty patients (11 female) with a median age of 60 years were enrolled. Sixty three percent of patients had received 〉 3 prior therapies and 26% had prior autologous stem cell transplantation. Patients received a median of 3 cycles of PTK787/ZK222584 (range 0–6). Ten patients were on study drug for at least 3 cycles and are evaluable for response: one patient had a CR, four patients had stable disease (SD), and the remaining 5 patients had progressive disease. The patient with a CR subsequently underwent autologous stem cell transplantation and was alive without evidence of disease 64 months after study completion. One patient with SD withdrew to pursue other treatment options and the other 3 continued study drug, but all developed progressive disease within the next 3 months. Of the 10 patients who withdrew prior to completing 3 cycles, six withdrew after a median of 1 cycle because of rapidly progressive disease. Three withdrew because of adverse events of sepsis resulting in death in one patient, altered mental status despite dose reductions in one, and recurrent grade 3 transaminitis in the third. One patient withdrew to pursue other treatment options. Eighteen of the 20 patients enrolled escalated to the full target dose of 1250mg, but 6 required at least 1 dose reduction due to adverse events (sepsis, vertigo, transaminitis, rash or fatigue). There were no episodes of grade 3 / 4 proteinuria but grade 3 / 4 hypertension occurred in 10% and grade 3 / 4 thrombocytopenia in 20%, with the remainder of grade 3 / 4 toxicities occurring in 〈 10%. The most common toxicities occurring in greater than 15% of patients across all grades included nausea (75%), fatigue (65%), anorexia (45%), anemia (35%), vomiting (35%), thrombocytopenia (25%), HTN (25%), diarrhea (25%), proteinuria (25%), fever (20%), constipation (20%), and dizziness (20%). Conclusion: PTK787/ZK222584 is an orally active VEGF inhibitor which was generally well tolerated in a heavily pretreated population of patients with DLBCL. Although 1 patient achieved a CR and remains disease free after autologous stem cell transplant, the remaining patients developed progressive disease or had adverse events suggesting that this agent is unlikely to be useful as a single agent in aggressive lymphoma. The excellent response in one patient, however, raises the possibility that drug response may occur in a subset of patients so the identification of tumor specific biomarkers to predict responding patients is needed. Disclosures: Rizzieri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy. Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200-600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous. Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%). Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200-600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50-88) years. The median (range) number of prior regimens was 2 (1-5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease. Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV. As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR). The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR. 4 had SD, 2 had PD, and 1 died before assessment (fatal TLS). 9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2-9) months. BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall. Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months. The median PFS has not been reached. At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03-32) months. 94% were alive at 12 months; the median OS has not been reached. Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups. 8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time. 2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4-24) months off VEN. The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate. Treatment-emergent AEs in 〉 25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in 〉 10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD. Key efficacy data are summarized in the table. Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile. 41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity. Remission off all therapy has been maintained in pts achieving MRD-negative CR. The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%. The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL. VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471). Table 1. Table 1. Disclosures Ma: Genentech, Pharmacyclics/Janssen and Gilead: Speakers Bureau; Genentech, Pharmacyclics/Janssen and Gilead: Consultancy; NCCN, AbbVie, Pharmacyclics, Novartis, Gilead, Celgene, and Xeme: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Seymour:Phebra: Consultancy, 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: 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; 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Barrientos:Gilead, Pharmacyclics, and AbbVie: Research Funding; Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Choi:AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Tam:Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Mason-Bright:AbbVie: Employment, Equity Ownership. Prine:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.

Abstract: Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor which exhibits a differentiated safety profile from other PI3Kδ inhibitors, both approved and in development, and has demonstrated activity in patients (pts) with advanced heme malignancies (ASH 2014). Herein we present updated safety and efficacy results from a Ph I study of TGR-1202 in pts with rel/ref CLL and lymphoma. Methods: TGR-1202 is administered orally once-daily (QD) following a 3+3 dose escalation design. Eligible pts have rel/ref non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other B-cell malignancy and an ECOG PS ≤ 2. Endpoints include safety, PK/PD, and efficacy. Results: As of August 2015, 75 pts are evaluable for safety including pts with CLL, FL, Hodgkin's (HL), DLBCL, MCL, and MZL. Patients had a median age of 65 yo (range: 22-85), 67% male, ECOG 0/1/2: 26/47/2, median prior Tx: 3 (range: 1-14), and 49% refractory to prior Tx. No Gr≥3 AEs were observed in ≥10% of pts. AEs (all grades, all causality) in 〉 20% of pts were limited to nausea (44%, Gr3/4 0%), diarrhea (36%, Gr3/4 1%), and fatigue (31%, Gr3/4 3%). Notably, general tolerability and the incidence of hepatotoxicity and colitis appear significantly less than that reported with other agents in this class. Expansion cohorts are open at 800 mg, 1000 mg, and 1200 mg QD. Of 16 evaluable CLL pts, 15 (94%) achieved a nodal PR (median nodal ↓ of 76%), of which 10 (63%) achieved a PR per Hallek 2008 criteria. Among the 32 evaluable NHL patients, 10 achieved an objective response, including 3/11 evaluable patients with DLBCL, while responses have been limited in pts with MCL (1/5) and HL (1/9). Of the 16 evaluable indolent NHL (FL & MZL) pts, 14 (88%) have achieved reductions in tumor burden with 6 pts on study for over 12 cycles (and durations upwards of 29+ cycles), with 5/12 FL and 1/4 MZL pts achieving an objective response to date. Notably, a strong exposure-response relationship has been observed. Of the 24 patients starting TGR-1202 at 800 mg or 1200 mg of the micronized formulation, 19 (79%) remain on therapy, with 9/18 (50%) evaluable pts (6 too early to evaluate) achieving an objective response to date (range on study 3 - 49+ weeks). Conclusions: TGR-1202 is well tolerated in pts with rel/ref heme malignancies with a distinct safety and tolerability profile from other PI3K-delta inhibitors (with 43% of pts on study 6+ Cyc) and promising activity in CLL and NHL. Enrollment continues in expansion cohorts and registration directed Phase 3 studies are planned. Disclosures Flinn: Celgene Corporation: Research Funding. Fenske:Millennium/Takeda: Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria; Pharmacyclics: Honoraria. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Kuhn:TG Therapeutics, Inc.: Consultancy; Otsuka American Pharmaceutical: Consultancy; Azaya Therapeutics: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership.

Abstract: We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry ( & lt;10−4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all & gt;2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

Abstract: Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82] ; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43] ; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%] ), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%] ). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

Abstract: Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.

Abstract: Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. The primary analysis of the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311) demonstrated that the umbralisib+ublituximab (U2) combination prolonged progression-free survival (PFS) compared to chemoimmunotherapy in both treatment-naïve (TN) and previously treated (PT) populations (Gribben et al. 2020). Herein, results are presented for patients treated with U2 by treatment status. Methods: Patients ≥18 years of age with TN or PT CLL requiring treatment, per iwCLL criteria with adequate organ function and ECOG PS ≤2, were eligible. Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Stratification factors included treatment status (treatment-naïve vs. previously treated) and deletion 17p status. Umbralisib was administered orally at 800 mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. The primary endpoint was independent review committee (IRC)-assessed PFS of U2 compared to O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response, undetectable minimal residual disease (uMRD), duration of response, and safety, assessed from the first dose until 30 days after the last dose of study medication. While the primary analysis reported results for the pooled intent-to-treat population, the current analysis focuses on outcomes in patients treated with U2 by treatment status. Results: At data cut-off date of May 1, 2020, U2-treated patients had a median follow-up of 35.27 months. Of the 210 patients treated with U2, 119 were TN and 91 were PT. TN patients had a median age of 68 years (39 - 88 years) and 63% were male. Median PFS for U2 in TN patients was 38.5 mos (95% CI, 33.2, NE) with an estimated 24-mo PFS rate of 76.6%. IRC-assessed ORR was 84.0% (95% CI, 77.5%-90.6%). The median duration of exposure to umbralisib and ublituximab was 26.5 and 29.5 mos, respectively. In TN patients, AEs of special interest (AESI) of grade ≥3 included: neutropenia (24.1%), diarrhea (13.8%), ALT increased (12.1%), AST increased (7.8%), non-infectious colitis (2.6%), infusion-related reaction (IRR, 0.9%), and pneumonitis (0.9%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 5.2% (neutropenia), 2.6% (diarrhea), 3.4% (ALT increase), 1.7% (AST increase), 1.7% (colitis), 0.9% (IRR), and 0.9% (pneumonitis) of patients. PT patients had a median of 2 prior (1 - 9) lines of therapy, the median age was 65 years (43 - 87 years) and 65.9% were male. Median PFS was 19.5 mos (95% CI, 14.6-27.7) with an estimated 24-mo PFS rate of 41.3%. The IRC-assessed ORR was 82.4% (95% CI, 74.6%-90.2%). Among 14 patients previously treated with ibrutinib, the ORR was 57%. The median duration of exposure to umbralisib and ublituximab were 15.6 mos and 14.6 mos, respectively. In PT patients, AESI of grade ≥3 included: neutropenia (40.0%), diarrhea (10.0%), IRR (3.3%), ALT increase (3.3%), AST increase (2.2%), and non-infectious colitis (2.2%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 1.1% (ALT increase), 1.1% (AST increase), and 1.1% (colitis) of patients. Conclusions: U2 demonstrated a tolerable safety profile in both the TN and PT populations. These results mark the first randomized Phase 3 trial of a PI3K in TN CLL, establishing a new mechanism of action in this setting. Disclosures Jacobs: Genentech: Consultancy; Jannsen: Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Verastem: Consultancy; AbbVie: Consultancy, Speakers Bureau; SecuraBio: Consultancy, Speakers Bureau; TeneoBio: Research Funding; MEI Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Flinn: ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Giannopoulos: Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Wróbel: Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria. Cultrera: Beigene: Research Funding. Danilov: Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Rigel Pharm: Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Burke: Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; Epizyme: Consultancy; AbbVie: Consultancy; MorphoSys: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Roche/Genentech: Consultancy; AstraZeneca: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Beach: TG Therapeutics: Speakers Bureau. Huntington: TG Therapeutics: Research Funding; DTRM Biopharm: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy, Honoraria; Flatiron Health Inc.: Consultancy; Bayer: Honoraria; Servier: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Thyme Inc: Consultancy; SeaGen: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sharman: TG Therapeutics: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Lilly: Consultancy; AbbVie: Consultancy. Siddiqi: AstraZeneca: 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; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; DTRM: Research Funding; Ascentage: Research Funding; Genentech: Consultancy, Research Funding; Novartis: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; MEI Pharma: Research Funding; LOXO: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; BeiGene: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Pagel: AstraZeneca: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Dlugosz-Danecka: Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; AbbVie: Research Funding; Macrogenics: Research Funding; Beigene: Research Funding; MEI Pharma: Research Funding; Incyte Corp.: Research Funding; Takeda: Research Funding. Ghosh: Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Weiss: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Gribben: Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Gilead/Kite: Honoraria; BMS: Honoraria; Abbvie: Honoraria; AZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria.

Abstract: Background: Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor FDA-approved for patients with del(17p) chronic lymphocytic leukemia (CLL) and who have received ≥1 prior therapy. Based on preclinical evidence of synergy, VEN plus rituximab is being assessed in an ongoing Phase 1b study. Methods: Patients with relapsed/refractory (R/R) CLL received daily VEN with stepwise ramp-up over 3-4 weeks to reach daily doses of 200-600mg. After 1 week at the target dose, monthly rituximab was added for 6 doses. Responses and progression were assessed by iwCLL criteria with CT scan and bone marrow biopsy. Bone marrow assessments were done at screening, completion of combination therapy (month 7), and 2 months after clinical/radiologic criteria of iwCLL response were met. Minimal residual disease (MRD) was assessed in peripheral blood and marrow aspirates using ≥4 color flow cytometry (min sensitivity: 0.01%). Data cutoff was 04March2016, with analysis focusing on updated safety of cytopenias experienced on the course of treatment. Results: Forty-ninepatients enrolled (48 CLL/1 SLL). Patients had received a median of 2 prior therapies (range: 1-5) and disease in 25 (51%) was considered refractory to the most recent therapy. Median time on study was 28 ( 〈 1-42) months, with 31 patients active on study. Eighteen patients discontinued: 11 due to disease progression, 3 due to toxicity (peripheral neuropathy [1], MDS [1] , and death due to TLS [1]), 3 withdrew consent, and 1 was lost to follow up. Across all doses, the most common AEs of any grade were diarrhea (57%), neutropenia (55%), upper respiratory tract infection (55%), and nausea (51%). Peripheral blood cytopenias were the most common Grade 3/4 AEs (neutropenia [53%] , thrombocytopenia [16%], anemia [14%] , febrile neutropenia [12%], and leukopenia [12%] ). Twenty-seven (55%) patients had a history of neutropenia, of whom 6 were receiving G-CSF support prior to starting VEN. Overall, in the first month of therapy, 15 (31%) experienced an AE of neutropenia (any grade). Thereafter, the rate of new AEs of neutropenia decreased over time. While there was individual patient variability, mean ANC was stable over time. Overall, 26 (53%) patients had Grade 3/4 neutropenia. Neutropenia was generally well tolerated and managed by G-CSF support in 24 patients, in addition to ≥1 dose modification in 11 of the 24 patients. Of 8 (16%) patients who experienced grade 3 infections, 2 were while neutropenic. There were no grade 4 infections. Among the 11 (22%) patients who developed any-grade thrombocytopenia, none occurred within 2 weeks of a reported bleeding-related AE. One patient had thrombocytopenia overlapping with disease progression on therapy. Objective response rate for all patients was 86% (n=42), with 51% (n=25) who had complete response (CR/CRi; 12 achieved CR/CRi by month 7). At the completion of combination therapy (month 7), 39 patients had evaluable bone marrow assessments. Thirty (77%) had no histologic evidence of CLL in the bone marrow and 22 patients (56%) had attained bone marrow MRD-negativity. In longer follow up at any point during treatment for all 49 patients, 37 (75%) patients achieved complete marrow clearance and 28 (57%) achieved marrow MRD-negativity. Conclusions: Transient manageable neutropenia was the most common AE, with first onset usually seen within the first month of treatment and the onset of new neutropenia AEs decreased over time. No patients discontinued the study due to cytopenias. Patients were able to continue on study and high rates of response to treatment were observed. VEN given with rituximab achieved rapid and profound reductions in disease burden in peripheral blood and bone marrow. 77% of evaluable patients achieved morphologic clearance by month 7, and 57% were MRD-negative at any point on study. Figure 1 Figure 1. Disclosures Brander: TG Therapeutics: Research Funding; Gilead: Honoraria. Roberts:AbbVie: Research Funding; Servier: Research Funding; Janssen: 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. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Lash:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Gilead: 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; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.