CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/day]; oral venetoclax [5-week ramp-up to 400 mg/day]). Primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. 159 patients were enrolled and treated, including 136 patients without del(17p). Median time on study was 27.9 months and 92% of patients completed all planned treatment. Primary endpoint was met, with CR rate of 56% (95% CI, 48-64) in patients without del(17p), significantly higher than prespecified 37% minimum rate (P<.0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood) and 60% (bone marrow); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome risk; after ibrutinib lead-in, only 1% remained in this category. Most common grade ≥3 adverse events were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free, fixed-duration regimen for patients with CLL. Fixed-duration ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Background : Ibr is the only once-daily inhibitor of Bruton tyrosine kinase with significant overall survival benefit demonstrated in 2 randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). Both Ibr and Ven, an oral inhibitor of BCL2, are approved in the US for treatment of CLL/SLL. The combination of Ibr + Ven may have synergistic anti-tumor activity given the capacity of Ibr to mobilize CLL cells from protected niches within lymphoid tissue to the blood where they may have greater dependence on BCL2 for survival. Recent clinical studies of Ibr + Ven in patients (pts) with CLL or mantle cell lymphoma show high rates of remission with undetectable minimal residual disease (uMRD) (Jain, NEJM 2018; Hillmen, JCO 2019; Tam, NEJM 2018). CAPTIVATE (PCYC-1142) is a multi-center phase 2 study (NCT02910583) evaluating the combination of Ibr + Ven to achieve deep response, including uMRD, in first-line treatment of CLL/SLL. We present results from the MRD cohort with 12 cycles of Ibr + Ven prior to MRD-guided randomized treatment discontinuation (data not yet available). Methods : Pts aged <70 y with previously untreated CLL/SLL requiring therapy received single-agent Ibr lead-in (420 mg/day PO) for 3 cycles followed by Ibr + Ven (5-week ramp-up to 400 mg/day PO) for 12 cycles. The key endpoints prior to MRD-guided randomization included uMRD (<10-4 by 8-color flow cytometry), Ven-related tumor lysis syndrome (TLS) risk, pharmacokinetics, and adverse events (AEs). MRD status was evaluated in peripheral blood (PB) after 6, 9, and 12 cycles of Ibr + Ven combination, and in bone marrow (BM) after 12 cycles of Ibr + Ven. Results : We enrolled 164 pts (median age 58 y; del(17p) in 16%; del(17p) or TP53 mutation in 20%; del(11q) without del(17p) in 16%; complex karyotype in 19%; unmutated IGHV in 59%; lymph nodes ≥5 cm in 32%). In total, 151 pts (92%) completed Ibr lead-in and all 12 cycles of Ibr + Ven. uMRD was achieved at any time after baseline in 75% of pts (122/163) in PB and 72% (111/155) in BM (Figure). The proportion of pts who had uMRD in PB increased over time from 57% after 6 cycles of combined Ibr + Ven to 68% after 9 cycles and 73% after 12 cycles of Ibr + Ven. The high rates of BM uMRD were consistent across high-risk subgroups, including in pts with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (84%), complex karyotype (83%), and unmutated IGHV status (81%). In pts with uMRD in PB with matched BM samples, 93% had uMRD in both PB and BM. Response by iwCLL criteria was achieved in 97% of pts. With median follow-up of 14.7 mo (range, 0.5-19.9) only 3 pts (2%) had disease progression (1 Richter's transformation during single-agent Ibr lead-in; 1 after discontinuation of Ibr lead-in due to AE; and 1 during treatment with Ibr + Ven) and no pts died. At baseline, 24% of pts were high-risk for Ven-related TLS, which was reduced to 2% after 3 cycles of single-agent Ibr lead-in. One pt met laboratory TLS criteria. Laboratory TLS was reported as an AE in 3 other pts during the first 2 weeks of Ven ramp-up but none met Howard criteria. No pts developed clinical TLS. Mean plasma levels of Ven (area under the curve; AUC) (n=151) was higher when co-administered with ibrutinib compared with historical data for single-agent Ven but was within the AUC range observed in doses previously studied. No change in Ibr AUC (n=112) was observed with concurrent Ven. Median duration of treatment was 14.7 mo (range 0.5-19.9) with Ibr and 12.0 mo (range 0.8-12.7) with Ven. The most common AEs of any grade (in ≥20% of pts) were diarrhea (31%) and arthralgia (22%) during single-agent Ibr, and diarrhea (60%), neutropenia (40%), nausea (34%), upper respiratory tract infection (24%), and fatigue (20%) during Ibr + Ven. Overall, AEs leading to dose reductions occurred in 20% of pts (Ibr: 14%; Ven: 9%). AEs leading to discontinuation were infrequent, occurring in 7% of pts overall (Ibr: 5%; Ven: 4%). Conclusions : First-line treatment with Ibr + Ven represents an all oral, once-daily, chemotherapy-free regimen that provides high rates of uMRD in both PB and BM in pts with CLL. The safety profile of Ibr + Ven was consistent with AEs known for both agents. Results from the MRD-guided randomized treatment discontinuation cohort and Fixed duration cohort of CAPTIVATE await further follow-up, and are expected to provide the evidence to support a time-limited treatment option with a fixed-duration regimen of 12 cycles of Ibr + Ven in pts with CLL. Disclosures Tam: Novartis: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria. Siddiqi:Astra Zeneca: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Kite: Research Funding; TG Therapeutics: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding. Allan:Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Opat:Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Barr:Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy. Tedeschi:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobs:AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; AstraZeneca: Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; Genentech: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Badoux:AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. Ghia:ArQule: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Juno/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Sukbuntherng:Pharmacyclics LLC, an AbbVie Company (self),: Employment; Theras, Inc. (spouse): Employment; AbbVie: Equity Ownership; Global Blood Therapeutics: Equity Ownership; Portola: Equity Ownership. Salem:AbbVie: Employment, Other: Stock/stock options. Russell:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Ninomoto:Amgen: Equity Ownership; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment; Celgene: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; AbbVie: Equity Ownership. Wierda:Cyclcel: Research Funding; KITE pharma: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Ibrutinib in combination with venetoclax is not approved in any indication.

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