Background: Ibr, a first-in-class, once-daily BTK inhibitor, is approved in the US and EU for CLL treatment, including del17p. Early studies support synergistic antitumor activity with combined ibr and ven, a BCL-2 inhibitor approved by FDA for relapsed del17p CLL. Single-agent ibr lead-in may lower tumor lysis syndrome (TLS) risk by debulking prior to adding ven. PCYC-1142 (CAPTIVATE) is a multicenter, phase 2 study of ibr + ven (I+V) in first-line CLL (NCT02910583) evaluating if remission with undetectable minimal residual disease (MRD(-)) after I+V can provide pts treatment holidays. Methods: Treatment-naïve pts <70 y with active CLL/SLL by IWCLL criteria receive single-agent ibr (420 mg/d PO) lead-in (3 x 28 d cycles) before initiating ven ramp-up to 400 mg/d PO. MRD (<0.01% by flow) is assessed in peripheral blood (PB) after 6 cycles I+V. MRD and response in bone marrow (BM) are assessed after 12 cycles I+V with planned randomization and intervention based on MRD status. Results: 163 pts were enrolled (median 58 y; 14% del17p; 15% del11q; 33% longest lymph node diameter [LDi] ≥5 cm). The first 14 pts enrolled for safety run-in completed ≥6 cycles I+V (median treatment duration, 9.9 mo ibr, 7.2 mo ven). No dose-limiting toxicities occurred during safety run-in; response was seen in 14/14 (CR confirmed in 1/5 early BM; 13/14 PR); PB was MRD(-) in 9/11 assessed pts. 97 pts (including 14 safety run-in pts) completed ibr lead-in plus ≥1 dose of ven (I+V Exposed). AEs in ≥20% of I+V Exposed pts were diarrhea (39%), fatigue (23%), nausea (23%) and arthralgia (21%); grade ≥3 AEs in ≥3% were neutropenia (10%), hypertension (3%) and thrombocytopenia (3%). No clinical TLS occurred; lab TLS was seen in 1/163 pts. In I+V Exposed pts with baseline LDi ≥5 cm, LDi decreased to <5 cm in 19/30 pts (63%) after ibr lead-in. TLS risk shifted from high to medium/low in 17/22 pts (77%); overall, proportion of high-risk TLS decreased from 23% at baseline to 3% after ibr lead-in. Conclusions: Early data show promising activity of I+V oral regimen with MRD(-) response in 82% in first-line CLL. Safety was consistent with AE profiles of single-agent ibr or ven. The protocol-specified efficacy analysis in the first 30 pts will be presented.
- Ibrutinib (ibr)
- Venetoclax (ven)
- Chronic Lymphocytic Leukemia (CLL)