Conference Correspondent

Phase 1b Results of a Phase 1b/2 Study of Obinutuzumab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Conference Correspondent - Conference Correspondent, ASH 2016 - Chronic Lymphocytic Leukemia

Venetoclax (VEN), a once-daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (OBI), where minimal residual disease (MRD)-negative responses have been observed in the majority of patients.1  Ibrutinib (IBR), a once-daily oral inhibitor of the Bruton tyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. In vitro combination studies have suggested a potential synergy between VEN and IBR in CLL.2  Jones and colleagues report phase 1b results of a single-institution phase 1b/2 study of OBI, IBR, and VEN to characterize the safety and preliminary efficacy of the combination.

Patients with CLL relapsed after or refractory to ≥1 prior therapies and who required treatment were eligible. OBI 1000 mg IV, IBR 420 mg daily, and VEN were started sequentially over the first 3 of fourteen 28-day cycles. To establish the safety of VEN in combination with OBI and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose-limiting toxicity (DLT) was defined during the third cycle. Adverse events (AEs) were assessed and graded using CTCAE v4.03, and clinical responses were assessed according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2008 criteria. Twelve R/R patients have been treated in the phase 1b portion of the trial; 11 remain on treatment and 1 has completed all 14 cycles of therapy. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of OBI and IBR. The most common grade ≥3 AEs were neutropenia (58%), lymphopenia (42%), hypertension (25%), and fatigue (17%). Grade 1/2 AEs occurring in over half the patients included bruising (all grade 1, 100%), infusion-related reaction (75%), hypertension (67%), headache (58%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 75%), AST and/or ALT elevation (50%), and rash (50%). No cases of either clinical or laboratory tumor lysis syndrome were observed. Of the 10 patients who remain on therapy at the time of this report and are evaluable for a treatment response,  all 10 have achieved objective responses: 8 partial responses, including 2 who were MRD-negative in peripheral blood (PB) and 4 who were MRD-negative in both PB and marrow, and 2 CRs with 1 MRD-negative PB.

The authors conclude that OBI, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. AEs were manageable and largely consistent with those reported in the single-agent phase 2 studies. Objective responses, including MRD-negative responses in 7/10 PB and 4/10 in PB and marrow, have been observed among all R/R patients from the first-dose cohorts. 

Jones JA, et al. ASH 2016. Abstract 639.

  1. Itchaki G, Brown JR. Ther Adv Hematol. 2016;7:270-287.
  2. Woodland RT, et al. J Immunol. 1996;156:2143-2154.
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