Phase 1/2 Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of Venetoclax in Japanese Subjects with Chronic Lymphocytic Leukemia

Background: Venetoclax (VEN) is an orally bioavailable, small molecule inhibitor of BCL-2, an important anti-apoptosis regulator that is commonly overexpressed in chronic lymphocytic leukemia (CLL). In previous studies, VEN demonstrated acceptable safety and antitumoral activity in the treatment of hematologic malignancies.

Methods: This arm of an open-label, multicenter, phase 1/2 study (NCT02265731) was designed to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of VEN in Japanese patients with relapsed or refractory (R/R) CLL or small lymphocytic leukemia (SLL). Main inclusion criteria were age ≥20 years, Eastern Cooperative Oncology Group performance score ≤1, and CLL or SLL that was R/R to standard treatment (eg, fludarabine- or alkylator-based regimen). Patients could not have undergone allogeneic or autologous stem cell transplantation. VEN monotherapy was started at a dosage of 20 mg/day given orally on Week 1 Day 1. If a patient developed electrolyte changes suggestive of tumor lysis syndrome (TLS), VEN was withheld until the changes resolved. Otherwise, the dosage of VEN was increased, as tolerated, to 50 mg/day in Week 2, to 100 mg/day in Week 3, to 200 mg/day in Week 4, and to 400 mg/day in Week 5 and afterward. Adverse events (AEs) and laboratory values were monitored for safety. Dose-limiting toxicities (DLTs) were determined during the step-up period (if applicable) until the completion of Week 7. Efficacy was measured as the overall response rate, complete remission (CR), and partial remission (PR).

Results: Six patients were enrolled: 4 with CLL and 2 with SLL. Their median age was 72 years (range, 38-73 years), and 4 (67%) were male. As of July 7, 2017, all 6 patients achieved objective responses, which included 1 CR (in a patient with 17p deletion CLL) and 5 PRs. No DLTs were reported, and no cases of laboratory or clinical TLS occurred during dosing ramp-up. Based on the preliminary analysis, average VEN exposure at the 400-mg dose was 20-30% higher in Japanese patients with CLL than in Western patients with CLL, but individual PK exposures were within the range of values previously reported in non-Japanese patients with CLL (Table). AEs of any grade possibly related to VEN (occurring in ≥2 patients) were neutropenia (n=6), lymphopenia (n=5), thrombocytopenia (n=2), and vomiting (n=2). AEs of grade ≥3 possibly related to study drug were neutropenia (n=5), lymphopenia (n=3 patients), myelodysplastic syndrome (n=1, serious AE), and disseminated Herpes zoster infection (n=1, serious AE). Other serious AEs, thought to be unrelated to study drug, were febrile neutropenia, pneumonia, septic shock, and large intestinal ulcer (all n=1). The large intestinal ulcer led to the only interruption of VEN. No deaths have occurred.

Conclusions: In Japanese patients with R/R CLL or SLL, VEN as monotherapy demonstrated a tolerable safety profile and produced an objective response in all 6 patients. The VEN PK exposure range was similar to that previously observed in non-Japanese patients.

Table

View largeDownload slide

Table

View largeDownload slide

Close modal