PB1890 VENETOCLAX ALONE OR IN COMBINATION WITH RITUXIMAB FOR JAPANESE PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

Abstract

Background: Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) have limited treatment options. Venetoclax is a potent and selective BCL-2 inhibitor that is approved in the US and other countries for treatment of R/R CLL, either as monotherapy or in combination with rituximab. Aims: This was an open-label multicenter Phase 1/2 study (NCT02265731) to evaluate the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with relapsed or refractory CLL or SLL. Methods: Patients enrolled in Phase 1 had CLL/SLL received a target of 400 mg/day venetoclax monotherapy. Patients enrolled in Phase 2 had CLL received 400 mg venetoclax, plus rituximab (375 mg/m2/day weeks 6–9 and 500 mg/m2/day thereafter). Daily venetoclax dosing was ramped up, weekly: 20 mg, 50 mg, 100 mg, 200 mg, and finally to the target dose of 400 mg at week 5; thereafter, any dose modifications for safety management were made at the discretion of the investigator. Efficacy was evaluated by overall response rate (ORR); complete remission (CR), partial remission (PR), duration of response (DOR), progression-free survival (PFS), safety and adverse events (AE) were also evaluated. Results: As of 09 May 2018, 12 patients were enrolled and treated; 6 each in Phases 1 and 2 described above. Because phase 2 (venetoclax plus rituximab) started enrollment after phase 1 (venetoclax monotherapy), the median duration of venetoclax was significantly longer for those treated with venetoclax monotherapy compared to those treated with the combination of venetoclax plus rituximab (Table); 5/6 patients being treated with the combination are still active on study. The ORR for Japanese patients treated with venetoclax monotherapy was 100% (6/6). Patients treated with venetoclax plus rituximab had an ORR of 67% (4/6); the other two patients had stable disease. For venetoclax monotherapy at 12 months, the estimated DOR was 83%, and estimated PFS was 100% (Table). Due to shorter follow-up times, the estimated DOR for venetoclax plus rituximab is not yet available, but the estimated PFS at 6 months is 100%. All patients (n = 12) had at least one AE, and all reported Grade ≥3 AEs. The most common (≥33% of patients) Grade ≥3 AEs were neutropenia (5/6; 83%) and lymphopenia (4/6; 67%) in both treatment arms; patients treated with the rituximab combination therapy also commonly had leukopenia (4/6; 67%). There were no observed cases of laboratory or clinical tumor lysis syndrome (TLS). Mean venetoclax Cmax and AUC24 for the 12 Japanese patients were comparable to the mean observed in Western subjects with CLL/SLL.Summary/Conclusion: Venetoclax 400 mg monotherapy or in combination with rituximab was well-tolerated in Japanese patients, with a safety profile consistent with other patient populations; dosing ramp up, dose modifications and standard-of-care prophylaxis were used successfully in AE management. Across all treated patients, the ORR was 83%. These data suggest that 400 mg venetoclax, alone or in combination with rituximab, is an efficacious treatment for Japanese patients with CLL/SLL.