A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: �BCL-2 is an anti-apoptotic protein that is commonly overexpressed in hematologic malignancies, including Non-Hodgkin Lymphoma (NHL).� Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor. Patients (pts) with relapsed/refractory (R/R) NHL were enrolled in a phase 1, open-label, dose-escalation, multicenter study to determine the safety, pharmacokinetics, and efficacy of venetoclax monotherapy. �We present updated data on the safety profile and efficacy as of June 10, 2015.

Methods: �Venetoclax was administered once-daily until progressive disease or unacceptable toxicity.� To mitigate the risk of tumor lysis syndrome (TLS), a 3-week period with a stepwise, intrapatient dose ramp-up was used, starting at 200 mg and reaching a maximum dose level of 1,200 mg in the dose escalation cohorts.� In a safety expansion cohort, stepwise escalation from 400 mg to 800 mg to 1200 mg was evaluated.� Adverse events (AEs) were graded according to NCI-CTCAE version 4.0.� Responses were assessed using 2007 Cheson IWG response criteria including CT scans beginning at week 6.

Results: �Accrual is complete with 106 pts enrolled.� NHL subtypes included in the dose escalation cohorts (200�1200 mg/day) were diffuse large B-cell lymphoma (DLBCL, n=20), follicular lymphoma (FL, n=14), mantle cell lymphoma (n=28), Waldenstr�m macroglobulinemia (n=4), marginal zone lymphoma (n=3), and multiple myeloma (n=1).� NHL subtypes enrolled in the safety expansion cohort (1200 mg/day) were DLBCL (n=21) and FL (n=15).

The current analysis focuses on pts with DLBCL and FL from the dose escalation and safety expansion cohorts. �Data on other subtypes will be presented at the meeting.� In total, 57/70 pts with DLBCL and FL have discontinued (n=49 due to PD, n=3 due to AE, n=2 withdrew consent, n=2 proceeded to transplant and n=1 due to non-compliance). Treatment emergent-AEs of any grade in ≥20% of the 70 pts with DLBCL or FL were diarrhea and fatigue (each 44%), nausea (33%) and vomiting (23%). �Treatment-emergent grade 3/4 AEs in ≥5 pts, were anemia (14%), fatigue (9%) and thrombocytopenia (7%). �Serious adverse events in ≥2 pts were hyponatremia (4%), and dehydration, diarrhea, and febrile neutropenia (each 3%). �Two events of laboratory TLS were previously reported.� There were no new events of laboratory TLS and no pts had clinical TLS.

Among 41 pts with DLBCL, 7 were DLBCL-Richter's transformation (RT) and 2 had primary mediastinal large B-cell lymphoma (PMBCL).� The median age was 68 (range: 25�86).� The median number of prior therapies was 3 (range: 1�8).� Five (12%) had rituximab-refractory disease.� The median time on venetoclax for pts with DLBCL was 5 months (range: 0.4�9).� The overall response rate (ORR) was 15% [3 (9%) CR and 2 (6%) PR] for pts with DLBCL (n=34).� The median duration of response for DLBCL was 3.3 months (range: 2�4) with no responses ongoing and the median duration of SD was 2.3 months (range: 1�15). �One pt with SD remains on study at 9 months of venetoclax.� Two responders (1 with DLBCL who achieved CR and 1 with PMBCL who achieved PR) proceeded to allogeneic hematopoietic stem cell transplant.� The ORR was 43% (3 PR) for pts with DLBCL-RT (n=7).� One pt with PR remains on study at 18 months of venetoclax.

Among 29 pts with FL, the median age was 64 (range: 46�75).� The median number of prior therapies was 3 (range: 1�10).� Eight (28%) had rituximab-refractory disease.� The median time on venetoclax was 7 months (range: 1�19).� The ORR was 34% [3 (10%) CR and 7 (24%) PR] for pts with FL (n=29).� All 3 patients with CR were enrolled in the dose escalation cohorts.� The median duration of response was 10 months (range: 1�30) and the median duration of SD was 4.2 months (range: 2�18). �Eleven patients remain on study. Response rates are summarized in the table.

Conclusions: �Venetoclax monotherapy demonstrated a tolerable safety profile in pts with R/R NHL.� Several pts with DLBCL had an initial response to venetoclax, but this response was not sustained.� In FL, venetoclax monotherapy achieved an ORR of 34% indicating clinical benefit, as evidenced by long durations on therapy.� These results suggest that the optimal role of venetoclax for treatment of DLBCL and FL will be in combination therapies.� Venetoclax is currently being evaluated in combination with bendamustine and rituximab and in combination with R or obinutuzumab plus CHOP in phase 2 studies of pts with FL.