Venetoclax Achieves Primary Endpoint in Pivotal Phase II CLL Study

Michael Severino, MD

Treatment with single-agent venetoclax (ABT-199) has met the primary endpoint of a pivotal phase II study for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion, according to top-line findings released by AbbVie and Genentech, the codevelopers of the BCL-2 inhibitor.

The primary endpoint of the open-label, single-arm phase II study was overall response rates (ORR) assessed using NCI-CWG criteria. Full data from the study were not yet made available and are being submitted for presentation at an upcoming medical meeting. Based on the findings, AbbVie and Genentech are preparing regulatory submissions to the FDA and European Medicines Agency, which they anticipated would be complete by the end of 2015.

"The results from this study demonstrate the clinical activity of venetoclax in patients with relapsed/refractory CLL who have 17p deletion, a patient population that has historically been difficult to treat," Michael Severino, MD, executive vice president of research and development and chief scientific officer, AbbVie, said in a statement. "Based on these results, we intend to advance regulatory submissions for venetoclax and remain committed to the further development of this investigational medicine, and others in our pipeline, with the goal of delivering new treatment options for people affected by cancer."

In the study, labeled M13-982, 107 patients were enrolled into a main efficacy cohort and 50 patients participated in a safety expansion arm. All patients were refractory or had relapsed on at least one prior therapy and had measurable disease. Secondary efficacy endpoints focused on complete response (CR), partial response (PR), and progression-free survival (PFS).

In a preceding phase I study, the venetoclax dose was escalated across cohorts in order to find a maximum tolerated dose. An early assessment revealed the occurrence of tumor lysis syndrome (TLS), resulting in the initiation of an expanded safety cohort. In this portion of the study, venetoclax was administered at 20-mg in week 1, 50-mg in week 2, 100-mg in week 3, and 400-mg in week 4. After this change, no additional TLS events were reported.

In the phase II trial, the primary goal of the safety expansion cohort was to validate the TLS prevention measures that were initiated in the phase I study. In the top-line results announced by the companies, it was indicated that "the safety profile was similar to previous studies and no unexpected safety signals were reported for venetoclax."

The preceding phase I study enrolled 105 patients at a median age of 66 years with CLL and small lymphocytic leukemia. Patients had received a median of 4 prior therapies and 28% harbored a 17p deletion. Eighty-three percent of patients had received prior therapy with fludarabine.

In results presented at the 2014 ASCO Annual Meeting, patients with deletion 17p CLL (n = 19) experienced an ORR of 79%, which consisted of 5 CRs (26%) and 10 PRs (53%). Additionally, 11% of patients had stable disease. Across all study populations, 11 of the 18 patients who experienced a CR or CR with incomplete hematologic recovery were assessed for minimal residual disease (MRD). MRD-negativity was achieved in 5 patients, 2 of which harbored a 17p deletion.

For patients who received the 400 mg or higher dose of venetoclax, the median PFS had not yet been reached at the April 2014 data cutoff. The estimated 24-month PFS rate at this dose level was 59%. The approximate median PFS across all doses was 18 months. For high-risk patients treated at the 400 mg dose or higher, the 24-month PFS rate was 54% (range, 31-71).

The most frequently reported all-grade adverse events (AEs) across all dose levels included diarrhea (40%), nausea (35%), neutropenia (36%), upper respiratory tract infection (33%), and fatigue (27%). The most frequently grade 3/4 AEs were neutropenia (33%), anemia (10%), and TLS, febrile neutropenia, thrombocytopenia, and hyperglycemia (7% each).

“Approximately 30% to 50% of people with relapsed or refractory chronic lymphocytic leukemia have the 17p deletion that makes their disease difficult to treat,” Sandra Horning, MD, chief medical officer and head of Global Product Development, said in a statement. “Venetoclax may help restore the natural process that allows these leukemic cells to self destruct, representing a potential new way of helping people with this form of CLL who typically have a poor prognosis and limited treatment options.”

Venetoclax received a breakthrough therapy designation from the FDA as a potential treatment for patients with 17p deletion CLL in May 2015. A rolling submission of clinical trial data is permitted under this program, which is intended to expedite the development of new agents.

Currently, there are two phase III trials assessing venetoclax in combination with anti-CD20 antibodies for patients with CLL. In one study, venetoclax plus rituximab is being compared with bendamustine and rituximab for those with relapsed or refractory CLL (NCT02005471). In the second study, venetoclax is being combined with obinutuzumab versus chlorambucil and obinutuzumab for patients with CLL and coexisting medical conditions (NCT02242942).

Seymour JF, Davids MS, Pagel JM, et al. ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete- response rate and durable disease control. J Clin Oncol. 2014;32:5s, (suppl; abstr 7015)