FDA Submission of Phase 2 Data Planned for Venetoclax in CLL

The investigational agent venetoclax (formally ABT-199) has successfully met the primary endpoint of a phase 2 study as a treatment for patients with high-risk relapsed or refractory chronic lymphocytic leukemia (CLL), according to a statement from AbbVie and Genentech.

Based on results from the phase 2 study, the companies hope to complete a regulatory filing by the end of 2015.

In May 2015, venetoclax, which targets a protein involved in cell death (BCL-2), received a breakthrough therapy designation from the FDA as a potential treatment for patients with CLL harboring the 17p deletion. This FDA program is meant to expedite the development and review process for promising novel therapeutics.

The primary endpoint of the open-label, single-arm phase 2 study was overall response rates (ORR) assessed using NCI-CWG criteria. 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).

Full data from the study were not yet made available and are being submitted for presentation at an upcoming medical meeting.

“Approximately 30 to 50 percent of people with relapsed or refractory chronic lymphocytic leukemia have the 17p deletion that makes their disease difficult to treat,” Sandra Horning, chief medical officer and head of Global Product Development at Genentech/Roche, 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.”

In a preceding phase I study, 105 patients at a median age of 66 years with CLL and small lymphocytic leukemia were treated with venetoclax at varying doses. Patients had received a median of 4 prior therapies and 28 percent harbored a 17p deletion. Eighty-three percent of patients had received prior therapy with fludarabine.

The estimated 24-month PFS rate at this dose level was 59 percent. 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 percent (range, 31-71).

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

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).

In results presented at the 2014 American Society of Clinical Oncology Annual Meeting, patients with deletion 17p CLL (n = 19) experienced an ORR of 79 percent, which consisted of 5 CRs (26 percent) and 10 PRs (53 percent). 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.