BCL-2 Inhibition in Acute Myelogenous Leukemia

A Phase 1b Study of ABT-199 (GDC-0199) in Combination With Azacitidine or Decitabine in Treatment-Naïve Subjects With Acute Myelogenous Leukemia Who Are ≥ 65 Years of Age and Who Are Not Eligible for Standard Induction Therapy

NCT02203773

AbbVie

160 participants

22 sites in the United States, Australia, France, and Germany

This study is a phase Ib, nonrandomized, multicenter, open-label, prospective trial that will measure the safety of combination ABT-199 and hypomethylating agents in older adults with acute myelogenous leukemia (AML), who are treatment-naïve and not eligible for standard induction therapy. Secondary outcomes will measure depth and duration of responses (including minimal residual disease [MRD]) and survival. Eligible patients must be 65 years or older with a good performance status (Eastern Cooperative Oncology Group score, 0-2), having not received any prior AML treatment except hydroxyurea. Patients may not have received prior chemotherapy or hypomethylating agent for an antecedent hematologic disorder. Patients with favorable risk cytogenetics, including acute promyelocytic leukemia, are excluded from participation. Dose-escalated ABT-199 is administered orally daily with either standard doses of decitabine or azacitidine for the first five or seven days of each cycle respectively, for a minimum of four cycles.

Reliance on the anti-apoptotic protein BCL-2 has been shown in preclinical studies to be important in the maintenance and survival of AML cells. Unlike disorders such as chronic lymphocytic leukemia (CLL), where there are discrete genetic causes for BCL-2 upregulation, specific genetic alterations that cause overexpression of BCL-2 are not known in AML. However, prior work has identified that AML cells are functionally more reliant on BCL-2 than normal hematopoietic stem cells, thus providing a therapeutic index for BCL-2 inhibition in AML. Therefore, there is hope that the efficacy of BCL-2 inhibition in AML might approach that seen with CLL, where ABT-199 treatment has resulted in sizable complete remissions, with some patients achieving MRD-negative status. Previously, a phase II study of ABT-199 as monotherapy in relapsed/refractory AML showed that five (16 percent) of 32 heavily pretreated patients achieved a complete response or complete response with incomplete blood count recovery (CR/CRi). The most common adverse events were nausea, vomiting, diarrhea, and neutropenia.

Thus far, data presented at the 2015 ASH Annual Meeting showed promising results with the combination of ABT-199 and hypomethylating agents. Two dose levels of ABT-199 (400 mg and 800 mg) were evaluated in a total of 22 patients. The rate of CR/CRi was 60 percent and 67 percent in the azacitidine and decitabine arms, respectively. Compared with monotherapy, combination therapy resulted in thrombocytopenia and leukopenia, necessitating treatment disruptions in 55 percent of patients. No episodes of tumor lysis syndrome occurred. The thrombocytopenia was unexpected since ABT-199 does not inhibit BCL-XL, whose inhibition was found to be the cause of thrombocytopenia with prior generation BCL-2 inhibitors. Potential effects of the combination treatment on BCL-XL or other antiapoptotic proteins in platelets therefore, should be investigated. However, based on the positive results thus far, the U.S. Food and Drug Administration has granted ABT-199 a breakthrough therapy designation for use in combination with hypomethylating agents in this patient population. Updated results for a total of 34 patients were presented in June 2016 with similar results: CR/Cri of 71 percent, with no dose-limiting toxicity reached to date. Furthermore, a similar study using ABT-199 in combination with low-dose cytarabine in treatment-naïve AML patients aged 65 years or older (NCT02287233) reported a 44 percent response rate in 18 patients. However, this study did identify a dose-limiting toxicity of grade 4 thrombocytopenia at the 800 mg dose-level, and the 600 mg dose was recommended for phase II development with that particular combination.

The superior results with ABT-199 combined with other agents in the upfront setting as compared to monotherapy in the relapsed/refractory setting (44% to 70% vs. 15% to 19%, respectively) invites the question as to whether disease context or the combination of agents is responsible for improved efficacy. A phase III, randomized trial of ABT-199 in combination with hypomethylating agent versus hypomethylating agent alone in a treatment-naïve AML population would certainly answer this question, and these trials are currently being planned. In the meantime, the phase Ib combination of ABT-199 with hypomethylating therapy is currently recruiting participants and offers an option for those patients age 65 or older who are not eligible for standard therapy or other targeted agents.