OPB-111077 in Combination with Decitabine and Venetoclax for the Treatment of Acute Myeloid Leukemia

Background

The landscape of acute myeloid leukemia (AML) treatment has changed with the FDA approval of the oral Bcl-2 inhibitor venetoclax in combination with a hypomethylating agent (HMA) for the up-front treatment of elderly patients with AML. However, while the results of clinical trials for first line treatment of AML with Bcl-2 inhibitors have been promising, the success of the combination in patients with relapsed/refractory disease have been less robust. Mitochondrial oxidative phosphorylation (OXPHOS) has been implicated as a mechanism of resistance to Bcl-2 inhibition in AML and, in one study, blocking OXPHOS via glutaminase inhibition was shown to enhance the apoptotic effects of venetoclax. Two studies have shown that the combination of venetoclax and an HMA targets OXPHOS in an amino acid dependent manner in de novo leukemic stem cells and suggest that relapsed leukemic stem cells are able to escape this mechanism by increasing fatty acid synthesis. These data suggest that targeting OXPHOS, fatty acid uptake, and/or amino acid metabolism may be a therapeutic strategy to target leukemic stem cells in the relapsed setting.

OPB-111077 is a novel, oral, low-molecular-weight compound that was shown in preclinical models to inhibit mitochondrial electron transport and have an inhibitory effect on the growth of AML cells. When given in combination with decitabine, OPB-111077 showed a more potent antitumor effect and was well tolerated in a KG-1 tumor-bearing mouse model, thus providing support for conducting clinical trials of combination chemotherapy with OPB-111077 and decitabine. We have evaluated the effects of OPB-111077 and venetoclax in AML cells and have found that the combination causes decreased proliferation and increased apoptosis rates to a greater degree than exposure to single agent OPB-111077 or venetoclax. The effects on proliferation and apoptosis of the combination of OPB-111077 and venetoclax were even more pronounced in AML cells that were genetically engineered to increase OXPHOS. Together, this preclinical work has formed the basis for a clinical trial evaluating triplet therapy with OPB-111077, venetoclax, and decitabine.

Study Design and Methods

This is a single center, Phase Ib, 3+3 dose-escalation study of OPB-111077 in combination with decitabine and venetoclax in patients with AML. Patients are eligible if they have non-APL AML that is refractory to or relapsed after any standard induction or salvage therapy, or if they have newly diagnosed AML and are not eligible for or willing to undergo intensive induction. OPB-111077 is administered daily starting on day 1 and continuing throughout the treatment cycle. Decitabine 20mg/m² is given for 5 days starting on day 4 of cycle 1. Venetoclax 70mg daily (if receiving posaconazole prophylaxis) or 100mg daily (if receiving voriconazole) is started on day 4 and given continuously until day 28. If a response is seen within 2 cycles, treatment continues until toxicity, disease progression, or availability of an alternative therapy. The primary endpoint of the study is dose limiting toxicity (DLT). Correlative studies including metabolomics, ATP measurement, apoptosis, and proliferative assay are performed on samples of blasts and non-cancerous cells that are collected from blood or marrow. 9 patients were treated with OPB-111077 at the 150mg dose level in combination with decitabine alone prior to the addition of venetoclax to the regimen. No dose limiting toxicities were identified. Clinical trial: NCT03063944