Background: The combination of a hypomethylating agent (HMA) and the Bcl-2 inhibitor venetoclax (VEN) has revolutionized the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML). However, patients treated with this regimen inevitably relapse and subsequent treatment options are limited. Furthermore, the success of this combination in the relapsed/refractory setting has been less impressive. Mechanisms of resistance to HMA/VEN are of great interest, and alterations in leukemic cell metabolism have been implicated. It is hypothesized that drugs that target oxidative phosphorylation (OXPHOS), fatty acid metabolism, and /or amino acid metabolism may be successful in overcoming HMA/VEN resistance.
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 in a KG-1 tumor-bearing mouse model, thus providing support for conducting clinical trials of this combination. AML cells treated with OPB-111077 and venetoclax have also been shown to have decreased proliferation and increased apoptosis. The effects on proliferation and apoptosis of the combination of OPB-111077 and venetoclax were more pronounced in AML cells that were genetically engineered to increase OXPHOS. These data formed the basis for the development of a clinical trial utilizing the triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML. Herein, we report results from the Phase Ib dose escalation study.
Methods: In this phase Ib single center study (NCT03063944), 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. Patients were enrolled in cohorts of escalating dose levels of OPB-111077 using a traditional 3+3 design.
The primary objectives were to determine preliminary safety and tolerability as well as maximum tolerated dose (MTD) of OPB-111077. The secondary objective was to measure preliminary efficacy. Correlative studies including metabolomics, ATP measurement, apoptosis, and proliferative assays were performed on samples of blasts and non-cancerous cells that were collected from blood or marrow.
Results: As of July 15, 2020, 2 patients with newly diagnosed AML and 7 patients with relapsed/refractory AML were treated with the triplet. Patients received OPB-111077 at 150mg (n=3), 200mg (n=3), and 250mg (n=3). Median age was 73 years (range, 23-79) and 7 patients (78%) were male. The median number of prior systemic anticancer regimens for patients with relapsed/refractory disease was 2 (range, 1-5); no patients had undergone prior stem cell transplant. The median treatment duration has not yet been reached; 3 patients are receiving ongoing treatment. No patients experienced a dose limiting toxicity. The most common Grade ≥3 adverse event (AE) was febrile neutropenia (56%). No patients discontinued due to AEs. No pts experienced tumor lysis syndrome. Three patients died after completing their study treatment, all due to progressive AML. The best overall response to therapy was a complete remission in 2 (22%) patients (1 with newly diagnosed AML and 1 with relapsed/refractory disease).
Metabolomics using liquid chromatography/mass spectrometry was performed on paired pre- and post-treatment samples and intracellular metabolic changes in glycolysis and the tricarboxylic acid (TCA) cycle were observed consistent with on-target effects.
Conclusion: The triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML was safe and well tolerated, and showed preliminary anti-leukemic efficacy. A planned expansion phase is underway utilizing the 250mg daily dose of OPB-111077.
Disclosures
Martinez-Outschoorn: Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding.
Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells
