A phase 1/1b study of the all-oral regimen CC-486 and venetoclax in acute myeloid leukemia

Venetoclax with azacitidine is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive induction chemotherapy. CC-486 is the oral formulation of azacitidine that is currently approved for postinduction chemotherapy maintenance in AML. In this single-center, open-label, phase 1/1b study, we investigated CC-486 and venetoclax in patients with relapsed and refractory AML and in those with newly diagnosed disease. In the dose-escalation phase, patients received CC-486 at 1 of 2 cohorts (200 mg by mouth on days 1-14 and 300 mg by mouth on days 1-14). Venetoclax was given at 400 mg/d by mouth for 28 days after an initial intrapatient dose escalation per the standard of care. Using a 3+3 study design for these 2 cohorts, we determined the recommended dose of CC-486 to be 300 mg daily on days 1 to 14. The most common adverse events included nausea, diarrhea, fatigue, and cytopenias. The incidence of grade ≥3 neutropenia or thrombocytopenia was 97% and 66%, respectively. There were no dose-limiting toxicities in either cohort. The expansion phase of the study consisted of 10 additional patients with relapsed and refractory AML and 16 patients with newly diagnosed AML. Responses were seen in all phases of the study, and 6 patients were successfully bridged to hematopoietic stem cell transplant. Correlative analyses including sequencing and metabolomics performed on patient samples suggested that this regimen had a similar effect on leukemia stem cells compared with conventional (IV) azacitidine and venetoclax. This trial was registered at www.clinicaltrials.gov as NCT05287568.