Results from a Clinical Study of the All-Oral Regimen of CC-486 (Oral Azacitidine) and Venetoclax for Newly Diagnosed and Relapsed and Refractory Acute Myeloid Leukemia
Authors: Amaya Maria L , McMahon Christine M. , Schwartz Marc , Gutman Jonathan , Kent Andrew , Abbott Diana , Sohalski Connor , Dell-Martin Jessica , Belachew Ayele , Stevens Brett M , Jordan Craig T , Pollyea Daniel A 
Published: December 2024

Background: Venetoclax (ven) with azacitidine (aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. However, this regimen requires 7 consecutive daily subcutaneous or intravenous doses of aza each month, which continues indefinitely. This relative inconvenience, and its negative impact on quality of life, may lead to early discontinuation, potentially decreasing the efficacy of this regimen. A more convenient all-oral regimen may improve quality of life and potentially result in increased efficacy due to improved compliance. CC-486 is the oral formulation of aza, with distinct pharmacokinetic properties, that is currently approved for post-induction chemotherapy maintenance in AML.
Methods: This is a single center, open label, investigator-initiated phase I/II study investigating CC-486 (oral azacitidine) and ven in AML patients. The MTD of CC-486 in combination with ven was previously reported as 300mg QD d1-14 in relapsed/refractory (R/R) AML (Amaya et al. 2023). The study is now enrolling two expansion cohorts: 1) 10 additional R/R patients; 2) 16 newly diagnosed (ND) AML patients. This is a planned interim analysis for futility, with the possibility to expand the ND cohort. All patients in the ND cohort must be ≥75 or unfit for intensive induction chemotherapy. Patients received 300mg of oral azacitidine daily for 14 days of a 28-day cycle in combination with ven per the FDA label.
Results: As of July 2024, a total of 24 subjects have been accrued for this study. N=17 R/R (N=9 dose escalation and N=8 expansion), and N=7 ND. For the R/R subjects, the median age was 63 and the median number of prior treatments was 1 (range 1-3). Nine of 17 (53%) had previously received venetoclax-based regimens. The overall response rate (ORR) was 5/17 (29%), with 3 CR, 1 CRi and 1 PR. 5/17 (29%) patients were bridged to transplant. For the ND cohort, the median age was 79. Six had ELN adverse risk and 1 had intermediate risk; 3/7 (43%) had a TP53 mutation. The ORR was 7/7 (100%), with N=6 CR, N=1 CRi. 6/7 ND subjects remain on study and have received a median of 2 cycles (range 1-5). The most common non-hematologic adverse events during cycle 1 for all subjects who received the MTD dose of CC-486 (N=21, R/R=14, ND=7) were: diarrhea (G1-2 38%), nausea (G1-2 38%), fatigue (G1-2 19%), and febrile neutropenia (G3-4 23%). Hematologic toxicities during cycle 1 regardless of attribution were neutropenia (G3-4 95%), anemia (G1-2 19%, G3-4 80%), and thrombocytopenia (G1-2 28%, G3-4 62%).
Conclusion: CC-486 (oral azacitidine) and ven is an all-oral regimen currently being investigated for the treatment of ND and R/R AML. The phase I portion of this study previously showed the MTD of CC-486 with ven to be 300mg d1-14 (Amaya et al. 2023). This study has now been expanded to include an additional 10 patients with R/R AML and 16 patients with ND AML, which are currently enrolling. High response rates have been seen in the newly diagnosed cohort with 7/7 (100%) of the patients achieving a CR/CRi, including 3/3 who harbor a TP53 mutation. Final results of the R/R cohort, as well as a larger sample size of the ND subjects, with genomic annotation, as well as translational studies exploring mechanistic differences and similarities with this all-oral regimen and conventional aza/ven, will be presented.