P540: results from a phase 1 clinical study of the all-oral regimen of cc-486 and venetoclax for relapsed and refractory acute myeloid leukemia (aml)

Topic: 4. Acute myeloid leukemia - Clinical Background: Venetoclax with azacitidine is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. It is well known that this treatment also has activity in the relapsed and refractory setting. However, this regimen requires seven consecutive daily subcutaneous or intravenous doses of azacitidine each month, which continues indefinitely. The relative inconvenience of this, and its negative impact on quality of life, may lead to its early discontinuation due to tolerability or convenience issues, which may decrease the overall efficacy or durability of this regimen. A more convenient all-oral regimen may decrease visits to an infusion center, improve quality of life, and potentially increase the efficacy of the regimen due to improved treatment compliance. CC-486 is the oral formulation of azacitidine that is currently approved for post-induction chemotherapy maintenance in AML. Aims: To report safety and tolerability of CC-486 in combination with venetoclax in patients with relapsed and refractory AML. Methods: This is a single center open label, phase 1 study investigating CC-486 and venetoclax in relapsed and refractory AML patients. In the dose escalation phase, subjects received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Venetoclax was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care (100mg on day 1, 200mg on day 2, 400 mg on days 3-28). Using a 3 + 3 study design for these two cohorts, we aimed to determine the maximum tolerated dose (MTD) of CC-486 in combination with venetoclax. An expansion cohort is planned for 10 additional patients treated at the MTD. Results: As of February 1, 2023, 8 patients have been accrued (Table). The average age at the time of enrolment was 64, and median prior treatment regimens was 1 (range 1-3). Four patients had received venetoclax in prior treatments. In cohort 1, there were no dose-limiting toxicity (DLT) events. There have been no DLT events in 5/6 patients enrolled in cohort 2. The most common hematologic toxicities were Gr 3-4 neutropenia (n = 7, 88%), Gr 3-4 anemia (n = 6, 75%), and Gr 3-4 thrombocytopenia (n = 4, 50%). The most common non-hematologic Gr 1-2 toxicities were nausea (n = 4, 50%), fatigue (n = 2, 25%), diarrhea (n = 2, 25%), and the most common non-hematologic Gr 3-4 toxicity was granulomatous folliculitis (n = 1, 13%). Best responses were complete remission (CR) (n = 2, 25%) partial remission (n= 1, 13%), and stable disease (n= 2, 25%). Three patients proceeded to an allogeneic stem cell transplant. Summary/Conclusion: CC-486 and venetoclax is an all-oral regimen currently being investigated for the treatment of relapsed and refractory AML. Our phase 1 dose escalation thus far has demonstrated a favorable safety profile for this regimen. Full phase 1 findings as well as the MTD will be presented at the meeting. Responses have been seen in both dose cohorts including 2 CRs and patients have been successfully bridged to hematopoietic stem cell transplant.Keywords: Relapsed acute myeloid leukemia, Adult