Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster II
Hematology Disease Topics & Pathways:
Combination therapy, Drug development, Treatment Considerations
Methods: Pts with R/R AML were eligible if aged ≥18 years, ECOG performance status ≤1, adequate organ function, and no prior CDK9i therapy. Dose escalation followed a 3+3 design, and DLTs were assessed in Cycle 1. Voruciclib was administered at 7 dose levels between 50 mg and 300 mg on days 1-14 of 28-day cycles. Venetoclax was administered at 200 mg on days 1-21 and 400 mg on days 22-28. Disease response was assessed by the 2017 ELN criteria. Mcl-1 protein expression and phosphorylation of RNA Pol IISer2 were evaluated in PBMC in cycle 1. The study is registered at clinicaltrials.gov (NCT03547115).
Results: Enrollment in this portion of the study is complete with 41 pts. Median age was 67 years (range 34-89). Median number of prior lines of therapy was 2 (range 1-7), with 93% of pts having received venetoclax and HMAs, 51% having received an anthracycline, and 20% having had prior allogeneic hematopoietic stem cell transplant (HSCT). 2017 ELN risk was adverse in 73% of pts and intermediate in 17%.
The median duration on therapy was 1.5 months (range 0.2 to 9+). No DLTs were observed, and based on PK/PD analysis, dose escalation was stopped at 300 mg without reaching the maximum tolerated dose. The most common adverse events (all grades/grade ≥3) were nausea (32%/0%), febrile neutropenia (27%/24%), dyspnea (22%/2%) diarrhea (22%/2%), hypokalemia (22%/5%) and thrombocytopenia (22%/20%). Seven pts died during treatment, 5 due to an infection and 2 due to hemorrhagic events.
Anti-leukemic activity was observed in 10 (31%) of 32 pts treated with voruciclib at doses from 100-300 mg; 2 pts had CRi (one referred to HSCT and one with 6 months of remission prior to progression), 1 pt had MLFS (ongoing at 9 months), and 7 pts had stable disease lasting ≥3 months. Among 25 pts with circulating peripheral blood blasts, 18 (75%) showed a significant reduction of circulating blasts by day 14 of the first cycle; however, circulating blasts increased again in 8 of 18 pts during single agent venetoclax administration on days 15 to 28.
Voruciclib pharmacokinetics (PK) was dose proportional. At 300 mg steady state, mean AUC0-24 was 21,526 ng x hr/mL and mean Ctrough was 644 ng/mL, exceeding concentrations needed for target inhibition in preclinical models. Voruciclib did not affect venetoclax PK. Pharmacodynamic studies including Mcl-1 protein expression and RNA Pol IISer2 phosphorylation in PBMC by flow cytometry showed on target effects and is reported separately.
Conclusion: The combination of voruciclib with venetoclax is well-tolerated and has activity in pts with AML and disease progression after venetoclax. Because of the rebound in peripheral blasts after 14 days off voruciclib, voruciclib administered on days 1-21 per cycle merits further evaluation.
Disclosures: Alvarado Valero: Jazz: Research Funding; CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Consultancy, Research Funding; Astex: Research Funding. Dinner: Pfizer: Consultancy; Rigel: Consultancy; Kite: Consultancy. Begna: Novartis: Membership on an entity's Board of Directors or advisory committees. Abedin: AbbVie, Daichii Sankyo, Servier: Consultancy, Honoraria; Actinium Pharmaceutical, AltruBio, Incyte: Research Funding. Al Malki: Stemline therapeutics: Research Funding; Incyte: Research Funding; Tr1X: Consultancy; NexImmune: Consultancy, Research Funding; Tscan: Consultancy; CareDx: Consultancy. Rajagopolan: MEI Pharma: Consultancy. Wiley: MEI Pharma: Current Employment. Ghalie: MEI Pharma: Current Employment, Current equity holder in publicly-traded company. Davids: BeiGene: Consultancy; Eli Lilly: Consultancy; Novartis: Research Funding; Surface Technology: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy; Merck: Consultancy; Genmab: Consultancy; Adaptive Biosciences: Consultancy; TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Research Funding; AstraZeneca: Consultancy, Research Funding.