Safety and efficacy of casein kinase 1α and cyclin dependent kinase 7/9 inhibition in patients with relapsed or refractory AML: A first-in-human study of BTX-A51.
Authors: Ball Brian , Borthakur Gautam , Stein Anthony Selwyn , Chan Kyle , Thai Dung Luong , Stein Eytan 
Published: June 2022

7030 Background: Inactivation of p53 and overexpression of Mcl1 are common mechanisms that cancer cells use to evade apoptosis. BTX-A51 is a novel, oral, direct inhibitor of casein kinase 1α (CK1α) and cyclin dependent kinase 7 and 9 that robustly increases p53 protein levels via CK1α inhibition while preferentially decreasing super-enhancer transcription of Myc and Mcl1, enabling selective apoptosis of leukemia cells. Here, we report the interim results of the first-in-human (FIH) study of BTX-A51 in patients (pts) with R/R AML. Methods: The study utilizes a hybrid accelerated titration with single pt cohorts and a Bayesian optimal interval design in dose escalation. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating the antileukemic activity, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 25 January 2022, 30 pts (28 with AML; 2 with HR-MDS) enrolled at dose levels between 1 and 42 mg; 2 pts remain on treatment. Monotherapy doses between 1 and 42 mg were administered orally 3 days/week (wk) (3 wk in a 28-day cycle) and at 21 mg (4 wk in a 28-day cycle). Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The most common treatment-emergent AEs (TEAEs) were hypokalemia, nausea, vomiting, diarrhea, and hypotension. The most common Grade 3 or higher TEAEs were anemia, febrile neutropenia, platelet count decreased, and hypokalemia. DLTs included grade 3 hepatic failure at the 42 mg dose in 1 pt and grade 3 alkaline phosphatase elevation in 1 pt at the 21 mg dose. All events resolved after holding study drug. Plasma PK of BTX-A51 was roughly dose-proportional between 1 and 42 mg with accumulation based on AUC between Day 1 and Day 5. Estimated half-life was between 18 and 55 hours. Among the 30 pts with R/R AML and MDS, CR/CRi rate was 10% (3/30) with 1 pt at the 11 mg and 2 pts at the 21 mg dose levels attaining CRi. Bone marrow (BM) blast reduction > 50% occurred in 4 patients including the 3 responders, all at the 11 and 21 mg dose levels. All 4 pts with > 50% BM blast reduction had RUNX1 mutations; 9 pt with RUNX1 enrolled in the trial. The median duration of response for pts achieving CR/CRi was approximately 1.5 month. Responses were not observed in MDS pts. PD data will be provided in the full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered 3 days/wk for 4 wk of a 28-day cycle. Conclusions: In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining > 50% BM blast reduction. Clinical trial information: NCT04243785.