BMS-986397, a first-in-class casein kinase 1α (CK1α) degrader in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS): A phase 1 dose escalation study

Abstract

Abstract Introduction: Patients with relapsed or refractory (R/R) AML or high-risk MDS (HR-MDS) have limited therapeutic options and poor outcomes. BMS-986397 (CC-91633) repurposes the CRL4CRBN E3 ubiquitin ligase to target Casein kinase 1α (CK1α) for ubiquitination and proteasomal degradation, which leads to the stabilization and activation of p53 resulting in cell cycle arrest and induction of apoptosis in AML blasts. Here, we present the first clinical data from CC-91633-AML-001 (NCT04951778), a first-in-human, multicenter, open-label study of BMS-986397 in patients with R/R AML and R/R HR-MDS. Methods: Patients were ≥18 years with R/R AML or HR-MDS without TP53 mutation or loss of 17p, who failed or were ineligible for any available therapies. BMS-986397 was given orally once daily (QD) for 3, 5 or 7 consecutive days on 28-days cycle. The observation period for dose-limiting toxicities (DLT) was cycle 1 (28 to 42 days). Primary objectives were to determine the safety and tolerability of BMS-986397 and to define the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose(s) and schedule(s). Secondary endpoints were to assess the preliminary efficacy and to characterize the pharmacokinetics of BMS-986397. Exploratory pharmacodynamic objectives included to evaluate molecular and/or cellular biomarkers in the bone marrow (BM) and peripheral blood (PB). Results: Fifty-two patients were enrolled in the study and treated with BMS-986397. Thirty-eight (73.1%) patients had AML, and 14 (26.9%) patients had HR-MDS. The median age was 75 years (range: 34-87). The median prior lines of therapy was 2 (range: 1-7) for AML and 1 (range: 1-4) for HR-MDS. Ten patients had secondary AML (sAML) from prior MDS. Patients received BMS-986397 at doses from 0.1mg to 5.0mg for a median of 2 cycles (range: 1-8). Median treatment duration was 6.1 weeks (range: 0.4-33.9). Treatment-emergent AEs (TEAEs) occurred in 98.1% of patients, forty-seven (90.4%) of which had at least 1 Grade 3/4 TEAE. The most common Grade 3/4 TEAEs occurring in ≥10% of patients were thrombocytopenia (42.3%), anemia (38.5%), asthenia and diarrhea (34.6%), neutropenia (32.7%) and ALT increase (30.8%). Four (7.7%) patients experienced a DLT: Grade 3 QT prolongation in 2 patients at 2.2mg and 3mg QD x7 days, respectively; and prolonged Grade 4 cytopenias beyond 42 days in the absence of active disease in 2 patients at 3mg QD x7 days and 3mg QD x5 days, respectively. Eleven (21.2%) patients experienced at least one TEAE leading to dose interruption (or delay in the start of next cycle) and 5 (9.6%) patients experienced at least one TEAE leading to dose reduction. The most common TEAEs that led to dose interruption or reduction were cytopenias. Forty-seven (87%) patients discontinued from treatment due to: progressive disease (53.7%), withdrawal by subject (9.3%), death (7.4%), TEAEs (5.6%), other reasons (7.4%) and physician decision (3.7%). Two (3.8%) patients discontinued from treatment due to death from TEAEs (not related to BMS-986458) of pneumonia and septic shock. Three (7.9%) AML patients achieved CRi and 1 patient (2.6%) achieved MLFS. Four (28.6%) HR-MDS patients achieved CR, 2 patients (14.3%) marrow CR (mCR) with hematologic improvement and 2 patients (14.3%) mCR. Three out of 4 (75%) of R/R AML patients that achieved CRi or MLFS had sAML from prior MDS. No correlation with molecular or cytogenetic factors and response was identified. A dose-dependent increase in exposure was observed for BMS-986397, with no apparent difference between patients with AML or HR-MDS. Steady state was reached by Day 5, with a median accumulation of approximately 15% in Cmax observed between Day 1 and Day 5. BMS-986397 at doses ≥1.5mg induced up to 90% CK1α degradation in blasts, regardless of its basal expression. Sustained stabilization of p53 during dosing days was observed at doses ≥2.2 mg of BMS-986397, which correlated with a dose-dependent increase of MIC-1 levels at the last dosing day. These changes translated into a rapid reduction of peripheral blasts (median: -87.8%) at doses ≥3mg of BMS-986397. Conclusions: Treatment with BMS-986397 monotherapy resulted in high response rates in R/R HR-MDS patients (CRR: 57.1%) and modest activity in R/R AML (ORR: 12.1%). The most common TEAEs were grade 3/4 cytopenias that led to dose interruptions or reductions. The MTD was not reached. Updated clinical data and additional translational analyses will be presented.