A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults

Introduction Oral tyrosine kinase inhibitors (TKIs) that inhibit the constitutively active ABL1 kinase have improved outcomes for BCR-ABL1+ acute lymphoblastic leukemia (ALL) and decreased reliance on cytotoxic chemotherapy (ctx). Later generation, more potent TKIs such as dasatinib (DAS) are particularly effective (Foa et al. Blood 2011; Foa et al. N Eng J Med 2020). ABL001 (asciminib) is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric inhibitor of ABL1 that binds to a site spatially distinct from all approved ATP-competitive TKIs. Combination treatment with an allosteric and an ATP-competitive TKI may deepen clinical responses and limit mutational resistance as supported by a cell line xenograft model of CML (Wylie et al. Nature 2017) and patient-derived xenograft models of BCR-ABL1+ ALL. We hypothesized that dual ABL blockade with catalytic domain and allosteric inhibitors would be tolerable and effective in BCR-ABL1+ ALL.

Methods This is an investigator initiated, phase I study (NCT03595917) of ABL001 in combination with DAS plus prednisone in BCR-ABL1+ ALL. The study employs a 3+3 dose escalation design with an expansion cohort with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary objectives include defining the depth and durability of responses. Patients (pts) ≥ 50 years (yrs) and younger unfit pts (18-49 yrs) with untreated BCR-ABL+ ALL or pts ≥ 18 yrs with relapsed/refractory ALL (no prior DAS or ABL001) are eligible. Pts are treated with DAS 140 mg daily and prednisone 60 mg/m2 days (d) 1-24 (max 120 mg daily, tapered d 25-32) with escalating doses of ABL001 once/d administered fasting (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS plus ABL001 are given in 28-day cycles. Pts receive CNS prophylaxis with intrathecal ctx. Bone marrow transplant (BMT)-eligible pts may be consolidated with BMT after d85; BMT-ineligible pts may remain on therapy if deriving clinical benefit. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study has since been amended to assess DLT via CTCAEv5. Correlative science aims to identify biomarkers of response to combined ABL1 blockade and to define targetable biological programs enriched in minimal residual disease.

Results The study has enrolled 12 pts (7 male/5 female). All 12 had untreated BCR-ABL1+ ALL. The median age at registration was 66 yrs (range 53 - 86; 4 pts 70+). DL1 (ABL001 40 mg/d) enrolled 3 pts without DLT; all have discontinued therapy (1 pt personal decision - C5, 2 pts to BMT- C5). DL2 (ABL001 80 mg daily) enrolled 3 pts without DLT (1 pt remains on study - C32, 1 pt discontinued for DAS pulmonary toxicity - C4, 1 pt discontinued for ALL progression - C11). DL3 (ABL001 160 mg daily) enrolled 3 pts with 2 pts developing asymptomatic CTCAEv4 Gr 3 amylase elevation during C1 meeting original DLT criteria (3 ^rd pt discontinued C2 due to DAS pulmonary toxicity and inadequate response). A 4th pt was enrolled on DL3 under protocol amendment defining asymp CTCAEv4 gr 3 amylase/lipase elevations persisting <=5d to not be a DLT. This pt experienced an asymptomatic CTCAEv4 gr 3 lipase elevation meeting DLT criteria (continued study with dose reduction). Thus, the study de-escalated to DL2 with 2 pts enrolled to date. The study remains open to accrual and pts will be assessed by CTCAEv5 under a new amendment. Of note, all DLTs to date would be <gr 3 under CTCAEv5 (all asymptomatic amylase/lipase <5xULN without clinical sequalae). All patients remain alive. Responses for evaluable pts are summarized in the Table. Pre-treatment tumor genotyping and serial on-treatment, single-cell profiling of tumor and microenvironment fractions have been performed in all pts to date, highlighting extensive biophysical, transcriptional, and genetic inter-tumor heterogeneity. We are interrogating the linked biophysical and transcriptomic data to develop predictive biomarkers and illuminate MRD biology.

Conclusion Dual ABL1 kinase inhibition with asciminib and DAS plus prednisone in BCR-ABL1+ ALL is feasible. Primary toxicity is asymptomatic amylase and lipase elevation. Enrollment continues at DL2 under CTCAEv5 to further define safety profile and determine MTD. An expansion cohort of 10 pts (age ≥18 yrs) at the RP2D is planned.

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