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

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Novel Therapies for ALL
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Clinical Research, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Monday, December 11, 2023: 5:30 PM

Marlise R. Luskin, MD1, Mark Alan Murakami, MD, MA, MMSc2, Julia Keating, MS3*, Eric S. Winer, MD2, Jacqueline S. Garcia, MD4, Maximilian Stahl, MD5, Martha Wadleigh, MD2, Yael Flamand, MS2*, Donna S. Neuberg, ScD3, Ilene Galinsky, ANP4, Rebecca Leonard4*, Ella Hagopian2*, Chase M Weizer2*, Carlin McLanahan6*, Richard M Stone, MD2, Eunice S. Wang, MD7, Wendy Stock, MD8 and Daniel J. DeAngelo2

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Dana-Farber Cancer Institute, Boston, MA
3Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
4Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
5Dana Farber Institute, Boston, MA
6Dana-Farber Cancer Institute, Boston
7Roswell Park Cancer Institute, Buffalo, NY
8University of Chicago Medicine, Chicago, IL

Introduction: Oral ABL1 kinase inhibitors rapidly produce deep remissions in BCR::ABL1+ acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). Second generation TKIs such as dasatinib (DAS) are more effective than imatinib (Foa et al. Blood 2011) but patients may develop resistance. Asciminib (ASC), previously ABL001, is a STAMP (Specifically Targeting the ABL Myristoyl Pocket) allosteric ABL1 inhibitor that binds to a site spatially distinct from 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 active in BCR::ABL1+ ALL and CML-LBC.

Methods: This investigator initiated, phase I study (NCT03595917) of asciminib (ASC) in combination with DAS plus prednisone (pred) for BCR::ABL1+ ALL studied ASC in escalating doses in a 3+3 design with the primary objective to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D); a 10 patient (pt) expansion cohort was then accrued. Secondary objectives define the depth and durability of responses. Pts with BCR::ABL1+ ALL or CML-LBC newly diagnosed ≥ 50 years (yrs), or unfit; or relapsed/refractory (no prior DAS or ASC) were eligible in dose escalation; all pts ≥18 yrs were eligible in dose expansion. Pts received DAS 140 mg/day(d) and pred 60 mg/m2/d 1-24 (max 120 mg/d, tapered d 25-32) with escalating daily doses of ASC (DL1: 40 mg; DL2: 80 mg; DL3: 160 mg). DAS and ASC were given in 28-d cycles indefinitely in setting of clinical benefit, with allogeneic stem cell transplant (SCT) consolidation after d85 per treating physician. Dose-limiting toxicity (DLT) was initially defined as CTCAEv4 non-heme toxicity grade (gr) 3+; the study was amended to assess DLT via CTCAEv5. Correlative science efforts seek to define biomarkers of response and resistance to dual ABL1 blockade.

Results: The study enrolled 25 pts (48% female), with 14 in dose escalation (13 evaluable), and 11 in expansion (10 evaluable). Most (92%) had new ALL (p190: 15/23, p210: 8/23; 8% had CML-LBC. Median age was 65 yrs (range 33 – 85; 8 pts 70+). Median WBC was 15.1 K/μL (range 0.9 – 251.9 K/μL). No pt had CNS disease. DL1 and DL2 enrolled 3 pts each without DLT. Two of 3 pts at DL3 developed asymptomatic CTCAEv4 gr 3 amylase elevation during C1 meeting original DLT criteria. A 4th pt enrolled on re-opened DL3 under an amendment defining asymptomatic 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. Thus, the study de-escalated to DL2, re-opening under an amendment assessing DLTs via CTCAEv5. Of note, all DLTs at DL3 would be gr <3 per CTCAEv5. Four more pts (3 evaluable) enrolled at DL2 without a DLT. Thus, ASC 80 mg/d was declared the RP2D, and 11 pts age ≥18 yrs enrolled in an expansion cohort, 10 of whom initiated study treatment. No pt had symptomatic pancreatitis. Rates of molecular response after 3 cycles among all evaluable patients were 58.3% (14/24) for MRD 3.0 and 25.0% (6/24) for MRD 4.0. Evaluable pts with new ALL treated at the RP2D achieved molecular response rates after 3 cycles of 78.6% (11/14) for MRD 3.0 and 42.9% (6/14) for MRD 4.0. Both patients with imatinib-refractory CML-LBC progressed (C9, C3). Of those with ALL, 8 bridged to SCT after 2-8 cycles; 2 elected local care (C5, C7); 1 transitioned to ponatinib for inadequate response plus recurrent DAS pulmonary toxicity (C4); 6 remained on study treatment until disease progression (C4 – MRD+, C45, C11, C11); 3 remain on study. Correlative science evaluation of serial pt biospecimens in pursuit of predictive biomarkers will be shared at the meeting.

Conclusion: Dual ABL1 kinase inhibition with ASC and DAS plus pred in BCR::ABL1+ ALL and CML-LBC is feasible and tolerable in adults with BCR::ABL1+ ALL and CML-LBC. DLTs at ASC 160 mg/d were asymptomatic amylase and lipase elevation, without clinical sequelae. ASC 80 mg/day was declared the RP2D, and an expansion cohort of 10 pts was completed. High rates of molecular response and bridging to transplant highlight encouraging preliminary activity. A phase II expansion cohort incorporating blinatumomab is now open.

Disclosures: Luskin: Pfizer: Honoraria; Novartis: Research Funding; Novartis: Honoraria; Jazz: Honoraria; AbbVie: Research Funding. Murakami: Novartis AG: Membership on an entity's Board of Directors or advisory committees; imCORE (Genentech/Roche): Research Funding. Winer: Curis Inc: Consultancy; Abbvie: Consultancy. Garcia: Gilead: Consultancy; Bristol Myers Squibb: Consultancy; Astellas: Consultancy; AbbVie: Consultancy, Research Funding; Prelude: Research Funding; Pfizer: Research Funding; New Wave: Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy; AstraZeneca: Research Funding. Stahl: Clinical care options: Other: GME activity ; Curis Oncology: Other: GME activity ; GSK: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Boston Consulting: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Haymarket Media: Other: GME activity ; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Kymera: Membership on an entity's Board of Directors or advisory committees; Dedham group: Consultancy. Neuberg: Madrigal Pharmaceuticals: Current equity holder in private company. Stone: Ligand Pharma: Consultancy; Hermavant: Consultancy; Lava Therapeutics: Consultancy; AvenCell: Consultancy; Takeda: Other: DSMB; Cellularity: Consultancy; Abbvie: Consultancy; Kura One: Consultancy; Rigel: Consultancy; Syntrix: Other: DSMB; CTI Biopharma: Consultancy; BerGenBio: Consultancy; Epizyme: Other: DSMB; Aptevo: Other: DSMB; GSK: Consultancy; Amgen: Consultancy; Jazz: Consultancy. Wang: Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy; PharmaEssentia: Consultancy; Dava oncology: Speakers Bureau; Kite: Consultancy, Speakers Bureau; Jazz: Consultancy; Novartis: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy; Kura Oncology: Speakers Bureau; Gilead: Consultancy; BMS: Consultancy; Astellas: Consultancy, Speakers Bureau; Abbvie: Consultancy. Stock: Amgen: Honoraria; Kite: Consultancy; Kura: Research Funding; Servier: Other: Data Safety Monitoring Board/Advisory Board; Newave: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy. DeAngelo: Jazz: Honoraria; Amgen: Honoraria; Servier: Honoraria; Takeda: Honoraria; Blueprint: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Novartis: Research Funding; GlycoMimetics: Research Funding; Kite: Honoraria; Incyte: Honoraria; Autolus: Honoraria; Blueprint: Honoraria.

*signifies non-member of ASH