Trial in Progress: Asciminib in Monotherapy 4 CML (AIM4CML), a Phase IIIb Study of Asciminib Monotherapy in Patients with Chronic Myeloid Leukemia in Chronic Phase without or with T315I Mutations
Authors: Andorsky David , Tomassetti Sarah , Deutsch Yehuda E. , Broun E Randolph , Issa Ghayas C. , Levy Moshe Y. , Deininger Michael W. , Maegawa Rodrigo , Shrestha Alok , Mauro Michael J. 
Published: November 2021

Abstract
BACKGROUND: Chronic myeloid leukemia (CML) is driven by the constitutively active BCR-ABL1 tyrosine kinase. Several adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) are approved that inhibit BCR-ABL1 activity, and these have transformed CML from a fatal disease to a chronic one with near-normal life expectancy. However, many patients (pts) experience resistance to or intolerance of successive lines of TKI therapy. These pts have poor outcomes and few remaining treatment options. Moreover, pts with CML harboring the T315I mutation have limited treatment options as they are resistant to all approved TKIs except for ponatinib. Hence, there is a need for new CML therapies that are effective and well tolerated. Asciminib is an investigational agent with a novel mechanism of action. It is the first BCR-ABL1 inhibitor that inhibits BCR-ABL1 kinase activity by Specifically Targeting the ABL Myristoyl Pocket (STAMP). This contrasts with approved TKIs that target the ATP site of BCR-ABL1 to inhibit its kinase activity but are not entirely BCR-ABL1-specific and may target other kinases.
In the phase III ASCEMBL trial in pts with CML in chronic phase (CP) after prior treatment with ≥2 ATP-competitive TKIs, asciminib showed superior efficacy vs bosutinib: major molecular response (MMR; BCR-ABL1 on the International Scale ≤0.1%) rate at week 24 was 25.5% vs 13.2%, respectively. In a large phase I trial, asciminib demonstrated promising efficacy and safety in pts with CML-CP without the T315I mutation previously treated with ≥2 TKIs and in those with the T315I mutation previously treated with ≥1 TKI: by 6 months, 37% and 25% of pts, respectively, achieved or maintained an MMR. Here, we describe the AIM4CML trial that was initiated to further assess the efficacy and safety of asciminib and explore a once-daily (QD) dosing regimen in pts with CML-CP (ClinicalTrials.gov, NCT04666259).
DESIGN: This is a multicenter, phase IIIb, open-label, 3-cohort study of asciminib in pts with CML-CP without T315I after ≥2 prior TKIs and pts with T315I after ≥1 prior TKI (Figure 1). Adults aged ≥18 years with a diagnosis of CML-CP are eligible. Pts must have treatment failure with (as per 2020 European LeukemiaNet recommendations) or intolerance of the most recent TKI at screening. Key eligibility criteria are described in Table 1. Pts without the T315I mutation will undergo random selection to receive either asciminib 40 mg twice daily (BID; cohort A) or 80 mg QD (cohort B); those with the T315I mutation will receive asciminib 200 mg BID (cohort C).
OBJECTIVES AND ENDPOINTS: The primary objective is to evaluate the safety profile of asciminib 40 mg BID and 80 mg QD in pts with CML-CP without T315I after ≥2 prior TKIs and of asciminib 200 mg BID in pts with T315I after ≥1 prior TKI. Primary endpoint analyses include incidence and severity of adverse events (AEs), serious AEs, changes in laboratory values and vital signs, and incidence of notable electrocardiogram abnormalities for 24 weeks. Primary and secondary study objectives/endpoints are summarized in Table 2.
CONCLUSIONS: The AIM4CML study is currently enrolling pts across multiple sites in the United States, with an anticipated enrollment of approximately 115 heavily pretreated pts with CML-CP. Asciminib has the potential to transform the standard of care in this pt population through its novel mechanism of action as a BCR-ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP).
This study is sponsored by Novartis.
Figure 1 Figure 1.

Disclosures
Andorsky: AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Research Funding; AstraZeneca: Other: served on steering committees; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding. Tomassetti: Seagene: Research Funding; Rigel: Research Funding; Beigene: Research Funding; Natera: Research Funding; Novartis: Research Funding; Parexel: Research Funding. Deutsch: Astellas: Membership on an entity's Board of Directors or advisory committees. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Levy: Dova: Consultancy, Other: Promotional speaker; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy. Maegawa: Novartis Pharmaceuticals Corporation: Current Employment, Current equity holder in publicly-traded company. Shrestha: Novartis: Current Employment. Mauro: Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding.