Randomized, Open-Label, Multicenter, Phase 2 Study of Asciminib (ABL001) As an Add-on to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response with Frontline Imatinib
Authors: Saglio Giuseppe , Hughes Timothy P. , Geissler Jan , Kapoor Shruti , Longin Anne-Sophie , Mukherjee Ayon , Cortes Jorge E. 
Published: November 2019

Background: In patients with chronic myeloid leukemia in chronic phase (CML-CP), the efficacy of ATP-competitive tyrosine kinase inhibitors (TKIs) has resulted in treatment-free remission (TFR) as a primary treatment goal for those with a sustained deep molecular response (DMR). However, most patients treated with imatinib fail to achieve a sustained DMR, meaning that they cannot benefit from TFR.
Asciminib is a potent and specific inhibitor of BCR-ABL1. Unlike BCR-ABL1 TKIs that target the ATP binding site, asciminib binds to the myristate pocket of ABL1. Preclinical data showed that the combination of asciminib with ATP-competitive TKIs may provide more potent BCR-ABL1 inhibition and prevent emergence of resistance mutations (Wylie et al. Nature. 2017;543:733-737). In an ongoing phase 1 study (NCT02081378), asciminib demonstrated clinical activity and was well tolerated as a single agent (Hughes et al. Blood. 2016;128 [abstract 625]). In the same study, asciminib in combination with imatinib showed promising preliminary efficacy and a good safety profile in patients resistant/intolerant of ≥2 prior TKIs (Cortes et al. HemaSphere. 2019;3(S1) [abstract S388]). These findings informed the dose of asciminib to be further evaluated in combination with imatinib.
An ongoing phase 3 study (NCT03106779) is evaluating asciminib vs bosutinib in patients previously treated with ≥2 ATP-binding site TKIs (Mauro et al. J Clin Oncol. 2019;37 [abstract TPS7070]). Here, we describe the ASCiminib add-on 4-arm study evaluating MOlecular REsponse (ASC4MORE) in patients. This is a phase 2 study evaluating the efficacy of adding asciminib to ongoing imatinib therapy in patients with CML-CP who have not achieved DMR with long-term frontline imatinib (CABL001E2201; NCT03578367).
Methods: Study participants are aged ≥18 years, have CML-CP, and have been treated with frontline imatinib for ≥12 months. Study entry requires patients to be receiving imatinib 400 mg once daily (QD) at randomization, have BCR-ABL1 transcript levels in the range of ≤1% to >0.01% on the International Scale (IS), no prior achievement of MR4 (BCR-ABL1IS ≤0.01%) confirmed by two consecutive tests, and no prior treatment failure. Overall, ~80 patients will be randomized 1:1:1:1 to one of four arms (Figure): either asciminib 40 mg QD or 60 mg QD added to imatinib 400 mg QD; continued treatment with imatinib 400 mg QD; or switch to nilotinib 300 mg twice daily. Study treatment will continue until treatment resistance or intolerance, or up to 96 weeks after the last randomized patient has begun treatment. The primary objective of this study is to assess whether asciminib add-on to imatinib is more effective than imatinib continuation; the primary endpoint is the rate of MR4.5 (BCR-ABL1IS ≤0.0032%) at 48 weeks. Secondary objectives include: to estimate the efficacy of switch to nilotinib; to estimate the difference in efficacy between asciminib add-on to imatinib and switch to nilotinib; and to characterize the safety of asciminib add-on to imatinib. Exploratory objectives include TFR eligibility at the end of the study and patient-reported outcomes. Patients in the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross over to receive add-on asciminib. This study is ongoing, with 23 patients randomized as of 22 July 2019.

Disclosures
Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. Geissler:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Amgen: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Biomarin: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; UCB: Consultancy, Speakers Bureau; Servier: Consultancy. Kapoor:Novartis: Employment. Longin:Novartis: Employment. Mukherjee:Novartis: Employment. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.