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Background: ABL001 is a potent, specific BCR-ABL inhibitor in development for the treatment of patients with CML and Ph+ ALL. ABL001 binds a pocket on the BCR-ABL kinase domain normally occupied by the autoregulatory myristoylated N-terminus of ABL1, which is lost upon fusion with BCR. ABL001 was designed to inhibit BCR-ABL in a non-ATP-competitive manner to maintain activity against BCR-ABL mutations that confer resistance to TKIs. Preclinically, combined with ATP-competitive TKIs, ABL001 eliminates early leukemic progenitors and diminishes emergence of resistant clones. Methods: Patients with CML-CP, -AP, or -BP with failure of ≥ 2 prior TKIs and Ph+ ALL patients with failure of ≥ 1 prior TKI due to resistance or intolerance were enrolled in this first-in-human, multicenter, open-label phase 1 dose-escalation study (CABL001X2101). Escalating doses of single-agent ABL001 were administered orally on continuous twice-daily (BID) or once-daily (QD) schedules or in combination with imatinib, nilotinib, or dasatinib. Therapy continued until disease progression, unacceptable toxicity, consent withdrawal, or death. Primary objectives were to estimate the maximum tolerated dose (MTD) of ABL001 administered as single agent or combined with TKIs. Secondary objectives included safety, preliminary efficacy, and pharmacokinetics of ABL001 alone and combined with TKIs. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) in cycle 1. Results: At data cutoff, 101 CML and Ph+ ALL patients had received ABL001 as either single agent or in combination. 67 CML and 6 Ph+ ALL patients have been treated at single-agent BID doses: 10 mg (n = 1), 20 mg (n = 14), 40 mg (n = 30), 80 mg (n = 14), 150 mg (n = 9), 200 mg (n = 5), with MTD not reached. A dose of 40 mg BID has been recommended for CML-CP patients. 19 CML patients have been treated with single-agent QD doses: 80 mg (n = 3), 120 mg (n = 10), 200 mg (n = 5), with MTD not yet reached. 9 CML patients have been treated in combination with TKIs with dose escalation ongoing. Median age was 55 y (range, 23-79 y). Most patients (98%) had baseline ECOG status 0-1. Patients were heavily pretreated; 65 (65%) had received > 2 prior TKIs. 70 patients were resistant to their last TKI. In 84 patients, treatment is ongoing at doses 20-200 mg BID or QD and at respective combination doses, with 17 patients discontinued (disease progression [n = 6], AEs [n = 7], consent withdrawal [n = 4]). Median duration of exposure is 34 wk (range, 0-98 wk). ABL001 pharmacokinetics was dose-proportional with minimal accumulation across dose and time. There were 5 DLTs: 2 Gr 3 lipase elevations (40 mg BID and 200 mg QD), 1 Gr 2 arthralgia (80 mg BID), 1 acute coronary syndrome (150 mg BID), and 1 Gr 3 bronchospasm (200 mg BID). 3 cases of Gr 2 acute pancreatitis occurred in cycle 5 at doses ≥ 80 mg BID. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs suspected related to ABL001 were lipase increase (8%), thrombocytopenia (7%), anemia (5%), and neutropenia (4%). 1 non-study drug-related death due to multiorgan failure occurred. 55 patients (10-200 mg BID) on therapy for ≥ 3 months had efficacy assessments. 7/9 patients in cytogenetic relapse (> 35% Ph+ metaphases at baseline) achieved CCyR by 6 months, with all 7 maintaining CCyR by 12 months. 13 of 55 (23.6%), 16 of 37 (43.2%), and 20 of 55 (57.1%) patients achieved or maintained MMR by 3, 6, and 12 months, respectively. Of 47 patients with baseline BCR-ABL > 0.1 % IS, 6 of 47 (12.8%), 9 of 30 (30%), and 13 of 28 (46.4%) patients achieved MMR by 3, 6 and 12 months, respectively. Of 32 patients with baseline BCR-ABL ≤ 10 % IS, 4 (12.5%), 9 (28%), and 11 (34%) achieved ≥ 1-log reduction of BCR-ABL % IS by 3, 6 and 9 months, respectively, with all maintained at 12 months. 17/20 patients who achieved MMR have maintained it. Clinical activity was seen in multiple TKI-resistant mutations. 7 patients with T3151I were enrolled: 3 achieved CCyR (1 relapse by 6 months) and 1 maintained baseline MMR at median follow-up of 8 months. Only 1/6 relapsed patients had detectable myristoyl-pocket mutations (V468F, I502L). Conclusion: ABL001 appears well tolerated to date and exhibits significant and durable activity in a heavily pretreated subgroup of CML patients. 40 mg BID has been recommended for CML-CP patients. Phase 1 accrual is ongoing for CML patients on QD or combination therapy, with T3151I mutations, and Ph+ ALL patients. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goh:Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ottmann:Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Fusion Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Minami:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Rea:Ariad: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Lang:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mauro:Ariad: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Baxter: Consultancy; Pfizer: Consultancy. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Hochhaus:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Ariad: Research Funding. Breccia:Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Novartis: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heinrich:MolecularMD: Consultancy, Equity Ownership; Novartis: Consultancy, Honoraria, Patents & Royalties; Ariad: Consultancy. Janssen:Pfizer: Honoraria; Novartis: Research Funding; Ariad: Honoraria; BMS: Honoraria. Steegmann:Pfizer: Honoraria, Other: research funding for the Spanish CML group; Novartis: Honoraria, Other: research funding for the Spanish CML group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Ariad: Honoraria, Other: Research funding for the Spanish CML Group. Mahon:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Duan:Novartis Institutes for Biomedical Research, Inc.: Employment. Iyer:Novartis Institutes for Biomedical Research, Inc.: Employment. Hynds:Novartis Institutes for Biomedical Research, Inc.: Employment. Vanasse:Novartis Institutes for Biomedical Research, Inc.: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; II-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.