ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Exhibits Safety and Promising Single- Agent Activity in a Phase I Study of Patients with CML with Failure of Prior TKI Therapy

Background: ABL001 is a potent, specific BCR-ABL inhibitor in development for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. ABL001 binds a pocket on the BCR-ABL kinase domain normally occupied by the myristoylated N terminus of ABL1, which serves an autoregulatory function subsequently lost upon fusion with BCR. ABL001 functionally mimics this autoregulatory role and restores negative regulation of kinase activity. In preclinical studies, ABL001 selectively inhibits the growth of BCR-ABL-positive cells, with activity noted against clinically observed TKI resistance mutations. ABL001 exhibits potent antitumor activity in KCL-22 xenografts, with evidence of complete tumor regression correlating with pSTAT5 inhibition. Animals receiving ABL001 and nilotinib in combination achieved sustained tumor regression without emergence of resistant disease even after treatment discontinuation.

Methods: Patients with CML in chronic or accelerated phase with failure of ≥ 2 prior TKIs due to resistance or intolerance were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CABL001X2101). Escalating doses of single-agent ABL001 were administered orally on a continuous twice daily (BID) dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of ABL001 administered as a single agent, orally, BID. Secondary objectives included safety, preliminary anti-CML activity, and pharmacokinetics of ABL001. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy analysis was based on hematologic, cytogenetic, and molecular assessments.

Results: At data cutoff, 35 patients had been treated at the following BID doses: 10 mg (n = 1), 20 mg (n = 5), 40 mg (n = 12), 80 mg (n = 11), 150 mg (n = 6), and MTD has not yet been reached. Median age was 56 years (range, 23-74 years). Most patients (97%) had baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated; 20 (57%) had received ≥ 3 prior TKIs. In 30 patients, treatment is ongoing at doses 20-150 mg BID, with median duration of exposure of 20.9 weeks (range, 0-49.7 weeks), and 5 patients discontinued (disease progression [n = 1], AEs [n = 3], stem cell transplant [n = 1]). Preliminary data suggests ABL001 pharmacokinetics is dose-proportional with minimal accumulation across dose and time. There were 3 DLTs: 1 grade 3 lipase elevation and 1 grade 2 arthralgia at 40 mg BID and 1 acute coronary syndrome at 150 mg BID. In addition, 3 cases of grade 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 were anemia (9%), thrombocytopenia (6%), neutropenia (6%), and lipase increase (6%). No deaths have occurred on study. 20 patients (10-80 mg) on therapy for ≥ 3 months had hematologic, cytogenetic, and molecular assessments. 17 patients were resistant to and 3 were intolerant of prior TKIs. Evidence of single agent activity was noted at doses ≥ 10 mg BID. All patients in complete hematologic (CHR) or complete cytogenetic (CCyR) response or with BCR-ABL ≤ 0.1 % IS at baseline have maintained responses. All 5 patients in hematologic relapse achieved CHR within 3 months. 9 of 11 TKI-resistant patients in cytogenetic relapse (> 65% Ph+ metaphases at baseline) achieved a major cytogenetic response by 3 months, including 6 who achieved CCyR. Of 17 TKI-resistant patients with baseline BCR-ABL > 0.1 % IS, 11 achieved a ≥ 1-log reduction in BCR-ABL % IS and 5 achieved major molecular response by 5 months. Clinical activity was seen across TKI-resistant mutations, including Y253H and V299L. Only 1 patient in accelerated phase has relapsed on study, with relapse due to a mutation in the myristoyl pocket.

Conclusion: ABL001 exhibits rapid dose-dependent antitumor activity and appears well tolerated to date in a heavily pretreated subgroup of patients with CML, providing proof of principle of the effectiveness of allosteric inhibition of the BCR-ABL kinase in the treatment of CML. The phase 1 study is ongoing in dose escalation.