A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph⁺) Leukemias Including Patients with T315I Mutation

DCC-2036 is a novel and potent tyrosine kinase inhibitor (TKI) which binds to a novel region called the switch pocket, thereby preventing BCR-ABL from adopting a conformationally active state. Efficacy against multiple imatinib-resistant BCR-ABL mutants has been demonstrated both in vitro and in vivo (Chan et al., Cancer Cell 2011;19:556). Importantly, DCC-2036 retains full potency against the T315I mutant in preclinical efficacy studies.

This study was designed to find the maximal tolerated dose (MTD) of DCC-2036 when administered daily as a single-agent on a 28-day cycle. Eligible patients included adults with Ph+ CML/ALL who were refractory/intolerant to ≥2 TKI's or were T315I positive. Initially DCC-2036 capsules were administered orally once daily (QD) at increasing dose levels. Only 1 patient was enrolled in each of the lowest dose cohorts of 57mg QD and 114 mg QD. For higher doses, 3– 6 patients were enrolled into each ascending dose cohort with standard dose limiting toxicity (DLT) rules evaluating safety in cycle 1 to determine dose escalation. A transition from unformulated capsules (C) to formulated tablets (T) occurred after the 1200 mg QD dose level. Paired blood samples were obtained for PK and PD assessments.

30 patients (16 males, 14 females; median age 59, range 31 – 80) with CML including 19 in Chronic (CP); 8 in Accelerated (AP) and 3 in Blast (BP) Phase were enrolled. Enrolled patients had received 1–6 prior CML treatments, and 11 patients had the T315I mutation. To date, a total of 212.5 (median 5.6; range 0.2 – 23.4) 28-day cycles were administered over 10 dose levels either as C (7 dose levels) or T (3 dose levels). The 7 C dose levels were studied first and included 57 mg QD through 1200 mg QD. Following transition to T, evaluation continued with 100 mg QD, 100 mg twice daily (BID), and 200 mg BID. Two reversible DLTs (Grade 3 peripheral neuropathy and Grade 4 lower extremity weakness) occurred during the initial treatment cycle at the 200 mg T BID dose level. Evaluation of 6 patients at the 150 mg T BID dose level determined that dose to be the MTD.

Preliminary safety data show that other Grade (Gr) 3/4 adverse events (AEs) were Gr 3 slurred speech and Gr 3 eruptive nevi. Gr 1/2 AEs included dry mouth, constipation, diarrhea, paresthesias, and retinal vein occlusion. There was 1 case of Gr 2 pancreatitis that recurred on rechallenge in a patient with previous pancreatitis with nilotinib.

Preliminary responses include one major molecular response in a CP patient with T315I mutation who started on capsules and transitioned to 100 mg T QD. There was one complete cytogenetic response in a CP patient at 100 mg T BID, and one partial cytogenetic response in a CP patient who started on capsules and transitioned to 100 mg T BID. One patient with AP CML and T315I mutation had a complete hematologic response at 450 mg C QD. Another patient with AP CML had a partial hematologic response after receiving 200 mg BID for 1 cycle and then downdosing to 100 mg T BID. Four out of 8 patients receiving 100 mg tablets and evaluable for efficacy (completed 3 cycles of treatment) had responses.

PK results indicate dose-related, nonlinear increases in both peak plasma concentration (Cmax) and exposure (AUC). PD results reveal both acute and steady state post-treatment reductions in phospho-protein levels on Days 1 and 8. Marked reductions in pSTAT5 and pCRKL have been observed in subjects with both CP and AP and appear to be required for clinical response.

The MTD of DCC-2036 tablets is 150 mg BID. Preliminary results suggest that DCC-2036 is well tolerated and has anti-leukemia activity in subjects with refractory CML and T315I positive disease. PD results are consistent with inhibition of BCR-ABL signaling in this first-in-man study of a switch pocket tyrosine kinase inhibitor.

Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Bixby:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Rafferty:Deciphera Pharmaceuticals: Employment. Berger:Deciphera Pharmaceuticals: Employment. Wise:Deciphera Pharmaceuticals LLC: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment. Smith:Deciphera Pharmaceuticals: Employment. Van Etten:Deciphera Pharmaceuticals: Consultancy, Research Funding.