Phase I study of NRC-an-019, a tyrosine kinase inhibitor, in imatinib-resistant chronic myeloid leukemia (CML) in an Indian tertiary care hospital.

Abstract

7080 Background: NRC-AN-019 is an orally administered tyrosine kinase inhibitor (TKI) of the Bcr-Abl protein-tyrosine kinase. The drug was given to patients as a ready-to-use liquid formulation. Methods: The primary objectives of the Phase-I study were to estimate the Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) of NRC-AN-019 and also to establish the safe dose for Phase II clinical trial. The secondary objectives were to study the pharmacokinetic properties and antileukemic activity of NRC-AN-019. Philadelphia positive CML patients in all phases, in the age group of 18-65 years were eligible. They had to be resistant or intolerant to Imatinib, with ECOG ≤ 2. Dosing was initiated at 50 mg/day and dose escalation was done in increments of 50 mg per each additional cohort. The maximum dose administered was 450 mg/day. The protocol-specific study duration was 30 days; patients continued to receive the study drug subsequently based on Investigator’s decision. Results: A total of 30 patients were enrolled (3 at 50 mg, 4 at 100 mg, 3 at 150 mg, 3 at 200 mg, 4 at 250 mg, 4 at 300 mg, 3 at 350 mg, 3 at 400 mg, and 3 at 450 mg). DLT was not observed and MTD was not reached. The recommended Phase II-A dose is 300 mg/day, with a scope for escalation up to 450 mg/day. The maximum plasma concentration of NRC-AN-019 was 9,342 ng/mL and AUC was 1,262,191 ng.hr/mL. Common adverse events were skin rash, nausea, and vomiting. Hematological response was observed in 11 patients, cytogenetic response in 7 patients and molecular response in 5 patients. The maximum duration a patient has been on NRC-AN-019 is 863 days. Conclusions: Based on the Phase-I data, NRC-AN-019 showed considerable safety and response; it could be a potential treatment option for imatinib-resistant CML. Clinical trial information: CTRI/2009/091/000204.