Exposure-Response of Veliparib to Inform Phase II Trial Design in Refractory or Relapsed Patients with Hematological Malignancies

Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure-response analysis to inform the phase II trial design. <p>Experimental Design: Pharmacokinetic, efficacy and safety data from 95 patients, who were administered 10 to 100 mg BID doses of veliparib for either 8, 14 or 21 days with T+C, were utilized for exposure-efficacy (objective response and overall survival) and exposure-safety (≥Grade 3  mucositis) analysis. Multivariate cox proportional hazards and logistic regression analyses were conducted. The covariates evaluated were disease status, duration of treatment and number of prior therapies.</p> <p>Results: The odds of having objective response were 1.08-fold with 1000 ng.hr/mL increase in AUC, 1.8-fold with >8 days treatment, 2.8-fold in patients with myeloproliferative neoplasms (MPN) and 0.5-fold with ≥2 prior therapies. Based on analysis of overall survival, hazard of death decreased by 1.5% for 1000 ng.hr/mL increase in AUC, 39% with >8 days treatment, 44% in patients with MPN, while increased by 19% with ≥2 prior therapies. The odds of having ≥Grade 3 mucositis increased by 29% with 1000 ng.hr/mL increase in AUC.</p> Conclusions: Despite shallow exposure-efficacy relationship, doses lower than 80 mg do not exceed veliparib single agent preclinical IC₅₀. Shallow exposure-mucositis relationship also supports the 80 mg dose. Based on benefit/risk assessment, veliparib at a dose of 80 mg BID for at least 14 days in combination with T+C is recommended to be studied in MPN patients.

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