TY - JOUR
T1 - Exposure–response of veliparib to inform phase II trial design in refractory or relapsed patients with hematological malignancies
AU - Mehrotra, Shailly
AU - Gopalakrishnan, Mathangi
AU - Gobburu, Jogarao
AU - Ji, Jiuping
AU - Greer, Jacqueline M.
AU - Piekarz, Richard
AU - Karp, Judith E.
AU - Pratz, Keith W.
AU - Rudek, Michelle A.
N1 - Funding Information:
The project described was supported in part by NCI Cooperative Agreement U01 CA070095 and UM1CA186691 (J.E. Karp and M.A. Rudek) and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 TR 001079). Grant Number UL1 TR 001079 is from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research.
Publisher Copyright:
©2017 AACR.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated a 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure–response analysis to inform the phase II trial design. Experimental Design: Pharmacokinetic, efficacy, and safety data from 95 patients, who were administered 10 to 100 mg b.i.d. 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. Results: The odds of having objective response were 1.08-fold with 1,000 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 1,000 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 1,000 ng.h/mL increase in AUC. 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 b.i.d. for at least 14 days in combination with T+C is recommended to be studied in MPN patients.
AB - Purpose: A phase I trial of veliparib in combination with topotecan plus carboplatin (T+C) demonstrated a 33% objective response rate in patients with hematological malignancies. The objective is to perform exposure–response analysis to inform the phase II trial design. Experimental Design: Pharmacokinetic, efficacy, and safety data from 95 patients, who were administered 10 to 100 mg b.i.d. 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. Results: The odds of having objective response were 1.08-fold with 1,000 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 1,000 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 1,000 ng.h/mL increase in AUC. 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 b.i.d. for at least 14 days in combination with T+C is recommended to be studied in MPN patients.
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U2 - 10.1158/1078-0432.CCR-17-0143
DO - 10.1158/1078-0432.CCR-17-0143
M3 - Article
C2 - 28751440
AN - SCOPUS:85033571364
VL - 23
SP - 6421
EP - 6429
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 21
ER -