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Phase I study of veliparib in combination with gemcitabine.
- Source :
-
Cancer Chemotherapy & Pharmacology . Sep2017, Vol. 80 Issue 3, p631-643. 13p. - Publication Year :
- 2017
-
Abstract
- <bold>Background: </bold>Veliparib (ABT-888) is an oral PARP inhibitor expected to increase gemcitabine activity. This phase I determined the maximal tolerable dose (MTD), dose-limiting toxicities (DLT), antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib combined with gemcitabine.<bold>Methods: </bold>Patients with advanced solid tumors received veliparib (10-40-mg PO BID) on chemotherapy weeks with gemcitabine 500-750-mg/m2 IV on days 1, 8, and 15 (28-day cycle), or on days 1 and 8 (21-day cycle). The MTD, DLT, adverse events, PK, and PD were evaluated.<bold>Results: </bold>Eleven patients were enrolled on the 28-day schedule. The 28-day schedule was considered intolerable and amended to a 21-day schedule, with 20 patients enrolled. Grade ≥ 3 adverse events were myelosuppression-related. The MTD was determined to be 750-mg/m2 gemcitabine IV on days 1 and 8- and 20-mg PO veliparib BID days 1-14 on a 21-day schedule. Of 27 patients evaluable for response, 3 had PR and 15 had SD. There was no evidence of any major drug-drug interaction, and PK parameter values for veliparib, gemcitabine, and dFdU were as expected. Analysis of PBMCs showed evidence of PARP inhibition and DNA damage associated with therapy.<bold>Conclusions: </bold>Gemcitabine at 750-mg/m2 IV on days 1 and 8 combined with veliparib at a dose of 20-mg PO BID days 1-14 on a 21-day schedule is relatively well-tolerated, with manageable, expected toxicities. Clinical responses were observed in a pretreated population of patients, suggesting that this combination should be further evaluated in the phase II setting. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ANTINEOPLASTIC agents
*PHARMACOKINETICS
*PHARMACODYNAMICS
*CANCER chemotherapy
*DNA damage
*DRUG therapy
*CLINICAL trials
*COMPARATIVE studies
*HETEROCYCLIC compounds
*RESEARCH methodology
*MEDICAL cooperation
*RESEARCH
*RESEARCH funding
*TUMORS
*EVALUATION research
*DEOXYCYTIDINE
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 80
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 124846255
- Full Text :
- https://doi.org/10.1007/s00280-017-3409-3