TY - JOUR
T1 - Phase I study of veliparib in combination with gemcitabine
AU - Stoller, Ronald
AU - Schmitz, John C.
AU - Ding, Fei
AU - Puhalla, Shannon
AU - Belani, Chandra P.
AU - Appleman, Leonard
AU - Lin, Yan
AU - Jiang, Yixing
AU - Almokadem, Salah
AU - Petro, Daniel
AU - Holleran, Julianne
AU - Kiesel, Brian F.
AU - Ken Czambel, R.
AU - Carneiro, Benedito A.
AU - Kontopodis, Emmanuel
AU - Hershberger, Pamela A.
AU - Rachid, Madani
AU - Chen, Alice
AU - Chu, Edward
AU - Beumer, Jan H.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - DNA damage
KW - Gemcitabine
KW - PARP
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - Phase I
KW - Solid tumors
KW - Veliparib
UR - http://www.scopus.com/inward/record.url?scp=85026776625&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026776625&partnerID=8YFLogxK
U2 - 10.1007/s00280-017-3409-3
DO - 10.1007/s00280-017-3409-3
M3 - Article
C2 - 28770300
AN - SCOPUS:85026776625
SN - 0344-5704
VL - 80
SP - 631
EP - 643
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 3
ER -