Phase I study of veliparib in combination with gemcitabine

Ronald Stoller, John C. Schmitz, Fei Ding, Shannon Puhalla, Chandra P. Belani, Leonard Appleman, Yan Lin, Yixing Jiang, Salah Almokadem, Daniel Petro, Julianne Holleran, Brian F. Kiesel, R. Ken Czambel, Benedito A. Carneiro, Emmanuel Kontopodis, Pamela A. Hershberger, Madani Rachid, Alice Chen, Edward Chu, Jan H. Beumer

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)631-643
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume80
Issue number3
DOIs
StatePublished - Sep 1 2017

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gemcitabine
Appointments and Schedules
Pharmacokinetics
Pharmacodynamics
Toxicity
Chemotherapy
veliparib
DNA Damage
Tumors

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Stoller, R., Schmitz, J. C., Ding, F., Puhalla, S., Belani, C. P., Appleman, L., ... Beumer, J. H. (2017). Phase I study of veliparib in combination with gemcitabine. Cancer Chemotherapy and Pharmacology, 80(3), 631-643. https://doi.org/10.1007/s00280-017-3409-3
Stoller, Ronald ; Schmitz, John C. ; Ding, Fei ; Puhalla, Shannon ; Belani, Chandra P. ; Appleman, Leonard ; Lin, Yan ; Jiang, Yixing ; Almokadem, Salah ; Petro, Daniel ; Holleran, Julianne ; Kiesel, Brian F. ; Ken Czambel, R. ; Carneiro, Benedito A. ; Kontopodis, Emmanuel ; Hershberger, Pamela A. ; Rachid, Madani ; Chen, Alice ; Chu, Edward ; Beumer, Jan H. / Phase I study of veliparib in combination with gemcitabine. In: Cancer Chemotherapy and Pharmacology. 2017 ; Vol. 80, No. 3. pp. 631-643.
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abstract = "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.",
author = "Ronald Stoller and Schmitz, {John C.} and Fei Ding and Shannon Puhalla and Belani, {Chandra P.} and Leonard Appleman and Yan Lin and Yixing Jiang and Salah Almokadem and Daniel Petro and Julianne Holleran and Kiesel, {Brian F.} and {Ken Czambel}, R. and Carneiro, {Benedito A.} and Emmanuel Kontopodis and Hershberger, {Pamela A.} and Madani Rachid and Alice Chen and Edward Chu and Beumer, {Jan H.}",
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Stoller, R, Schmitz, JC, Ding, F, Puhalla, S, Belani, CP, Appleman, L, Lin, Y, Jiang, Y, Almokadem, S, Petro, D, Holleran, J, Kiesel, BF, Ken Czambel, R, Carneiro, BA, Kontopodis, E, Hershberger, PA, Rachid, M, Chen, A, Chu, E & Beumer, JH 2017, 'Phase I study of veliparib in combination with gemcitabine', Cancer Chemotherapy and Pharmacology, vol. 80, no. 3, pp. 631-643. https://doi.org/10.1007/s00280-017-3409-3

Phase I study of veliparib in combination with gemcitabine. / Stoller, Ronald; Schmitz, John C.; Ding, Fei; Puhalla, Shannon; Belani, Chandra P.; Appleman, Leonard; Lin, Yan; Jiang, Yixing; Almokadem, Salah; Petro, Daniel; Holleran, Julianne; Kiesel, Brian F.; Ken Czambel, R.; Carneiro, Benedito A.; Kontopodis, Emmanuel; Hershberger, Pamela A.; Rachid, Madani; Chen, Alice; Chu, Edward; Beumer, Jan H.

In: Cancer Chemotherapy and Pharmacology, Vol. 80, No. 3, 01.09.2017, p. 631-643.

Research output: Contribution to journalArticle

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.

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U2 - 10.1007/s00280-017-3409-3

DO - 10.1007/s00280-017-3409-3

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