Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies

Leonard J. Appleman, Jan H. Beumer, Yixing Jiang, Yan Lin, Fei Ding, Shannon Puhalla, Leigh Swartz, Taofeek K. Owonikoko, R. Donald Harvey, Ronald Stoller, Daniel P. Petro, Hussein A. Tawbi, Athanassios Argiris, Sandra Strychor, Marie Pouquet, Brian Kiesel, Alice P. Chen, David Gandara, Chandra P. Belani, Edward ChuSuresh S. Ramalingam

Research output: Contribution to journalArticle

Abstract

Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. Methods: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1–7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard “3 + 3” design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC–MS/MS and AAS during cycles 1 and 2. Results: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1–16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. Conclusion: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.

Original languageEnglish (US)
Pages (from-to)1289-1301
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume84
Issue number6
DOIs
StatePublished - Dec 1 2019

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Carboplatin
Paclitaxel
Pharmacokinetics
Neoplasms
Area Under Curve
Toxicity
Maximum Tolerated Dose
Poly(ADP-ribose) Polymerase Inhibitors
veliparib
Febrile Neutropenia
Chemotherapy
Poly(ADP-ribose) Polymerases
Hyponatremia
Cytotoxins
Peripheral Nervous System Diseases
Neutropenia
Thrombocytopenia
Tumors
Drug Therapy

Keywords

  • Advanced cancer
  • Carboplatin
  • Clinical trial
  • Paclitaxel
  • Phase 1
  • Poly(ADP-ribose) polymerase
  • Veliparib

ASJC Scopus subject areas

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

Cite this

Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies. / Appleman, Leonard J.; Beumer, Jan H.; Jiang, Yixing; Lin, Yan; Ding, Fei; Puhalla, Shannon; Swartz, Leigh; Owonikoko, Taofeek K.; Donald Harvey, R.; Stoller, Ronald; Petro, Daniel P.; Tawbi, Hussein A.; Argiris, Athanassios; Strychor, Sandra; Pouquet, Marie; Kiesel, Brian; Chen, Alice P.; Gandara, David; Belani, Chandra P.; Chu, Edward; Ramalingam, Suresh S.

In: Cancer Chemotherapy and Pharmacology, Vol. 84, No. 6, 01.12.2019, p. 1289-1301.

Research output: Contribution to journalArticle

Appleman, LJ, Beumer, JH, Jiang, Y, Lin, Y, Ding, F, Puhalla, S, Swartz, L, Owonikoko, TK, Donald Harvey, R, Stoller, R, Petro, DP, Tawbi, HA, Argiris, A, Strychor, S, Pouquet, M, Kiesel, B, Chen, AP, Gandara, D, Belani, CP, Chu, E & Ramalingam, SS 2019, 'Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies', Cancer Chemotherapy and Pharmacology, vol. 84, no. 6, pp. 1289-1301. https://doi.org/10.1007/s00280-019-03960-w
Appleman, Leonard J. ; Beumer, Jan H. ; Jiang, Yixing ; Lin, Yan ; Ding, Fei ; Puhalla, Shannon ; Swartz, Leigh ; Owonikoko, Taofeek K. ; Donald Harvey, R. ; Stoller, Ronald ; Petro, Daniel P. ; Tawbi, Hussein A. ; Argiris, Athanassios ; Strychor, Sandra ; Pouquet, Marie ; Kiesel, Brian ; Chen, Alice P. ; Gandara, David ; Belani, Chandra P. ; Chu, Edward ; Ramalingam, Suresh S. / Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies. In: Cancer Chemotherapy and Pharmacology. 2019 ; Vol. 84, No. 6. pp. 1289-1301.
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T1 - Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies

AU - Appleman, Leonard J.

AU - Beumer, Jan H.

AU - Jiang, Yixing

AU - Lin, Yan

AU - Ding, Fei

AU - Puhalla, Shannon

AU - Swartz, Leigh

AU - Owonikoko, Taofeek K.

AU - Donald Harvey, R.

AU - Stoller, Ronald

AU - Petro, Daniel P.

AU - Tawbi, Hussein A.

AU - Argiris, Athanassios

AU - Strychor, Sandra

AU - Pouquet, Marie

AU - Kiesel, Brian

AU - Chen, Alice P.

AU - Gandara, David

AU - Belani, Chandra P.

AU - Chu, Edward

AU - Ramalingam, Suresh S.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. Methods: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1–7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard “3 + 3” design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC–MS/MS and AAS during cycles 1 and 2. Results: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1–16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. Conclusion: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.

AB - Purpose: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. Methods: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1–7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard “3 + 3” design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC–MS/MS and AAS during cycles 1 and 2. Results: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1–16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. Conclusion: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.

KW - Advanced cancer

KW - Carboplatin

KW - Clinical trial

KW - Paclitaxel

KW - Phase 1

KW - Poly(ADP-ribose) polymerase

KW - Veliparib

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