Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer

Shivaani Kummar, James L. Wade, Amit M. Oza, Daniel Sullivan, Alice P. Chen, David R Gandara, Jiuping Ji, Robert J. Kinders, Lihua Wang, Deborah Allen, Geraldine O’Sullivan Coyne, Seth M. Steinberg, James H. Doroshow

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.

Original languageEnglish (US)
Pages (from-to)355-363
Number of pages9
JournalInvestigational New Drugs
Volume34
Issue number3
DOIs
StatePublished - Jun 1 2016

Fingerprint

Triple Negative Breast Neoplasms
Cyclophosphamide
Mutation
Lymphopenia
Poly(ADP-ribose) Polymerases
Poly(ADP-ribose) Polymerase Inhibitors
veliparib
Cytotoxins
Therapeutics
DNA Damage
Disease-Free Survival
Disease Progression
Appointments and Schedules
Cell Death
Drug Therapy

Keywords

  • BRCA
  • DNA damage repair
  • HR defect
  • Metronomic cyclophosphamide
  • PARP inhibition

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer. / Kummar, Shivaani; Wade, James L.; Oza, Amit M.; Sullivan, Daniel; Chen, Alice P.; Gandara, David R; Ji, Jiuping; Kinders, Robert J.; Wang, Lihua; Allen, Deborah; Coyne, Geraldine O’Sullivan; Steinberg, Seth M.; Doroshow, James H.

In: Investigational New Drugs, Vol. 34, No. 3, 01.06.2016, p. 355-363.

Research output: Contribution to journalArticle

Kummar, S, Wade, JL, Oza, AM, Sullivan, D, Chen, AP, Gandara, DR, Ji, J, Kinders, RJ, Wang, L, Allen, D, Coyne, GOS, Steinberg, SM & Doroshow, JH 2016, 'Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer', Investigational New Drugs, vol. 34, no. 3, pp. 355-363. https://doi.org/10.1007/s10637-016-0335-x
Kummar, Shivaani ; Wade, James L. ; Oza, Amit M. ; Sullivan, Daniel ; Chen, Alice P. ; Gandara, David R ; Ji, Jiuping ; Kinders, Robert J. ; Wang, Lihua ; Allen, Deborah ; Coyne, Geraldine O’Sullivan ; Steinberg, Seth M. ; Doroshow, James H. / Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer. In: Investigational New Drugs. 2016 ; Vol. 34, No. 3. pp. 355-363.
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abstract = "Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.",
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AU - Oza, Amit M.

AU - Sullivan, Daniel

AU - Chen, Alice P.

AU - Gandara, David R

AU - Ji, Jiuping

AU - Kinders, Robert J.

AU - Wang, Lihua

AU - Allen, Deborah

AU - Coyne, Geraldine O’Sullivan

AU - Steinberg, Seth M.

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N2 - Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.

AB - Background In tumors carrying BRCA mutations, DNA damage caused by standard cytotoxic chemotherapy can be potentiated by poly [ADP-ribose] polymerase (PARP) inhibitors, leading to increased cell death through synthetic lethality. Individuals carrying mutations in BRCA have an increased incidence of triple negative breast cancer (TNBC). In order to assess the role of PARP inhibition in the treatment of TNBC, we conducted a randomized phase II trial of the combination of veliparib, a small molecule PARP inhibitor, with the cytotoxic agent cyclophosphamide versus cyclophosphamide alone in patients with refractory TNBC. Methods Adult patients with TNBC were randomized to receive oral cyclophosphamide 50 mg once daily with or without oral veliparib at 60 mg daily in 21-day cycles. Patients on the cyclophosphamide arm could crossover to the combination arm at disease progression. Results Forty-five patients were enrolled; 18 received cyclophosphamide alone and 21 received the combination as their initial treatment regimen. Lymphopenia was the most common grade 3/4 toxicity noted in both arms. One patient in the cyclophosphamide alone arm, and 2 in the combination arm had objective responses. Response rates and median progression free survival did not significantly differ between both treatment arms. Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer.

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