A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix

An NRG oncology/gynecologic oncology group study

Charles Kunos, Wei Deng, Dawn Dawson, Jayanthi S. Lea, Kristine M. Zanotti, Heidi J. Gray, David P. Bender, Perry P. Guaglianone, Jori S. Carter, Kathleen N. Moore

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. Experimental Design: This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m2) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. Results: Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. Conclusions: Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.

Original languageEnglish (US)
Pages (from-to)484-492
Number of pages9
JournalInternational Journal of Gynecological Cancer
Volume25
Issue number3
DOIs
StatePublished - Mar 10 2015

Fingerprint

Topotecan
Cervix Uteri
Carcinoma
Uterine Cervical Neoplasms
Poly(ADP-ribose) Polymerases
Disease Progression
Therapeutics
Triage
Leukopenia
Neutropenia
Thrombocytopenia
pegfilgrastim
veliparib
Filgrastim
Anemia
Neutrophils
Research Design
Biomarkers
Confidence Intervals
Survival

Keywords

  • Cervical cancer
  • Poly (ADP-ribose) polymerase
  • Topotecan
  • Veliparib

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix : An NRG oncology/gynecologic oncology group study. / Kunos, Charles; Deng, Wei; Dawson, Dawn; Lea, Jayanthi S.; Zanotti, Kristine M.; Gray, Heidi J.; Bender, David P.; Guaglianone, Perry P.; Carter, Jori S.; Moore, Kathleen N.

In: International Journal of Gynecological Cancer, Vol. 25, No. 3, 10.03.2015, p. 484-492.

Research output: Contribution to journalArticle

Kunos, Charles ; Deng, Wei ; Dawson, Dawn ; Lea, Jayanthi S. ; Zanotti, Kristine M. ; Gray, Heidi J. ; Bender, David P. ; Guaglianone, Perry P. ; Carter, Jori S. ; Moore, Kathleen N. / A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix : An NRG oncology/gynecologic oncology group study. In: International Journal of Gynecological Cancer. 2015 ; Vol. 25, No. 3. pp. 484-492.
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abstract = "Purpose: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. Experimental Design: This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m2) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. Results: Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59{\%}), thrombocytopenia (44{\%}), leukopenia (22{\%}), and neutropenia (19{\%}). There were 2 partial responses (7{\%} [90{\%} confidence interval, 1{\%}-22{\%}]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. Conclusions: Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.",
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