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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
  1. Charles Kunos, MD, PhD*,
  2. Wei Deng, PhD,
  3. Dawn Dawson, MD,
  4. Jayanthi S. Lea, MD§,
  5. Kristine M. Zanotti, MD,
  6. Heidi J. Gray, MD,
  7. David P. Bender, MD#,
  8. Perry P. Guaglianone, MD**,
  9. Jori S. Carter, MD, MS†† and
  10. Kathleen N. Moore, MD‡‡
  1. *Summa Cancer Institute, Summa Health System, Akron, OH;
  2. NRG Oncology/Gynecologic Oncology Group Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY;
  3. Case Western Reserve University, Cleveland, OH;
  4. §UT Southwestern Medical Center, Dallas, TX;
  5. University Hospitals Case Medical Center, Cleveland, OH;
  6. University of Washington, Seattle, WA;
  7. #University of Iowa, Iowa City, IA;
  8. **Decatur Memorial Hospital, Cancer Care Specialists of Central Illinois, Decatur, IL;
  9. ††Virginia Commonwealth University, Richmond, VA; and
  10. ‡‡Oklahoma University Health Science Center, Oklahoma City, OK.
  1. Address correspondence and reprint requests to Charles Kunos, MD, PhD, Department of Radiation Oncology, Summa Cancer Institute, 161 N Forge St, Akron, OH 44304. E-mail: kunosc@summahealth.org.

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.

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

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Footnotes

  • This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical Office (CA 37517), and NRG Oncology (1 U10 CA180822).

  • The authors declare no conflicts of interest.

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