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.

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.

• Authors: 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
• Journal: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) Vol. 25 Issue 3 Pg. 484-92 (Mar 2015) ISSN: 1525-1438 [Electronic] England
• PMID: 25594147 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzimidazoles
• Cell Cycle Proteins
• Recombinant Proteins
• veliparib
• Granulocyte Colony-Stimulating Factor
• pegfilgrastim
• Polyethylene Glycols
• Topotecan
• RRM2B protein, human
• Ribonucleotide Reductases
• PARP1 protein, human
• PARP2 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Filgrastim

Topics

• Adult
• Aged
• Anemia (chemically induced)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Benzimidazoles (administration & dosage, adverse effects)
• Carcinoma (chemistry, drug therapy)
• Cell Cycle Proteins (analysis)
• Disease Progression
• Female
• Filgrastim (therapeutic use)
• Granulocyte Colony-Stimulating Factor (therapeutic use)
• Humans
• Middle Aged
• Neoplasm Recurrence, Local (chemistry, drug therapy)
• Neutropenia (chemically induced, prevention & control)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (analysis)
• Polyethylene Glycols
• Recombinant Proteins (therapeutic use)
• Ribonucleotide Reductases (analysis)
• Thrombocytopenia (chemically induced)
• Topotecan (administration & dosage, adverse effects)
• Uterine Cervical Neoplasms (chemistry, drug therapy)