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

Abstract

Purpose 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 1–5 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.

A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852)

“…In the current trial despite all patients having had chemoradiation and over 40% of patients having an adverse histology of adenocarcinoma which is substantially higher than the above trials, the PFS was 6.2 months indicating potential activity of veliparib in this patient population. These results contrast with the phase I/II NRG trial evaluating veliparib and topotecan in a recurrent cervical cancer patient population that had at least one chemotherapy regimen prior to enrollment which found only a 7% clinical benefit rate and did not proceed to phase II [12]. Importantly in this trial, veliparib 10 mg on days 1-5 was likely a sub therapeutic dose and schedule may not have been ideal [18].…”

“…Compared to normal cells, PARP-1 expression is higher in cancer cells, including cervical cancer cells [11]. Additionally, higher expression of PARP-1 in cancer cell lines has been correlated with resistance to chemotherapy and PARPi have been shown to sensitize cancer cells to chemotherapy [12].…”

The prophylactic effects of long-acting granulocyte colony-stimulating factor for febrile neutropenia in newly diagnosed patients with epithelial ovarian cancer: a randomised controlled study

“…However, based on the findings of a systematic review of real-world comparative effectiveness studies, the risks of FN and FN-related complications are generally lower for prophylaxis with pegfilgrastim versus prophylaxis with short-acting G-CSF 8. Regarding patients with gynaecological cancer, filgrastim or pegfilgrastim was integrated in an NRG Oncology/Gynecologic Oncology Group study for the treatment of persistent or recurrent carcinoma of the uterine cervix, in which grade 3/4 neutropenia occurred in 5 of 27 patients (18.5%) 24. In a phase I study of patients with advanced ovarian cancer who were treated with biweekly dose-dense carboplatin/paclitaxel together with 6 mg of pegfilgrastim on day 2, FN (1/40, 2.5%) was a dose-limiting toxicity that resulted in treatment discontinuation 25…”

Profile of veliparib and its potential in the treatment of solid tumors

“…Veliparib doses of 40 mg bid (and an equivalent dose of 25 mg/m 2 in a pediatric trial) together with temozolomide 150 mg/m 2 /day for 5 days appear tolerable and are associated with some extent of disease stabilization in glioma 38 and prostate cancer, 39 although minimal activity was observed for those with refractory hepatocellular carcinoma. 40 Other combinations with topotecan have been reported 41 , 42 and continue to be under investigation ( Table 2 ).…”