Introduction 50–70% of epithelial ovarian cancers overexpress epidermal growth factor receptor, and its expression has been correlated with poor prognosis. We conducted a phase Ib/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with epidermal growth factor receptor positivity.
Methods Patients with measurable recurrent or persistent cancer after treatment with a platinum containing regimen with positive epidermal growth factor receptor expression, as determined by immunohistochemistry, were eligible for the study. Initial treatment was 250 mg/day gefitinib (oral) and 2.0 mg/m2 topotecan (intravenous) on days 1, 8, and 15, on a 28 day cycle. Dose escalations were planned for topotecan (dose levels 1–3: 2, 3, and 4 mg/m2) until the maximum tolerated dose was reached.
Results 19 patients received a total of 61 cycles. Median age was 59.8 years (range 42–76 years). Histologic types in treated patients included 74% serous (n=14), 11% mixed (n=2), 11% transitional (n=2), and 5% clear cell (n=1). For phase Ib, three patients were treated at dose level 1, three at dose level 2, and three at dose level 3 for topotecan. The maximum tolerated dose was 4.0 mg/m2 (days 1, 8, and 15) for topotecan and 250 mg (daily) for gefitinib. Therefore, dose level 3 was used for phase II. Among the 19 patients, 63.2% (n=12) had progressive disease, 15.8% (n=3) had stable disease, 10.5% (n=2) had a partial response, and 10.5% (n=2) were not evaluable. The most serious adverse events of any grade attributed to the therapy were anemia (89.4%), neutropenia (68.4%), abdominal pain (84%), constipation (78.9%), and diarrhea (78.9%).
Conclusion Although the drug combination was relatively well tolerated, this prospective phase Ib/II clinical trial did not show sufficient clinical activity of topotecan combined with gefitinib in patients with epidermal growth factor receptor positive recurrent ovarian, fallopian tube, or peritoneal cancers.
- ovarian neoplasms
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Contributors Conception and design: all authors. Provision of study materials or patients: CL, BS, and JW. Collection and assembly of data: AC-R and RC. Data analysis and interpretation: AC-R and RC. Manuscript writing: AC-R. Final approval of the manuscript: all authors. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests BS is consultant for Abbvie, AstraZeneca, Clovis, GOG Foundation, GSK, Merck, and Myriad. DCB receives research grants from the National Cancer Institute. DG has equity interest in Biogen, Bristol Myers Squibb, Johnson & Johnson, Procter and Gamble; is a consultant for Genentech; received research grants from the National Cancer Institute and Novartis; received royalities from Elsevier and UpToDate; and is a board member of NCI Clinical Trials and Translational Research Advisory Committee. RC has clinical research funding from Merck, AstraZeneca/Medimmune, Genentech/Roche, Novartis, Clovis Oncology, Abbvie, and Janssen Pharmaceuticals. RC receives consulting fees from Genmab, Tesaro, Agenus, OncoMed, Novocure, Oncoquest, Merck, AstraZeneca/Medimmune, Genentech/Roche, Novartis, Clovis Oncology, Abbvie, Janssen Pharmaceuticals, Aravive, and OncoSec.
Patient consent for publication Not required.
Ethics approval The study was registered on the clinical trial website of the National Cancer Institute (clinicaltrials.gov NCT00317772) and approved by the the University of Texas MD Anderson Cancer Center institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.