Phase II trial of lapatinib and topotecan (LapTop) in patients with platinum-refractory/resistant ovarian and primary peritoneal carcinoma |
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Authors: | Weroha S John Oberg Ann L Ziegler Katie L Allen Dakhilm Shaker R Rowland Kendrith M Hartmann Lynn C Moore Dennis F Keeney Gary L Peethambaram Prema P Haluska Paul |
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Affiliation: | a Departments of Medical Oncology, Mayo, Rochester, MN 55905, USAb Division of Biomedical Statistics and Informatics within the Department of Health Sciences Research, Mayo, Rochester, MN 55905, USAc Wichita Community Clinical Oncology Program, Wichita, KS 67214, USAd Carle Cancer Center, Urbana, IL 61801, USAe Division of Biomedical Statistics and Informatics within the Department of Pathology, Mayo, Rochester, MN 55905, USA |
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Abstract: | ObjectiveResistance to chemotherapy is a major challenge in the treatment of ovarian/peritoneal cancer. One purported mechanism of topotecan resistance is the breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp). We designed a phase II clinical trial evaluating the efficacy and adverse event profile of concomitant topotecan and lapatinib, a small molecule pan-erbB inhibitor that can block BCRP/Pgp efflux of topotecan.MethodsPatients with platinum-refractory or resistant epithelial ovarian/peritoneal cancer were treated with topotecan 3.2 mg/m2 IV on Day 1, 8 and 15 and lapatinib 1250 mg PO daily, continuously in 28 day cycles. The primary endpoint was response rate. For correlative studies, archived tissue was assessed for expression of EGFR, HER2, HIF-1α, CD31, and BCRP.ResultsEighteen patients were enrolled and treated. Four experienced evidence of clinical benefit: one partial response and three with stable disease. Using a two-stage Simon design, the trial was stopped after the first stage due to insufficient activity. Grades 3+ and 4+ adverse events (AE) were experienced in 14 and 4 patients, respectively. The most common grade 3/4 AE were neutropenia (56%), thrombocytopenia (28%), and diarrhea (22%).ConclusionsThe combination of lapatinib plus topotecan for the treatment of platinum refractory/resistant epithelial ovarian cancer lacks sufficient activity to warrant further investigation. In particular, hematologic adverse events were substantial. Expression of correlative study markers did not reveal patterns of predicted benefit or toxicity. Disruption of erbB signaling and BCRP/Pgp efflux with lapatinib was insufficient for overcoming topotecan resistance, suggesting alternative mechanisms of resistance are involved. |
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Keywords: | Lapatinib Topotecan Ovarian cancer Refractory Resistant |
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