Sandro Pignata1, Domenica Lorusso2, Giovanni Scambia3, Daniela Sambataro4, Stefano Tamberi5, Saverio Cinieri6, Anna M Mosconi7, Michele Orditura8, Alba A Brandes9, Valentina Arcangeli10, Pierluigi Beneditti Panici11, Carmela Pisano12, Sabrina C Cecere12, Marilena Di Napoli12, Francesco Raspagliesi2, Giuseppa Maltese2, Vanda Salutari3, Caterina Ricci3, Gennaro Daniele13, Maria Carmela Piccirillo13, Massimo Di Maio13, Ciro Gallo14, Francesco Perrone13. 1. Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione GPascale IRCCS, Naples, Italy. Electronic address: s.pignata@istitutotumori.na.it. 2. Unità di Ginecologia Oncologica, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 3. Dipartimento per la Tutela della Salute della Donna della Vita Nascente del Bambino e dell' Adolescente, Università Cattolica del Sacro Cuore, Rome, Italy. 4. Unità di Oncologia Medica, AORN Garibaldi - Nesima, Catania, Italy. 5. UO di Oncologia Medica, Presidio Ospedaliero di Faenza, Faenza, Italy. 6. Oncologia Medica & Breast Unit, Ospedale Antonio Perrino, Brindisi, Italy; Istituto Europeo di Oncologia, Milan, Italy. 7. Oncologia Medica, Ospedale S Maria della Misericordia, Perugia, Italy. 8. U O C Oncoematologia, Dipartimento di Medicina Sperimentale e Clinica F Magrassi, Seconda Università degli Studi di Napoli, Naples, Italy. 9. Dipartimento di Oncologia Medica, Ospedale Bellaria-Maggiore Hospital, Azienda USL-IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. 10. U O Oncologia, Ospedale Infermi, Rimini, Italy. 11. Ginecologia Oncologica, Policlinico Umberto I, Università La Sapienza, Rome, Italy. 12. Dipartimento di Oncologia Uroginecologica, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione GPascale IRCCS, Naples, Italy. 13. Unità Sperimentazioni Cliniche Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione GPascale IRCCS-Italia, Naples, Italy. 14. Cattedra di Statistica Medica, Seconda Università degli Studi, Naples, Italy.
Abstract
BACKGROUND: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. METHODS: We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0-1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m(2) with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. FINDINGS:Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5-20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36-11·02] vs 3·49 months [2·01-5·66]; hazard ratio 0·42 [95% CI 0·25-0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3-4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. INTERPRETATION: Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. FUNDING: National Cancer Institute of Napoli and GlaxoSmithKline.
RCT Entities:
BACKGROUND: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. METHODS: We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0-1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m(2) with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. FINDINGS: Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5-20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36-11·02] vs 3·49 months [2·01-5·66]; hazard ratio 0·42 [95% CI 0·25-0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3-4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. INTERPRETATION: Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. FUNDING: National Cancer Institute of Napoli and GlaxoSmithKline.
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