Javier Martin-Broto1, Silvia Stacchiotti2, Antonio Lopez-Pousa3, Andres Redondo4, Daniel Bernabeu5, Enrique de Alava6, Paolo G Casali2, Antoine Italiano7, Antonio Gutierrez8, David S Moura9, Maria Peña-Chilet10, Juan Diaz-Martin9, Michele Biscuola11, Miguel Taron9, Paola Collini12, Dominique Ranchere-Vince13, Xavier Garcia Del Muro14, Giovanni Grignani15, Sarah Dumont16, Javier Martinez-Trufero17, Emanuela Palmerini18, Nadia Hindi19, Ana Sebio3, Joaquin Dopazo10, Angelo Paolo Dei Tos20, Axel LeCesne16, Jean-Yves Blay21, Josefina Cruz22. 1. Department of Medical Oncology, University Hospital Virgen del Rocío, Sevilla, Spain; Institute of Biomedicine of Sevilla, Sevilla, Spain. Electronic address: jmartin@mustbesevilla.org. 2. Adult Mesenchymal and Rare Tumor Unit, Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 3. Department of Medical Oncology, Sant Pau Hospital, Barcelona, Spain. 4. Department of Medical Oncology, University Hospital La Paz, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain. 5. Musculoskeletal Imaging Section, University Hospital La Paz, Madrid, Spain. 6. Department of Pathology, University Hospital Virgen del Rocío, Sevilla, Spain; Institute of Biomedicine of Sevilla, Sevilla, Spain; CIBERONC, Madrid, Spain. 7. Department of Oncology, Institut Bergonié, Bordeaux, France. 8. Department of Hematology, University Hospital Son Espases, Palma, Balearic Islands, Spain. 9. Institute of Biomedicine of Sevilla, Sevilla, Spain. 10. Clinical Bioinformatics Area, Fundación Progreso y Salud, University Hospital Virgen del Rocío, Sevilla, Spain. 11. Department of Pathology, University Hospital Virgen del Rocío, Sevilla, Spain; CIBERONC, Madrid, Spain. 12. Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 13. Department of Pathology, Centre Léon Bérard, Université Claude Bernard Lyon, Lyon, France. 14. Catalan Institute of Oncology, Barcelona, Spain; Institut d'Investigació Biomédica de Bellvitge, University of Barcelona, Barcelona, Spain. 15. Sarcoma Unit, Division of Medical Oncology, Candiolo Cancer Institute, FPO, IRCCS, Candiolo, Italy. 16. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 17. Department of Medical Oncology, University Hospital Miguel Servet, Zaragoza, Spain. 18. Chemotherapy Unit, Istituto Ortopedico Rizzoli, Bologna, Italy. 19. Department of Medical Oncology, University Hospital Virgen del Rocío, Sevilla, Spain; Institute of Biomedicine of Sevilla, Sevilla, Spain. 20. Department of Medicine, University of Padua School of Medicine, Padua, Italy. 21. Department of Medical Oncology, Centre Léon Bérard, Université Claude Bernard Lyon, Lyon, France. 22. Department of Medical Oncology, University Hospital of Canarias, Tenerife, Spain.
Abstract
BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here. METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15. FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]). INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials. FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here. METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15. FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patientsdied. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]). INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials. FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
Authors: Wei-Lien Wang; Nalan Gokgoz; Bana Samman; Irene L Andrulis; Jay S Wunder; Elizabeth G Demicco Journal: Mod Pathol Date: 2020-10-02 Impact factor: 7.842
Authors: P Schöffski; I Timmermans; D Hompes; M Stas; F Sinnaeve; P De Leyn; W Coosemans; D Van Raemdonck; E Hauben; R Sciot; P Clement; O Bechter; B Beuselinck; F J S H Woei-A-Jin; H Dumez; P Nafteux; T Wessels Journal: Sarcoma Date: 2020-03-26