J Martin-Broto1,2, A Redondo3, C Valverde4, M A Vaz5, J Mora6, X Garcia Del Muro7, A Gutierrez8, C Tous2, A Carnero2,9, D Marcilla10, A Carranza1, P Sancho1, J Martinez-Trufero11, R Diaz-Beveridge12, J Cruz13, V Encinas14, M Taron2, D S Moura2, P Luna15, N Hindi1,2, A Lopez-Pousa16. 1. Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla. 2. Instituto de Biomedicina de Sevilla (HUVR, CSIC, Universidad de Sevilla), Sevilla. 3. Medical Oncology Department, Hospital Universitario La Paz, Instituto de Investigación La Paz (IdiPAZ), Madrid. 4. Medical Oncology Department, Hospital Universitario Vall d'Hebron, Barcelona. 5. Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid. 6. Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona. 7. Institut Catala d´Oncologia, IDIBELL, Universitat de Barcelona, Barcelona. 8. Hematology Department, Hospital Universitario Son Espases, Palma, Illes Baleares. 9. CIBER de Cancer, Sevilla. 10. Pathology Department, Hospital Universitario Virgen del Rocío, Sevilla. 11. Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza. 12. Medical Oncology Department, Hospital Universitari i Politècnic La Fe, Valencia. 13. Medical Oncology Department, Hospital Universitario de Canarias, Tenerife. 14. Radiology Department, Hospital Universitario Virgen del Rocío, Sevilla. 15. Medical Oncology Department, Hospital Universitario Son Espases, Palma, Illes Baleares. 16. Medical Oncology Department, Hospital Sant Pau, Barcelona, Spain.
Abstract
BACKGROUND: Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. PATIENTS AND METHODS: A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. RESULTS: Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. CONCLUSION: Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.
BACKGROUND: Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. PATIENTS AND METHODS: A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. RESULTS: Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. CONCLUSION: Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.
Authors: Juan Martin-Liberal; Antonio López-Pousa; Javier Martínez-Trufero; Javier Martín-Broto; Ricardo Cubedo; Javier Lavernia; Andrés Redondo; José Antonio López-Martín; Nùria Mulet-Margalef; Xavier Sanjuan; Òscar M Tirado; Xavier Garcia-Del-Muro Journal: Target Oncol Date: 2018-02 Impact factor: 4.493
Authors: Chia-Chin Wu; Hannah C Beird; J Andrew Livingston; Shailesh Advani; Akash Mitra; Shaolong Cao; Alexandre Reuben; Davis Ingram; Wei-Lien Wang; Zhenlin Ju; Cheuk Hong Leung; Heather Lin; Youyun Zheng; Jason Roszik; Wenyi Wang; Shreyaskumar Patel; Robert S Benjamin; Neeta Somaiah; Anthony P Conley; Gordon B Mills; Patrick Hwu; Richard Gorlick; Alexander Lazar; Najat C Daw; Valerae Lewis; P Andrew Futreal Journal: Nat Commun Date: 2020-02-21 Impact factor: 14.919