Giovanni Grignani1, Emanuela Palmerini2, Virginia Ferraresi3, Lorenzo D'Ambrosio4, Rossella Bertulli5, Sebastian Dorin Asaftei6, Angela Tamburini7, Ymera Pignochino4, Dario Sangiolo4, Emanuela Marchesi2, Federica Capozzi4, Roberto Biagini8, Marco Gambarotti9, Franca Fagioli6, Paolo Giovanni Casali5, Piero Picci10, Stefano Ferrari2, Massimo Aglietta4. 1. Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. Electronic address: giovanni.grignani@ircc.it. 2. Chemotherapy, Musculoskeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. 3. Medical Oncology A, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 4. Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy. 5. Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. 6. Pediatric Onco-Hematology, Città della Salute e della Scienza di Torino, Turin, Italy. 7. Paediatric Onco-Hematology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Firenze, Italy. 8. Oncological Orthopaedics Department, IRCCS Regina Elena National Cancer Institute, Rome, Italy. 9. Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. 10. Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
Abstract
BACKGROUND: Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. METHODS: We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. FINDINGS: We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. INTERPRETATION: Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. FUNDING: Italian Sarcoma Group.
BACKGROUND: Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. METHODS: We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. FINDINGS: We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. INTERPRETATION: Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. FUNDING: Italian Sarcoma Group.
Authors: Ya Zhang; Jingqing Yang; Na Zhao; Cao Wang; Santosh Kamar; Yonghong Zhou; Zewei He; Jifei Yang; Bin Sun; Xiaoqian Shi; Lei Han; Zuozhang Yang Journal: Oncol Lett Date: 2018-09-12 Impact factor: 2.967
Authors: Stanley I Gutiontov; Zachary S Zumsteg; Benjamin H Lok; Sean Berry; Chiaojung J Tsai; Sean M McBride; Nadeem Riaz; Oren Cahlon; Nancy Y Lee Journal: Int J Part Ther Date: 2017-03-14
Authors: Valerae O Lewis; Eswaran Devarajan; Marina Cardó-Vila; Dafydd G Thomas; Eugenie S Kleinerman; Serena Marchiò; Richard L Sidman; Renata Pasqualini; Wadih Arap Journal: Proc Natl Acad Sci U S A Date: 2017-07-11 Impact factor: 11.205