Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group
Autor: | Angelo Paolo Dei Tos, Rossella Bertulli, Alberto Pisacane, Dario Sangiolo, Stefano Ferrari, Massimo Aglietta, Francesco Tolomeo, Lorenzo D'Ambrosio, Luca Novara, Sandra Aliberti, R. Piana, Giovanni Grignani, Emanuela Marchesi, Giulia Chiabotto, Maurizio D'Incalci, Paola Boccone, Alice Bartolini, Alberto Bardelli, Emanuela Palmerini, Sara Miano, Silvia Stacchiotti, Massimo Zucchetti, Piero Picci, Ymera Pignochino |
---|---|
Přispěvatelé: | Grignani G, D'Ambrosio L, Pignochino Y, Palmerini E, Zucchetti M, Boccone P, Aliberti S, Stacchiotti S, Bertulli R, Piana R, Miano S, Tolomeo F, Chiabotto G, Sangiolo D, Pisacane A, Dei Tos AP, Novara L, Bartolini A, Marchesi E, D'Incalci M, Bardelli A, Picci P, Ferrari S, Aglietta M. |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Oncology ope-label Time Factors Tabectedin Soft Tissue Neoplasms TOMAS Piperazines chemistry.chemical_compound 0302 clinical medicine Olaparib Antineoplastic Combined Chemotherapy Protocols sarcomas Trabectedin Osteosarcoma Sarcoma Middle Aged Progression-Free Survival Tabectedin Olaparib sarcomas TOMAS ope-label bone and soft-tissue phase 1b study Italian Sarcoma Group Italy Tolerability Response Evaluation Criteria in Solid Tumors 030220 oncology & carcinogenesis Female medicine.drug Adult medicine.medical_specialty phase 1b study Trabectedin olaparib bone sarcoma soft tissue sarcoma advanced non resectable Bone Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Neutropenia 03 medical and health sciences Internal medicine medicine Humans Progression-free survival Antineoplastic Agents Alkylating business.industry Italian Sarcoma Group medicine.disease bone and soft-tissue 030104 developmental biology chemistry Phthalazines business Febrile neutropenia |
Popis: | Summary Background Trabectedin is an alkylating drug with a unique mechanism of action causing single-strand and double-strand DNA breaks that activate DNA damage-response pathways. Based on our preclinical data, we hypothesised that poly(ADP-ribose) polymerase 1 (PARP1) inhibitors might be an ideal partner of trabectedin and aimed to assess the safety, identify the recommended phase 2 dose, and explore preliminary signs of activity of trabectedin and olaparib combination treatment in patients with bone and soft-tissue sarcoma. Methods We did an open-label, multicentre, phase 1b study, recruiting patients from the national Italian sarcoma network aged 18 years and older with histologically confirmed bone and soft-tissue sarcoma progressing after standard treatments with Eastern Cooperative Oncology Group performance status of 1 or less. In a classic 3 + 3 design, patients received a 24 h infusion of trabectedin on day 1 and olaparib orally twice a day in 21-day cycles across six dose levels (trabectedin 0·675–1·3 mg/m2 every 3 weeks; olaparib 100–300 mg twice a day from day 1 to 21). Intermediate dose levels were permitted to improve safety and tolerability. The primary endpoint was determination of the recommended phase 2 dose (the maximum tolerated dose). Safety and antitumour activity were assessed in all patients who received at least one dose of the study drugs. We report the results of the dose-escalation and dose-expansion cohorts. The trial is still active but closed to enrolment, and follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT02398058. Findings Between Nov 17, 2014, and Jan 30, 2017, of 54 patients assessed for eligibility, we enrolled 50 patients: 28 patients in the dose-escalation cohort and 22 patients in the dose-expansion cohort. Patients received a median of four cycles of treatment (IQR 2–6; range 1–17 [the patients who received the highest number of cycles are still on treatment]) with a median follow-up of 10 months (IQR 5–23). Considering all dose levels, the most common grade 3–4 adverse events were lymphopenia (32 [64%] of 50 patients), neutropenia (31 [62%]), thrombocytopenia (14 [28%]), anaemia (13 [26%]), hypophosphataemia (20 [40%]), and alanine aminotransferase concentration increase (9 [18%]). No treatment-related life-threatening adverse events or deaths occurred. One (2%) patient interrupted treatment without progression without reporting any specific toxicity. Observed dose-limiting toxicities were thrombocytopenia, neutropenia for more than 7 days, and febrile neutropenia. We selected intermediate dose level 4b (trabectedin 1·1 mg/m2 every 3 weeks plus olaparib 150 mg twice a day) as the recommended phase 2 dose. Seven (14%; 95% CI 6–27) of 50 patients achieved a partial response according to Response Evaluation Criteria In Solid Tumors 1.1. Interpretation Trabectedin and olaparib in combination showed manageable toxicities at active dose levels for both drugs. Preliminary data on antitumour activity are encouraging. Two dedicated phase 2 studies are planned to assess activity of this combination in both ovarian cancer (EudraCT2018-000230-35) and soft-tissue sarcomas. Funding Italian Association for Cancer Research, Italian Sarcoma Group, Foundation for Research on Musculoskeletal and Rare Tumors, and Italian Ministry of Health. |
Databáze: | OpenAIRE |
Externí odkaz: |