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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.
Grignani, Giovanni; D'Ambrosio, Lorenzo; Pignochino, Ymera; Palmerini, Emanuela; Zucchetti, Massimo; Boccone, Paola; Aliberti, Sandra; Stacchiotti, Silvia; Bertulli, Rossella; Piana, Raimondo; Miano, Sara; Tolomeo, Francesco; Chiabotto, Giulia; Sangiolo, Dario; Pisacane, Alberto; Dei Tos, Angelo Paolo; Novara, Luca; Bartolini, Alice; Marchesi, Emanuela; D'Incalci, Maurizio; Bardelli, Alberto; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo.
Afiliação
  • Grignani G; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy. Electronic address: giovanni.grignani@ircc.it.
  • D'Ambrosio L; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
  • Pignochino Y; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
  • Palmerini E; Chemotherapy, Musculoskeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • Zucchetti M; Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
  • Boccone P; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
  • Aliberti S; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
  • Stacchiotti S; Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
  • Bertulli R; Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
  • Piana R; Department of Orthopaedic Oncology, Azienda Ospedaliera Città della Salute e della Scienza, Centro Traumatologico Ortopedico, Turin, Italy.
  • Miano S; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
  • Tolomeo F; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
  • Chiabotto G; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
  • Sangiolo D; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
  • Pisacane A; Pathology Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
  • Dei Tos AP; Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy; Department of Medicine, University of Padova School of Medicine, Padova, Italy.
  • Novara L; Molecular Oncology, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
  • Bartolini A; Molecular Oncology, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
  • Marchesi E; Italian Sarcoma Group Clinical Trial Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • D'Incalci M; Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
  • Bardelli A; Molecular Oncology, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
  • Picci P; Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • Ferrari S; Chemotherapy, Musculoskeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • Aglietta M; Medical Oncology-Sarcoma Unit, Istituto di Candiolo-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy; Department of Oncology, University of Torino, Regione Gonzole, Orbassano, Italy.
Lancet Oncol ; 19(10): 1360-1371, 2018 10.
Article em En | MEDLINE | ID: mdl-30217671
ABSTRACT

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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ftalazinas / Piperazinas / Sarcoma / Neoplasias de Tecidos Moles / Neoplasias Ósseas / Protocolos de Quimioterapia Combinada Antineoplásica / Osteossarcoma / Antineoplásicos Alquilantes / Inibidores de Poli(ADP-Ribose) Polimerases / Trabectedina Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Female / Humans / Male / Middle aged País/Região como assunto: Europa Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ftalazinas / Piperazinas / Sarcoma / Neoplasias de Tecidos Moles / Neoplasias Ósseas / Protocolos de Quimioterapia Combinada Antineoplásica / Osteossarcoma / Antineoplásicos Alquilantes / Inibidores de Poli(ADP-Ribose) Polimerases / Trabectedina Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Female / Humans / Male / Middle aged País/Região como assunto: Europa Idioma: En Ano de publicação: 2018 Tipo de documento: Article