Randomized phase III trial on Trabectedin (ET 743) vs clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube cancers.

Presentazione sul tema: "Randomized phase III trial on Trabectedin (ET 743) vs clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube cancers."— Transcript della presentazione:

1 Randomized phase III trial on Trabectedin (ET 743) vs clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients MITO – 23

2 Randomized phase III STRATIFICATION CRITERIA: Measurable Disease Platinum Sensitivity Number of Previous CHT Lines Mutational status II line chemotherapy (physician choice): - PLD 40 mg/mq d1 q28; - Topotecan 4 mg/mq d1,8,15 q 28 - Weekly Paclitaxel 80 mg/mq d1,8,15 q28 Gemcitabine 1000 mg/mq gg1,8,15 q28 Carboplatin AUC 5 g 1 q 21 Random1.1 Recurrent ovarian, primary peritoneal or fallopian tube cancers of BRCA mutated or BRCAness phenotype patients Trabectedin 1.3 mg/mq d1 q 21 in 3 hours (central line) MITO - 23 2

3 STUDY OBJECTIVES Primary: The primary objective is to compare the treatment groups in terms of overall survival (OS) Secondary: Progression free survival (PFS) Radiological response rate (in patients with measurable disease) Duration of response CA-125 response rate per GCIG Toxicity profile Quality of life using the QLQ-C30 and QLQ-0V28 MITO - 23 3

4 INCLUSION CRITERIA Female of age 18 years or older
Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer Platinum resistant or sensitive patients with either: BRCA mutated patients BRCAness phenotype patients: patients who have received and responded (subsequent PFI>6 months) to at least 2 previous platinum based chemotherapy lines Platinum sensitive patients who are not able to receive or not willing to receive other platinum treatments Measurable and evaluable disease per RECIST 1.1(Subjects with isolated rising CA-125 without radiologically visible disease are excluded) ECOG performance status 0 or 1 No limits in the number of previous chemotherapy lines, previous treatment with parp inhibitors is allowed Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal Life expectancy of at least 3 months Adequate organ functions No other invasive malignancy within the past 3 years except non-melanoma skin cancer or in situ cervical cancer (patients with previous cancers may be enrolled providing that no recurrences have be reported in the last 3 years) Written Informed Consent Adequately recovered from the acute toxicity of any prior treatment For agents in the standard arm, also refer to the local prescribing information with regards to warnings, precautions, and contraindications MITO - 23 4

5 EXCLUSION CRITERIA Prior exposure to trabectedin
Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone Subjects with borderline ovarian cancer, ie. Subject with low malignant potential tumors are excluded Less than 2 reported responses to platinum (i.e. subsequent recurrences at least 6 months after the first and the second platinum based treatment), unless BRCA mutation is documented. Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer Known clinically relevant CNS metastases, unless treated and asymptomatic Other serious illnesses, such as: Congestive heart failure or angina pectoris; myocardial infarction within 1 year before enrolment; uncontrolled arterial hypertension or arrhythmias. Psychiatric disorder that prevents compliance with protocol Active viral hepatitis; or chronic liver disease. Active infection. Any other unstable medical conditions. MITO - 23 5

6 Written Informed Consent Before study procedures
Assessment Screening Cycle End of Treatment Follow Up Day Day 1 Day 8 Day 15 Day 16-21 Written Informed Consent Before study procedures Demographic Data - 28 to 0 Medical History Prior surgical and/or chemotherapy treatments - 14 to 0 Vital Signs (heart rate, blood pressure, temperature) X Complete Physical Examination (assessment of signs and symptoms of desease) Performance Status (ECOG) ECG Repeat if clinically indicated Echocardiogram -28 to 0 Repeat every 3 cycle only in case of PLD and T treatments, in all other cases repeat only if clinically indicated Concomitant Disease and Medication Throughout the study Adverse Events Hematology -7 to 0 Xa Coagulation Test Chemistry and Liver Panel QoL assessments Every 3 chemotherapy cycles Radiologic evaluations Every 12 +/- 1 week Xb CA 125

7 STATISTICS PROTOCOL Phase III The primary endpoint is OS
Hazard Ratio: 0.67 Median OS expected in the control arm: 10 months Median OS hoped for the experimental arm : 15 months Two-sided log-rank test at the error alfa= 0.05 Statistical Power 80% 198 events are required Overall 244 patients will be enrolled in 30 months (8 patients/months) Interim futility analysis at ~ 99 events MITO - 23 7

8 MITO-23: TRANSLATIONAL STUDIES
Evaluating the impact of altered gene and microRNA (miRNA) expression on trabectedin efficacy with the aim of identify which genes are involved in the so called BRCAness phenotype; Analysis of cellular infiltrate present on tumor specimens of patients treated with trabectedin; DNA sequencing in order to evaluate mutation/genetic aberration profile in selected panels of genes associated to tumor sensibility to trabectedin (BRCA test). MITO - 23 8

9 TRANSLATIONAL STUDIES: Specimens
Tumor histological blocks (FFPE material): samples will be collected at primary surgery and/or interval debulking surgery (or before trabectedin treatment by dedicated biopsies). Storage and analysis will be centralized at Fondazione Istituto Nazionale dei Tumori. Characterization of tumor infiltrate by IHC (2 slides per marker & 1 HE slide & 3 backup slides); Extraction of RNA from tissue sections for gene expression by DASL microarray analysis; Extraction of DNA from tissue sections for targeted sequencing of “Panel cancer related genes” (in collaboration with Istituto Mario Negri, Milan). Blood samples: Blood samples will be collected at baseline (registration), at third cycle of treatment and at progression. Storage and analyses will be centralized at Fondazione IRCCS Istituto Nazionale Tumori, Milan. 10 ml blood sample will be taken at each time point, centrifuged in EDTA, processed to obtain 5 ml plasma collected and stored at -20°C or at -80°C when possible. Analysis of miRNA profile by Agilen microarrays or evaluation of selected miRNA by RT-qPCR (in collaboration with Fondazione Istituto Nazionale dei Tumori) MITO - 23 9

10 10 Site Principal Investigator Status Ethical Committee MITO - 23
IRCCS Istituto Nazionale Tumori – Milano COORDINATING CENTER Francesco Raspagliesi/ Domenica Lorusso In approvazione Fondazione Policlinico Universitario A. Gemelli - Roma Giovanni Scambia In valutazione Istituto Nazionale Tumori Pascale - Napoli Carmen Pisano Ospedale San Raffaele – Milano Giorgia Mangili In istruttoria Fondazione del Piemonte per l'Oncologia - Istituto di Candiolo Giorgio Valabrega Ospedale Fatebenefratelli - Roma Enrico Breda In compilazione ULLS 13 - Mirano Grazia Artioli IRST - Meldola Ugo De Giorgi A.O. di Perugia - Ospedale Santa Maria Misericordia - Perugia Anna Maria Mosconi Sapienza Università di Roma-Policlinico Umberto I - Roma Pierluigi Benedetti Panici CRO IRCCS - Aviano Roberto Sorio IRE-Istituto Nazionale Tumori REGINA ELENA - Roma Patrizia Vici AOU Federico II Sabino De Placido Fondazione IRCCS Policlinico S.Matteo di Pavia Stefano Bogliolo U.O.Oncologia Medica - Ospedale Vito Fazzi - Lecce Graziana Ronzino Ospedale degli Infermi - Faenza Stefano Tamberi AULSS 21 Regione Veneto - Legnago Filippo Greco Ospedale Civile SS. Trinità - Sora Teresa Gamucci A.O. S.Giuseppe Moscati - Avellino Cesare Gridelli Ospedale Santa Croce - Fano Rodolfo Mattioli A.O. Carlo Poma - Mantova Maria Giovanna Cavazzini Ospedale S.Maria delle Croci - Ravenna Claudia Casanova A.O.U. Santa Maria della Misericordia - Udine Claudia Andreetta Centro Sociale Oncologico AAS1 Triestina - Trieste Rita Ceccherini IRCCS AOU San Martino - IST - Genova Serafina Mammoliti Ospedale Civile G.Fornaroli - Magenta Silvia Elvira Negretti Istituto Europeo di Oncologia - Milano Nicoletta Colombo Arcispedale sant'anna - Cona, Ferrara Antonio Frassoldati Spedali Civili di Brescia - Brescia Germana Tognon AOU Maggiore della Carità - Novara Roberta Buosi MITO - 23 10

11 ADMINISTRATIVE INFORMATION
Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: February 2016 Pharma-Mar support: Trabectedin supply , financial support for insurance, translational studies and data management. MITO - 23 11