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
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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)
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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
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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
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5. 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
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6. 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).
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7. 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)
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8. ADMINISTRATIVE INFORMATION
Academic trial
NCI of Milan sponsor
Data center: NCI of Milan (MITO center)
Study start: 11 April 2016
Pharma-Mar support: Trabectedin supply , financial support for insurance, translational studies and data management.
Activated centres: 19/30
Enrolled patients: 134/244
Geico Group joing soon: 15 centres/ 40 patients
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