1. Claudia Marchetti Pierluigi Benedetti Panici
Randomized phase II randomized trial on Letrozole vs clinician’s choice chemotherapy in heavily pretreated recurrent ovarian, primary peritoneal or fallopian tube cancers
MITO – XX
Claudia Marchetti Pierluigi Benedetti Panici

2. `
A maximum of three lines of subsequent relapse treatment seems to be beneficial for patients with recurrent ovarian cancer.
Optimal primary tumor debulking and platinum sensitivity remain independent prognostic factors even after more frequent relapses.

3. RATIONALE AND BACKGROUND

4. RATIONALE AND BACKGROUND
DETERMINAZIONE DELL'AGENZIA ITALIANA DEL FARMACO, 9 DICEMBRE 2008
(Gazzetta Ufficiale n. 1 del , Supplemento ordinario n. 1)

5. Recurrent ovarian, primary peritoneal or fallopian tube cancers
Platinum resistant/refractory
>3 lines CT
Physician’s choice
Random1:1
Recurrent ovarian, primary peritoneal or fallopian tube cancers
Letrozole, Oral 2.5 mg daily 5

6. STUDY OBJECTIVES
Primary:
DCR= 12-week disease control rate (DCR; CR, PR or SD; according to RECIST v1.1)
Secondary:
Quality of life using the QLQ-C30 and QLQ-0V28, FOSI (every 3 /4 weeks)
TSST
PFS OS
Radiological response rate (in patients with measurable disease)
Duration of response
CA-125 response rate per GCIG
Toxicity profile
Biomarker analysis (ER status)
PROs were assessed with three instruments: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30),5 EORTC QLQ Ovarian Cancer Module 28 (OV28),6 and the eight-item Functional Assessment of Cancer Therapy–Ovarian Cancer Symptom Index (FOSI). 6

7. 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 refractory
>3 previous chemotherapy lines
primary tumor specimen available for measurement of biochemical markers
ECOG performance status 0 -2
Measurable and evaluable disease per RECIST 1.1(Subjects with isolated rising CA-125 without radiologically
visible disease are excluded)
Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal
Adequate organ functions 7

8. EXCLUSION CRITERIA
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 3 lines of previous therapy
Platinum sensitive diseaseor refractory
primary tumor specimen unavailable for measurement of biochemical markers
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 8

9. STATISTICS PROTOCOL Phase II randomized PICK-THE-WINNER
The sample size in this trial was decided to be either 40 or 100
patients depending on the results of the interim efficacy analysis.
DCR at week 12 for patients treated with an investigator choice of chemotherapy was assumed to be 30%. The number of patients in the trial would be chosen to give a probability of 67% of correctly picking the letrozole treatment arm as the winner if the DCR for the letrozole arm was 35%.
2-step trial design allowed for an early safety analysis after random assignment of 40 patients (20 per arm) and treatment of at least 12 weeks and after radiological assessment.
The trial will continue continue if either > 1 of the first 12 patients with at least one measurable lesion included in the letrozole arm had a complete response (CR) or PR at weeks 6 or 12, or if > 5 of the first 20 patients included in the letrozole arm showed a CR, PR, or stable disease (SD) at week 12.
All treated patients who received at least one cycle of letrozole or chemotherapy will be included in the safety and efficacy analyses. 9

10. ADMINISTRATIVE INFORMATION
Academic trial
Sapienza University of Roma sponsor
Data center: Sapienza of Roma (MITO center)
Planned study start: April 2017
Epionpharma support: financial support for insurance, IHC and data management.
MITO - 23 10