HE-4 TRIAL Prospective phase II trial on the prognostic and predictive value of HE-4 regression during neoadjuvant chemotherapy for advanced ovarian, Fallopian tube or primary peritoneal carcinoma

HE-4 TRIAL Objectives Primary: To assess the significance of HE-4 regression as a predictor of optimal cytoreduction at interval debulking surgery (IDS) in women with ovarian, Fallopian tube or primary peritoneal carcinoma receiving 3 cycles of neo- adjuvant chemotherapy. Secondary: To assess the significance of HE-4 regression as a prognostic indicator in women with ovarian or primary peritoneal carcinoma receiving neo- adjuvant chemotherapy; To assess the correlation between end of treatment HE-4 value and Progression free survival (PFS) and Overall survival (OS); To assess the correlation between HE-4 regression and objective response to neoadjuvant treatment as per Recist version 1.1 criteria; To assess the correlation between CA 125 and HE4 regression during the neoadjuvant chemotherapy;

HE-4 TRIAL Inclusion Criteria Female of age 18 years or older; Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer not suitable of primary cytoreduction. Subjects with borderline ovarian cancer and patients with low malignant potential tumors are excluded; Measurable or evaluable disease per RECIST 1.1; ECOG performance status < 3; Life expectancy of at least 3 months; Adequate organ functions to receive neoadjuvant chemotherapy; 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 during the last 3 years); Written Informed Consent.

HE-4 TRIAL Exclusion Criteria 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 that contraindicate performance of IDS.

HE-4 TRIAL Statistical consideration The sample size is estimated on the assumption that the expected HE4 levels will decrease more than 40% during NACT. Based on this feature, 60 patients will be included to achieve a statistical difference in HE4 levels (5% levels of significance and 95% power), before and after NACT. To allow for a 40% rate due to exclusion for chemotherapy discontinuation or protocol deviation a total of 100 patients will be included Stratification Factor: Residual tumor at IDS; Histotype; Antiangiogenic therapy Study duration: 2 years

HE-4 TRIAL Samples storage Blood samples will be collected at baseline (registration), at each cycles and 30 days after the last chemotherapy; Storage and analyses will be centralized at Istituto Nazionale Tumori, Milan. 10 ml blood sample will be taken at each time point and stored at -80°C.

HE-4 TRIAL Administrative Information Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: February 2016 NCI of Milan organize courier for samples Fujirebio Diagnostics support: supply of laboratory kits for HE-4 tests

HE-4 TRIAL Participating Sites Site NamePrincipal Investigator Fondazione IRCCS Istituto Nazionale Tumori – Milano Promotore Francesco Raspagliesi/Domenica Lorusso Fondazione Policlinico Universitario A. Gemelli - RomaGiovanni Scambia Istituto Nazionale Tumori - Fondazione Pascale - Napoli Sandro Pignata Istituto Nazionale Tumori REGINA ELENA - RomaPatrizia Vici A.O.U. Federico II - Napoli Carmine Nappi Ospedale S.Maria della Misericordia - Perugia Anna Maria Mosconi Fondazione IRCCS Policlinico S.Matteo – PaviaStefano Bogliolo Azienda Ospedaliera Spedali Riuniti - BergamoLuigi Frigerio Arcispedale Santa Maria Nuova - Reggio EmiliaMartino Abrate Policlinico Sant'Orsola - BolognaPierandrea De Iaco Centri inseriti al prossimo emendamento IRCCS Burlo Garofolo - TriesteGiuseppe Ricci In attesa di Parere Unico del Comitato Etico Coordinatore