To Assess the Tolerance of Intraperitoneal (IP) Nivolumab After Extensive Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients With Advanced Ovarian Carcinoma, Through a Phase Ib/II Study Including Patients at 3 Dose-levels for Nivolumab
To Assess the Tolerance of Intraperitoneal (IP) Nivolumab After Extensive Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients With Advanced Ovarian Carcinoma, Through a Phase Ib/II Study Including Patients at 3 Dose-levels for Nivolumab
Spread pattern, the lack of alternative treatments, and emerging data on the activity of anti-Programmed death ligand 1 (PDL1) targeted checkpoint inhibitor therapy in gynecological cancers provide the rationale for this investigation.
Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are likely to increase the tumor-antigen expression and the mutational load. As a result, it would be interesting to combine this approach with immunotherapy. Moreover, Intraperitoneal (IP) infusion will directly target the peritoneal cavity and potentially enhance the immune response. Indeed some recent papers indicate that the peritoneum could be considered as a lymphoid organ, involving "milky spots", thus able to produce a better immune response when immunotherapy is given by IP route rather than intravenous (IV) route.
The investigating team in Lyon, France is one of the major groups for HIPEC research in Europe (Pr O. Glehen et al) - Reference center for the tumors of the peritoneum (French National Cancer Institute).
The aim of this study is to assess in this I/II phase study, the feasibility of extensive debulking surgery and HIPEC followed by Intraperitoneal (IP) nivolumab dose escalation in patients with advanced ovarian carcinoma.
Inclusion Criteria:
Patients at least 18 years of age.
Signed informed consent and ability to comply with treatment and follow-up.
Histological or cytological proven primary epithelial ovarian carcinoma or peritoneal cancer or fallopian tube carcinoma in relapse, including serous papillary adenocarcinoma, mucinous adenocarcinoma, clear-cell carcinoma, undifferentiated carcinoma, mixed mullerian tumor and endometrioid adenocarcinoma. Patients with low grade tumors can be included.
Not eligible for front-line cytoreduction in first platinum-sensitive relapse
Eligible for surgical cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) after one or more lines of chemotherapy. All chemotherapy regimens usually recommended for the treatment of ovarian cancer are accepted :
Satisfactory haematological evaluation: neutrophil rate greater than 1500/millimeters cubed, platelet count greater than 100 grams/liter;
Satisfactory renal and hepatic function: serum creatinine ≤1.5 times the normal upper values or creatinine clearance ≥50 milliliters/minute, bilirubin ≤1.25 times upper normal values, ratio aspartate transaminase/alanine transaminase (AST/ALT) ≤1.5 times the upper normal values (≤5 times the upper normal values for patients with liver metastases)
No unstable conditions: myocardial infarction within 6 months prior to the start of the study, congestive heart failure, unstable angina, active cardiomyopathy, unstable rhythm disorder, uncontrolled hypertension, uncontrolled psychiatric disorders, severe infection, peptic ulcer or any condition that could be aggravated by treatment or limit compliance (investigator assessment)
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days prior to the start of study drug.
Women of childbearing potential should use an adequate method of contraception to avoid pregnancy during nivolumab treatment until 5 months after the last dose of investigational drug.
Exclusion Criteria: