MOST-CIRCUIT: This phase II trial is trying to determine the clinical benefit of using two types of immunotherapy (nivolumab combined with ipilimumab) to treat neuroendocrine cancers, biliary tract cancers, gynaecological cancers and MSI-H cancers (excluding colorectal cancer)Ipilimumab and Nivolumab Combination Therapy in Patients With Selected Immunotherapy Sensitive Advanced Rare Cancers

Inclusion

1. Signed Written Informed Consent

   • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study

2. Target Population

   • a) Histologically confirmed Neuroendocrine cancers: Atypical bronchial carcinoid, neuroendocrine carcinoma and Grade 3 NETs independent of primary site (SCLC excluded); Biliary Tract Cancers: Intrahepatic cholangiocarcinoma, gallbladder carcinoma; Gynaecological malignancies: Ovarian clear cell carcinoma, uterine clear cell carcinoma, uterine/ovarian carcinosarcoma, uterine leiomyosarcoma, vaginal/vulva squamous cell carcinoma; Mismatch repair protein deficient (MSI-H) cancers (excluding colorectal carcinoma)
   • Eastern Cooperative Oncology Group (ECOG) performance status of ≤1
   • Prior systemic therapy (≤1) for advanced disease is permitted if it was completed at least 4 weeks prior to enrolment, and all related adverse events have either returned to baseline or stabilized or participants are not suitable for, or if declining established standard therapies. For MSI-H rare cancers and atypical bronchial carcinoid only, patients will be eligible independent of the number of prior lines of systemic treatment received as long as treatment has been completed at least 4 weeks prior to enrolment.
   • Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
   • Measurable disease by CT or MRI per RECIST 1.1 criteria
   • Tumour tissue from an unresectable or metastatic site of disease must be available for biomarker analyses.

   • Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:

     • WBC (white blood cells) > or = to 2000/μL
     • Neutrophils > or = to 1500/μL
     • Platelets > or = to 100 x103/μL
     • Hemoglobin > 9.0 g/dL
     • Serum creatinine < or = to 1.5 x ULN or creatinine clearance (CrCl) 40 mL/min (using the Cockcroft-Gault formula)
     • AST/ALT (aspartate transaminase/alanine transaminase) < or = to 3 x ULN (in the event of metastatic liver disease, an exception to this upper limit may be accepted in consultation with the study physician).
     • Total Bilirubin < or = to 1.5 x ULN (Upper limit of normal) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
   • Subject Re-enrolment: This study permits the re-enrolment of a subject that has discontinued the study as a pre-treatment failure (i.e. subject has not been treated) after obtaining agreement from the medical monitor prior to re enrolling a subject. If re-enrolled, the subject must be re-consented.

3. Age and Reproductive Status

   • Men and women, > or = to 18 years of age
   • Women of childbearing potential (WOCBP) must use method(s) of contraception. WOCBP should therefore use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half lives) after the last dose of investigational drug.
   • Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
   • Women must not be breastfeeding
   • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1 percent per year. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives. The half life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Given the blinded nature of the study, men who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half lives) after the last dose of investigational drug.
   • Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile and azoospermic men do not require contraception.