Rare cancers: This phase II trial is evaluating two immunotherapy drugs (Ipilimumab and Nivolumab) for the treatment of rare gastrointestinal, neuroendocrine and female reproductive cancersA Phase II Clinical Trial Evaluating Ipilimumab and Nivolumab in Combination for the Treatment of Rare Gastrointestinal, Neuro-Endocrine and Gynaecological 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

   • Histologically confirmed Upper GI malignancies (Cholangiocarcinoma/ duodenal carcinoma - collect MSI (microsatellite instability) status); Neuroendocrine tumours (inc. pancreatic, bronchial and intestinal carcinoid tumours) and Rare Gynaecological tumours (including but will not be limited to: vaginal or vulval carcinomas, clear cell carcinoma of the ovary, low grade serous ovarian cancer, mixed Mullarian tumours (carcinosarcoma), sarcomas of the female genital tract and granulosa cell tumours).
   • Eastern Cooperative Oncology Group (ECOG) performance status of 1
   • Prior systemic therapy 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 subjects are not suitable for, or if declining established standard therapies.
   • 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 provided for biomarker analyses. If an insufficient amount of tumour tissue from an unresectable or metastatic site is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumour tissue for performance of 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
     • 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.