Study of NIVOLUMAB/IPILIMUMAB Maintenance in Unresectable Locally Advanced or Metastatic Urothelial Cancer

Inclusion Criteria:

1\. Male or female subjects ≥ 18 years old.

2- Written informed consent approved by the Independent Ethics Committee (IEC), prior to the performance of any trial activities.

3- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

4- Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium.

* Also termed urothelial cell carcinoma \[UCC\] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).

  5- Stage IV disease (T4b, N0, M0; any T, N1-N3, M0; any T, any N, M1) at the start of first line chemotherapy.

  6- Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine plus cisplatin and/or gemcitabine plus carboplatin.

  7- Patient inclusion within the trial must occur within 3-12 weeks after the last dose of chemotherapy (3-12 weeks treatment-free interval).

  8- Only patients without progressive disease as per RECIST v1.1 guidelines after 4-6 cycles of chemotherapy will be allowed to be included. Baseline CT scan before inclusion should confirm that patients are on CR, PR or SD according to RECIST 1.1 criteria.

  9- Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition) must be available at baseline.

Note: Fine Needle Aspiration \[FNA\] and bone metastases samples are not acceptable. If an insufficient amount of tumor 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 tumor tissue. This may be discussed with the PI if a new biopsy is feasible.

10- Patients with adequate normal organ and marrow function as defined below:

1. Haemoglobin ≥ 9.0 g/dL.
2. Absolute neutrophil count (ANC) \> 1500 per mm3.
3. Platelet count ≥ 100,000 per mm3.
4. Serum bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤ 2X ULN. This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology); however, they will be allowed only in consultation with their physician.
5. Serum transaminases (ALT, AST and GGT) ≤ 2.5X institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 3X ULN.
6. Measured creatinine clearance (CL) \> 30 mL/min or Calculated creatinine CL \> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for the determination of creatinine clearance.

   11- Female subjects of childbearing potential (WOCBP) must provide a negative urine pregnancy test at screening, and must agree to use a medically accepted and highly effective birth control method (i.e. those with a failure rate less than 1%; refer to ANNEX III) for the duration of the study treatment and for 5 months after the last dose of study treatment.

A woman is considered of childbearing potential ( i.e. fertile) following menarche and until becoming post-menopausal unless permanently sterile. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:

1. Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal treatments
2. Luteinizing hormone (LH) and/or follicle stimulating hormone and/or estradiol levels in the post-menopausal range
3. Radiation induced oophorectomy with last menses \>1 year ago
4. Chemotherapy induced menopause with \>1 year interval since last menses
5. Surgical sterilization (bilateral oophorectomy or hysterectomy)
6. Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
7. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

   12- Willingness and ability of patients to comply with the protocol for the duration of the study including undergoing treatment as well as availability for scheduled visits and examinations including follow up.

   Exclusion Criteria:
   1. ECOG performance status of \>1 (Karnofsky \< 70%).
   2. Patients whose disease progressed by RECIST v1.1 on or after first-line chemotherapy for urothelial cancer in the advanced or metastatic setting.
   3. Prior immunotherapy with IL-2, IFN-a or treatment with any immune checkpoint inhibitor therapy (e.g, CTLA4, PD-1, or PD-L1 targeting agent) for the unresectable metastatic setting.

      Note: Patients may have received immunotherapy in the adjuvant setting as long as the last dose of adjuvant was administered at least 12 months prior to the first dose of trial treatment.
   4. Receipt of any type of systemic chemotherapy or anticancer therapy within 3 weeks before starting treatment.
   5. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
   6. History of allogeneic organ transplant.
   7. Any non-cancer treatment with vaccines used for the prevention of infectious diseases (up to 1 month before or after any dose of ipilimumab and nivolumab).
   8. Major surgery (i.e. cystectomy) less than 28 days prior to the first dose of study treatment.
   9. Patients with known symptomatic central nervous system (CNS) metastases requiring steroids. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to inclusion, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
   10. Subjects that have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 28 days prior to the first dose of trial treatment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid).
   11. Active or prior documented autoimmune disease within the past 2 years which requires systemic therapy.

       Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Subjects with Type I diabetes mellitus are not excluded.
   12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis).
   13. Inadequate haematological/organ function.
   14. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or symptomatic pulmonary embolism.
   15. Persistence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI-CTCAE v5.0) or baseline before administration of study treatment.
   16. Active hepatitis B virus or hepatitis C virus.
   17. Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines (i.e. SARS-CoV-2 and Influenza vaccines will be permitted).
   18. Patients who have a known secondary malignancy that is progressing or has required active treatment within the past 2 years.

       Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are eligible.
   19. Pregnant or lactating females. Fertile and sexually active patients that are not willing to use the appropriate highly effective contraceptive methods.
   20. Any underlying medical or psychiatric disorder, which, in the opinion of the investigator, makes the administration of ipilimumab and nivolumab unsafe or interferes with the informed consent process or trial procedures.
   21. Participation in other studies involving investigational drug(s) within 4 weeks prior to inclusion. Observational studies are permitted.