slow enrollment

Phase 2 single arm study that evaluated the addition of metformin to nivolumab in pre-treated metastatic renal cell carcinoma (mRCC) patients.

Primary aim: to investigate the efficacy of the combination of nivolumab+metformin in mRCC patients previously treated with VEGFR-TKI

Secondary aims:

• to assess the activity, safety and efficacy of the experimental combination
• to assess the quality of life of enrolled patients

Enrolled patients will received:

• nivolumab 240 mg e.v. every 14 day
• metformin 500 mg orally twice a day continuously Patients will be trated untill disease progression, or unexpected toxicity, whichever comes first

Inclusion Criteria:

1. Willing and able to provide written informed consent

2. Male and female aged 18 years and above

3. Histological confirmation of RCC with a clear cell component

4. Advanced or metastatic RCC

5. Measurable disease as defined by RECIST1.1criteria

6. Must have received at least one prior systemic treatment regimen in the advanced or metastatic setting, and must have evidence of progression on or after the last treatment regimen received

7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

8. Adequate bone marrow and chemistry values defined as:

   1. Hemoglobin ≥ 9.0 g/dL independent of transfusion
   2. Platelet count ≥100.000/μL
   3. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥ 40 mL/min
   4. Liver function:

   i. Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert's disease) ii. AST or ALT < 2.5 x ULN

9. Life expectancy of at least 6 months

10. WOCBP must use method(s) of contraception as determined to be acceptable by the principal investigator and sponsor during the study and for 23 weeks after last study drug administration.

11. Patients who are sexually active with WOCBP must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 31 weeks after last study drug administration.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study:

1. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection
2. Any active known or suspected autoimmune disease
3. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease
4. Uncontrolled adrenal insufficiency
5. Evidence of active pneumonitis during screening, except for pulmonary fibrosis induced by prior thoracic irradiation
6. Dialitic patients
7. Diabetes mellitus
8. Any history of biguanide-based therapy within 1 year prior to enrollment
9. Current severe, uncontrolled systemic disease
10. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline
11. Other malignancy with a previous diagnosis within 5 years (with the exclusions of NMIBC, CIN).
12. Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
13. WOCBP who are pregnant or breastfeeding
14. Women with a positive pregnancy test at enrollment or prior to administration of study medication