Nivolumab Plus Metformin in Metastatic Renal Cell Carcinoma (NivoMet)

A Phase II Study of Nivolumab Combined With Metformin in Pretreated Metastatic Renal Cell Carcinoma (mRCC) Patients. NivoMet TWINS-GU002 Study

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

Study Overview

• Status: Terminated
• Conditions: Metastatic Renal Cell Carcinoma
• Intervention / Treatment: Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Roma, Italy
    • Giampaolo Tortora
  • Viterbo, Italy
    • Francesca Primi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: experimental; nivolumab plus metformin Participants will receive nivolumab 240 mg e.v. every 14 days. Treatment will continue until progressive disease or discontinuation. Participants will receive metformin 500 mg orally twice a day. Treatment will continue until progressive disease or discontinuation.	Drug: Metformin; Drug: metformin tablet 500 mg, 1 tablet twice a day (total dose 1000 mg daily), administered orally continuously + Biological: Nivolumab 240 mg via IV infusion every 14 days Other Names: Opdivo®; Other Names: Nivolumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
9-months PFS rate	The percentage of patients without disease progression after 9 months from the start of therapy	9 months after the last enrolled patient

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	objective response rate (percentage of patients with complete or partial response	the ORR analysis will be performed after 12 months from the last patient enrolled
median PFS	median time of survival without disease progression	the PFS analysis will be performed after 12 months from the last patient enrolled
median OS	median time of overall survival	the OS analysis will be performed after 12 months from the last patient enrolled
Adverse Events	description and rate of treatment-related adverse events	AEs will be collected until 3 months from the discontinuation of the experimental therapy by the last patient enrolled

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Principal Investigator: Giampaolo Tortora, Fondazione Policlinico Universitario A. Gemelli, IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2020
• Primary Completion (Actual): September 13, 2023
• Study Completion (Actual): September 13, 2023

Study Registration Dates

• First Submitted: March 14, 2023
• First Submitted That Met QC Criteria: March 18, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 18, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Kidney Neoplasms; Carcinoma; Carcinoma, Renal Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Nivolumab; Metformin
• Other Study ID Numbers: 3209

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No