Nivolumab and Metformin in Patients With Treatment Refractory MSS Colorectal Cancer

NCT03800602 | Completed Phase 2 Results DMC FDA Drug

• 4 other identifiers: IRB00106678NCI-2018-02201Winship4494-18P30CA138292
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 3

Brief Summary

This phase II trial studies how well nivolumab and metformin work in treating patients with microsatellite stable (MSS) stage IV colorectal cancer that has not responded to previous treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Metformin is an antidiabetic drug that and may reduce the risk of colorectal cancer development in patients. Giving nivolumab and metformin may work better in treating patients with refractory microsatellite metastatic colorectal cancer.

Conditions

Colorectal Adenocarcinoma; Metastatic Microsatellite Stable Colorectal Carcinoma; Refractory Colorectal Carcinoma; Stage IV Colorectal Cancer; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer; Stage IVC Colorectal Cancer; Colorectal Cancer Metastatic

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1., and rate will be calculated as a proportion (responders/total patients).

  Up to 1 year after study start

Secondary Outcomes (3)

• Progression Free Survival (PFS)

  Assessed up to 2 years after study start

• Overall Survival (OS)

  Assessed up to 2 years after study start

• Biological Response: Carcinoembryonic Antigen (CEA)

  Up to 1 year after study start

Study Arms (1)

Treatment (nivolumab, metformin)

EXPERIMENTAL

Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal.

Drug: Metformin; Biological: Nivolumab

Interventions

Metformin DRUG

Given PO

Also known as: Glucophage, Glumetza, Fortamet

Treatment (nivolumab, metformin)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Treatment (nivolumab, metformin)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed stage IV colorectal adenocarcinoma with measurable disease
• Prior treatment with 5 Fluorouracil (or capecitabine), oxaliplatin and irinotecan containing chemotherapy (needs to be treated with anti-epidermal growth factor receptor (EGFR) agent if extended RAS wild type)
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky ≥ 70%)
• Life expectancy of greater than 3 months
• Absolute neutrophil count ≥ 1,500/µL
• Platelets ≥ 100,000/µL
• Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min/1.73 m² for patients with creatinine levels \> 1.5 x ULN. Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin \> 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase\[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\] ≤ 2.5 x institutional upper limit of normal
• Serum albumin ≥ 2.5 mg/dl
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Patients with diabetes mellitus should be on a stable diabetic treatment regimen for at least 1 month prior to trial enrollment and keep a blood glucose level log at home for the first 4 weeks of the trial
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Metformin use in the last 3 months
• Patients who are receiving any other investigational agents
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and metformin
• Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has known substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti-PD-L2 agent
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

Sponsors & Collaborators

• Emory University: lead
• Bristol-Myers Squibb: collaborator
• National Cancer Institute (NCI): collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (3)

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342, United States

Location

Related Publications (1)

• Akce M, Farran B, Switchenko JM, Rupji M, Kang S, Khalil L, Ruggieri-Joyce A, Olson B, Shaib WL, Wu C, Alese OB, Diab M, Lesinski GB, El-Rayes BF. Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer. J Immunother Cancer. 2023 Oct;11(10):e007235. doi: 10.1136/jitc-2023-007235.

  PMID: 37852737 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Metformin; Nivolumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Olumide B. Gbolahan MBBS, MSc
• Organization: Emory University

ogbolah@emory.edu

404-778-0032

Study Officials

• Olumide B. Gbolahan, MBBS, MSc

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 9, 2019
• First Posted: January 11, 2019
• Study Start: January 15, 2019
• Primary Completion: September 4, 2020
• Study Completion: September 4, 2021
• Last Updated: September 5, 2024
• Results First Posted: September 5, 2024

Record last verified: 2024-09

Locations

US (3)