Clinical Trials /

Nivolumab and Metformin in Patients With Treatment Refractory MSS Colorectal Cancer

NCT03800602

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Metformin in Patients With Treatment Refractory MSS Colorectal Cancer
  • Official Title: Phase II Trial of Nivolumab and Metformin in Patients With Treatment Refractory MSS Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: IRB00106678
  • SECONDARY ID: NCI-2018-02201
  • SECONDARY ID: Winship4494-18
  • NCT ID: NCT03800602

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

Interventions

DrugSynonymsArms
MetforminGlucophage, Glumetza, FortametTreatment (nivolumab, metformin)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, metformin)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the effect of nivolumab and metformin combination on the overall response rate
      (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      SECONDARY OBJECTIVES:

      I. To determine the effect of nivolumab and metformin combination on clinical outcomes,
      progression free survival and overall survival, and biochemical response (CEA).

      II. To compare the effect of nivolumab and metformin combination on immune and metabolic
      biomarkers in the tumor microenvironment and systemic circulation (pre and post treatment
      paired biopsies required).

      OUTLINE:

      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

      After completion of study treatment, patients are followed up at day 30 and then periodically
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, metformin)ExperimentalPatients 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.
  • Metformin
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception, starting with the first dose of study therapy through 120 days after
             the last dose of study therapy.

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the subject

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study medication

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the subject

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  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)

          -  Has known active hepatitis B (e.g., hepatitis surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has received a live vaccine within 30 days of planned start of study therapy.

               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
                  are live attenuated vaccines, and are not allowed

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris or
             myocardial infraction within 6 months of study entry, serious cardiac arrhythmia
             requiring medications, baseline corrected QT (QTc) > 450 msec or previous history of
             QT prolongation while taking other medications

          -  Other medications, or severe acute/chronic medical or psychiatric condition, or
             laboratory abnormality that may increase the risk associated with study participation
             or study drug administration, or may interfere with the interpretation of study
             results, and in the judgment of the investigator would make the subject inappropriate
             for entry into this study

          -  Has a known additional malignancy that is progressing or requires active treatment;
             exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer;
             subjects with prior malignancies are eligible if the subject has been disease free for
             > 5 years

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 120 days
             after the last dose of trial treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 1 year after study start
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Assessed up to 2 years after study start
Safety Issue:
Description:For progression free survival, progression or death from any cause will be defined as the event. Patients will be censored at time of last follow-up.
Measure:Overall survival (OS)
Time Frame:Assessed up to 2 years after study start
Safety Issue:
Description:For overall survival, death from any cause will be defined as the event. Patients will be censored at time of last follow-up.
Measure:Biological response: carcinoembryonic antigen (CEA)
Time Frame:Up to 1 year after study start
Safety Issue:
Description:Tumor marker carcinoembryonic antigen (CEA) will be assessed.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

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