Clinical Trials /

Nivolumab and Metformin Hydrochloride in Treating Patients With Stage III-IV Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

NCT03048500

Description:

The purpose of this study is to find the benefits of combining nivolumab with metformin in advanced non-small cell lung cancer with and without prior treatment with immunotherapy. We will also be looking at the safety of the combination. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Metformin is approved by the US Food and Drug Administration (FDA) to treat diabetes. In this study, Metformin is being used to treat cancer. This use is not approved by the FDA; therefore, in this study, it is considered experimental. Experimental means the U.S. FDA has not approved the drug for use in your type of cancer. Nivolumab is an antibody (a human protein that sticks to a part of the tumor and/or immune cells) designed to allow the body's immune system to work against tumor cells. It is believed that metformin has immune modifying properties, meaning it can boost your immune system. As a result, it may help certain cancer treatments, known as immunotherapy, to work better.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Metformin Hydrochloride in Treating Patients With Stage III-IV Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
  • Official Title: Parallel Proof of Concept Phase 2 Study of Nivolumab and Metformin Combination Treatment in Advanced Non-small Cell Lung Cancer With and Without Prior Treatment With PD-1/PD-L1 Inhibitors

Clinical Trial IDs

  • ORG STUDY ID: NU 16L04
  • SECONDARY ID: STU00204354
  • SECONDARY ID: NU 16L04
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2017-00060
  • NCT ID: NCT03048500

Conditions

  • Recurrent Non-Small Cell Lung Carcinoma
  • Stage III Non-Small Cell Lung Cancer
  • Stage IIIA Non-Small Cell Lung Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Metformin HydrochlorideCidophage, Dimefor, Glifage, Glucoformin, Glucophage, Glucophage ER, Metformin HCl, Riomet, SioforTreatment (metformin hydrochloride, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (metformin hydrochloride, nivolumab)

Purpose

The purpose of this study is to find the benefits of combining nivolumab with metformin in advanced non-small cell lung cancer with and without prior treatment with immunotherapy. We will also be looking at the safety of the combination. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Metformin is approved by the US Food and Drug Administration (FDA) to treat diabetes. In this study, Metformin is being used to treat cancer. This use is not approved by the FDA; therefore, in this study, it is considered experimental. Experimental means the U.S. FDA has not approved the drug for use in your type of cancer. Nivolumab is an antibody (a human protein that sticks to a part of the tumor and/or immune cells) designed to allow the body's immune system to work against tumor cells. It is believed that metformin has immune modifying properties, meaning it can boost your immune system. As a result, it may help certain cancer treatments, known as immunotherapy, to work better.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess anti-tumor activity of the combination treatment of metformin hydrochloride
      (metformin) with nivolumab in patients with non-small cell lung cancer with and without prior
      exposure to PD-1/PD-L1 inhibitors.

      SECONDARY OBJECTIVES:

      I. To assess the efficacy of the combination treatment of metformin with nivolumab according
      to depth, duration, and persistence of response, disease control rate (DCR; complete response
      [CR], partial response [PR], and stable disease [SD] at 24 weeks), progression-free survival
      (PFS), and overall survival (OS) in patients with non-small cell lung cancer with and without
      prior exposure to PD-1/PD-L1 inhibitors using Response Evaluation Criteria in Solid Tumors
      (RECIST) criteria version (v)1.1.

      II. To assess the efficacy of the combination treatment of metformin with nivolumab according
      to depth, duration, and persistence of response, objective response rate (ORR), DCR, PFS, and
      OS in the above population using immune-related RECIST (irRECIST) criteria.

      III. To assess the safety and tolerability profile of the combination treatment of metformin
      with nivolumab in the above population using Common Terminology Criteria for Adverse Events
      (CTCAE) version 4.03.

      TERTIARY OBJECTIVES:

      I. To assess the immune-related tumor and blood biomarkers including T cell markers and their
      association with treatment response in the above population.

      II. To assess the dynamic change in both immune and genomic biomarkers in blood that may
      correlate with response to metformin.

      OUTLINE:

      Patients receive metformin hydrochloride orally (PO) once daily (QD) on days -7 to -1 and
      1-28. Patients also receive nivolumab intravenously (IV) over 30 minutes on days 1 and 15 of
      courses 1-4, then over 60 minutes on day 1 beginning course 5. Courses repeat every 28 days
      in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.

      After completion of study treatment, patients are followed up for 30 days, every 3 months for
      1 year, then every 6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (metformin hydrochloride, nivolumab)ExperimentalPatients receive metformin hydrochloride PO once QD on days -7 to -1 and 1-28. Patients also receive nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4, then over 60 minutes on day 1 beginning course 5. Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity, or withdrawal of consent.
  • Metformin Hydrochloride
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed, locally advanced or metastatic stage IV
             or non-resectable stage III non-small cell lung cancer (NSCLC)

          -  Patients may have received any number and type of prior treatment regimens for their
             NSCLC (aside from patients in arm A, who cannot have had PD-1/PD-L1 inhibitors)

          -  Arm A: patients must be treatment naive to single agent PD-1/PD-L1 inhibitors
             including but not limited to durvalumab, pembrolizumab, atezolizumab, nivolumab, and
             avelumab

               -  Arm B: patients' tumor must be either refractory to or progressed on one of the
                  above agents

               -  Both cases are defined by initial progressive disease (PD) or PD after CR, PR, or
                  SD using RECIST criteria, respectively

          -  Patients must have measurable disease according to the standard RECIST version 1.1

               -  NOTE: computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to
                  assess the measurable disease must have been completed with 28 days prior to the
                  study drug initiation

          -  Patients need to have adequate kidney, bone marrow, and liver functions =< 14 days of
             registration as specified below:

          -  Absolute neutrophil >= 1,000/mcL; transfusion and/or growth factor are permitted
             within any timeframe

          -  Platelets >= 50,000/mcl; transfusion and/or growth factor are permitted within any
             timeframe

          -  Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (or =< 3
             times ULN in case of liver metastasis or Gilbert syndrome)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT])
             =< 2.5 X institutional ULN (or =< 5 times ULN in case of liver metastasis)

          -  Creatinine =< 1.4 ng/mL for females; =< 1.5 ng/mL for males; patients with creatinine
             =< 2.0 ng/mL may still be eligible if in the opinion of the investigator, the benefits
             of treatment outweigh the risks

          -  Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
             of =< 2

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent prior to registration on study

          -  Females of child-bearing potential (FOCBP) and men who are sexually active must agree
             to follow instructions for method(s) of contraception for the duration of treatment
             and the designated post-treatment period

               -  NOTE: a FOCBP is any woman (regardless of sexual orientation, having undergone a
                  tubal ligation, or remaining celibate by choice) who meets the following
                  criteria:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy

                    -  Has had menses at any time in the preceding 12 consecutive months (and
                       therefore has not been naturally postmenopausal for > 12 months)

          -  FOCBP must have a negative pregnancy test =< 7 days prior to registration on study

          -  Patients with known history of central nervous system (CNS) metastases are eligible if
             CNS disease has been radiographically and neurologically stable for at least 6 weeks
             prior to study registration and do not require corticosteroids (of any dose) for
             symptomatic management

               -  NOTE: CNS imaging is only required at baseline for patients with known history of
                  CNS metastases

          -  Patients must have the ability to swallow oral medications

          -  Patients who are known to be EGFR- or ALK-positive must have received prior EGFR- or
             ALK-targeted therapy, respectively

               -  NOTE: in such cases, documentation of EGFR mutation or ALK translocation status
                  should be provided if available

        Exclusion Criteria:

          -  Both arms: patients should not have received metformin within 6 months prior to
             registration

               -  Arm B: patients who were on metformin while on PD-1/PD-L1 inhibitors are not
                  eligible

          -  Patients should not have received prior immunotherapies (exception; arm B); they
             include but are not limited to interleukin-2 and other immune checkpoint antagonist
             targeting CTLA-4, LAG-3, TIM-3, KIR etc. and/or agonists targeting OX40, ICOS, CD137,
             etc

               -  NOTE: prior cancer vaccine treatments are permitted; for arm B, exposure to
                  single agent PD-1/PD-L1 inhibitors are allowed >= 14 days from registration

          -  Arm B: patients must not have had prior exposure to combination treatment with
             PD-1/PD-L1 inhibitors and another systemic treatment

               -  NOTE: radiation therapy and surgery do not count as combination treatment

          -  Patients who are intolerant to PD-1/PD-L1 inhibitors and/or metformin are excluded

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including chronic prolonged systemic corticosteroids (defined as corticosteroid use of
             duration one month or greater), should be excluded; these include but are not limited
             to patients with a history of:

               -  Immune related neurologic disease

               -  Multiple sclerosis

               -  Autoimmune (demyelinating) neuropathy

               -  Guillain-Barre syndrome

               -  Myasthenia gravis

               -  Systemic autoimmune disease such as systemic lupus erythematosus (SLE)

               -  Connective tissue diseases

               -  Scleroderma

               -  Inflammatory bowel disease (IBD)

               -  Crohn's

               -  Ulcerative colitis

               -  Patients with a history of toxic epidermal necrolysis (TEN)

               -  Stevens-Johnson syndrome

               -  Anti-phospholipid syndrome

                    -  NOTE: subjects with vitiligo, type I diabetes mellitus, residual
                       hypothyroidism due to autoimmune condition only requiring hormone
                       replacement, psoriasis not requiring systemic treatment, or conditions not
                       expected to recur in the absence of an external trigger are permitted to
                       enroll

          -  Patients are ineligible who have any condition requiring systemic treatment with
             corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
             medications =< 14 days prior to registration

               -  NOTE: inhaled steroids and adrenal replacement steroid doses > 10 mg daily
                  prednisone equivalents are permitted in the absence of active autoimmune disease;
                  a brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg,
                  contrast dye allergy) or for treatment of non-autoimmune conditions (eg,
                  delayed-type hypersensitivity reaction caused by a contact allergen) is permitted

          -  Patients who have an uncontrolled intercurrent illness including, but not limited to
             any of the following, are not eligible:

               -  Uncontrolled hypertension - blood pressure >= 150/90 mmHg despite medical therapy

               -  Ongoing or active infection requiring systemic treatment

               -  Symptomatic congestive heart failure

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

               -  Any other illness or condition that the treating investigator feels would
                  interfere with study compliance or would compromise the patient's safety or study
                  endpoints

          -  Patients must not have had another primary malignancy within 2 years prior to starting
             study treatment with the exception of adequately treated basal cell carcinoma,
             squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of
             the uterine cervix, or any local cancers that are deemed to be cured from
             investigator's point of view

          -  Patients may not be receiving any other investigational agents =< 14 days from
             registration

          -  Patients with known history of testing positive for human immunodeficiency virus (HIV)
             or known acquired immunodeficiency syndrome (AIDS) are excluded

          -  Patients who have any positive test for hepatitis B or hepatitis C virus indicating
             acute or chronic infection are excluded

          -  Patients with known diabetes whose glucose control or general health condition may be
             adversely affected by the use of metformin as per the study protocol as deemed by
             either the study investigator or endocrinologist are excluded

          -  Patients must not have any of the following contraindications to metformin:

               -  Hypersensitivity to metformin or any component of the formulation

               -  Kidney dysfunction or abnormal creatinine (Cr < 2 ng/mL) from any cause

               -  Acute or metabolic acidosis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:24 weeks from start of treatment
Safety Issue:
Description:Anti-tumor activity will be assessed by ORR (complete response and partial response) using RECIST criteria v1.1.

Secondary Outcome Measures

Measure:Depth of Response
Time Frame:24 weeks from start of treatment
Safety Issue:
Description:Depth of response (SD or PR) defined as the change in the sum of the largest tumor diameters per RECIST v1.1 and irRECIST criteria.
Measure:Duration of Response
Time Frame:Up to 3 years
Safety Issue:
Description:Duration of response will be evaluated using RECIST v1.1 and irRECIST criteria.
Measure:Persistence of Response
Time Frame:Up to 3 years
Safety Issue:
Description:Persistence of response will be assessed using RECIST v1.1 and irRECIST criteria.
Measure:Disease Control Rate (DCR)
Time Frame:24 weeks from start of treatment
Safety Issue:
Description:DCR will be evaluated using RECIST v1.1 and irRECIST criteria.
Measure:Progression-Free Survival (PFS)
Time Frame:At 1 year than at 2 years
Safety Issue:
Description:PFS will be assessed using RECIST v1.1 and irRECIST criteria.
Measure:Overall Survival (OS)
Time Frame:At 1 year than at 2 years
Safety Issue:
Description:OS will be assessed using RECIST v1.1 and irRECIST criteria.
Measure:ORR
Time Frame:24 weeks from start of treatment
Safety Issue:
Description:ORR (complete response and partial response) will be evaluated using irRECIST criteria.
Measure:Incidence of Adverse Events
Time Frame:Up to 3 years
Safety Issue:
Description:Assess the safety and tolerability of the combination treatment of metformin with nivolumab by evaluating the number, frequency, and severity of adverse events using CTCAE version 4.03.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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