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A Trial of Pembrolizumab and Metformin Versus Pembrolizumab Alone in Advanced Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03311308
Recruitment Status : Recruiting
First Posted : October 17, 2017
Last Update Posted : September 16, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Yana Najjar, University of Pittsburgh

Brief Summary:
The purpose of this study is to evaluate the effectiveness and safety of the combination of Pembrolizumab (KEYTRUDA®) and the investigational drug, Metformin.

Condition or disease Intervention/treatment Phase
Advanced Melanoma Drug: Pembrolizumab Injection [Keytruda] Drug: Metformin Phase 1

Detailed Description:

Patients are being asked to take part in this clinical research study because they have advanced, un-resectable stage III or IV Melanoma. If they participate they will be randomized to receive Pembrolizumab (KEYTRUDA®) or the combination of Pembrolizumab (KEYTRUDA®) plus Metformin.

This research study will evaluate the effectiveness and safety of the combination of Pembrolizumab (KEYTRUDA®) and the investigational drug, Metformin.

Patients will be randomized into one of two groups - either Arm A or Arm B. In Arm A, patients will receive pembrolizumab alone. In Arm B, patients will receive both pembrolizumab and metformin.

If patients are randomized to Arm A, they will be administered pembrolizumab (200 mg), by IV, every three weeks. Pembrolizumab can be administered up to two years, if disease does not progress or have unacceptable toxicity. However, if the disease progresses the patient may continue on the study if they are clinically stable or clinically improved.

If patients are randomized to Arm B, they will be administered pembrolizumab (200 mg), by IV, every three weeks, plus metformin (500 mg), once a day for nine weeks. Metformin will be taken in the morning with food.

Discontinuation of treatment may be considered for patients who have attained a confirmed complete response that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments with pembrolizumab beyond the date when the initial complete response was declared.

Patients will be followed for 5 years after removal from study or until death, whichever occurs first, through standard of care visits, phone call or by medical records review.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Profiling and Reversing Metabolic Insufficiency in the Tumor Microenvironment in Advanced Melanoma: A Trial of Pembrolizumab and Metformin Versus Pembrolizumab Alone in Advanced Melanoma
Actual Study Start Date : December 6, 2017
Estimated Primary Completion Date : January 2027
Estimated Study Completion Date : December 2028


Arm Intervention/treatment
Active Comparator: Pembrolizumab
Pembrolizumab (Keytruda), 200 mg, by IV, every three weeks, for up to 2 years
Drug: Pembrolizumab Injection [Keytruda]
200mg, IV, every three weeks, up to two years
Other Name: Keytruda

Experimental: Pembrolizumab and Metformin Combination
Pembrolizumab (Keytruda), 200mg, by IV, every three weeks, for up to 2 years will be taken in combination with Metformin, 500mg, once a day, for nine weeks
Drug: Pembrolizumab Injection [Keytruda]
200mg, IV, every three weeks, up to two years
Other Name: Keytruda

Drug: Metformin
500 mg, by mouth, once a day for nine weeks.




Primary Outcome Measures :
  1. Ki-67 proliferation index in T cell [ Time Frame: up to 4 years ]
    determine the cell cycle status


Secondary Outcome Measures :
  1. Number of participants experiencing adverse events [ Time Frame: up to 4 years ]
    Number of participants that received a combination of Pembrolizumab and Metformin who experience treatment-related adverse events as assessed by CTCAE v4.0

  2. Hypoxia in the primary tumor by IHC Staining [ Time Frame: up to 4 years ]
  3. Mitochondrial functional restoration in Tumor Infiltrating Lymphocytes by mitochondrial mass [ Time Frame: up to 4 years ]
    patients treated with metformin and pembrolizumab compared to pembrolizumab alone

  4. Cell cycle status of peripheral blood T lymphocytes by Flow Cytometry [ Time Frame: up to 4 years ]
    patients treated with pembrolizumab and metformin compared to patients treated with pembrolizumab alone

  5. overall tumor response rate [ Time Frame: up to 4 years ]
    patients treated with metformin and pembrolizumab compared to pembrolizumab alone, as measured by clinical tumor measurement and radiological tumor measurement on PET/CT scans.

  6. Mitochondrial functional restoration in Tumor Infiltrating Lymphocytes by Seahorse metabolic profiling [ Time Frame: up to 4 years ]
    patients treated with metformin and pembrolizumab compared to pembrolizumab alone


Other Outcome Measures:
  1. Functional restoration of peripheral blood T lymphocytes [ Time Frame: up to 4 years ]
  2. Progression free survival [ Time Frame: up to 5 years ]
  3. Correlating hypoxia measurements in the tumor with FDG avidity on PET. [ Time Frame: up to 4 years ]
  4. MDSC in the tumor microenvironment and peripheral blood by flow cytometry. [ Time Frame: up to 4 years ]
  5. Melanoma tumor antigen specific T cell responses by flow cytometry. [ Time Frame: up to 4 years ]
  6. Overall survival [ Time Frame: up to 5 years ]
  7. Treg levels in the tumor microenvironment by flow cytometry [ Time Frame: up to 4 years ]
  8. Degree of mitochondrial functional restoration in TIL of patients treated with metformin and pembrolizumab compared to pembrolizumab alone [ Time Frame: up to 4 years ]
    flow cytometry will be used to measure mitochondrial mass and glucose uptake in T cells



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be willing and able to provide written informed consent for the trial.
  • Have un-resectable (stage III) or advanced (stage IV) melanoma.
  • Be 18 years of age or older on day of signing informed consent
  • Have measurable disease based on RECIST 1.1. Patients without measurable disease may be included on study after discussion with the Sponsor, given that the primary endpoint of the study is Ki-67 of TIL (flow cytometry)
  • Have biopsiable disease. Be willing to provide tissue from a newly obtained biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 30 days prior to initiation of treatment on Day 1.
  • Patients may have received prior adjuvant therapy with anti-PD-1, anti-CTLA-4, or BRAF/MEK inhibitors.
  • Patients may be immunotherapy treatment naïve in the advanced setting or may be on anti-PD-1 therapy with SD or PR for at least 12 weeks. Patients may have received ipilimumab plus nivolumab in the metastatic setting with SD or PR for at least 12 weeks on maintenance anti-PD1.
  • Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.
  • Have a baseline HbA1c ≤ 6.4.
  • Demonstrate adequate organ function. All screening labs should be performed within 14 days of treatment initiation.

    1. Absolute neutrophil count (ANC) ≥1,500 /mcL
    2. Platelets ≥100,000 / mcL
    3. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
    4. Serum creatinine OR Measured or calculateda creatinine clearance ≤1.5 X upper limit of normal (ULN) (GFR can also be used in place of creatinine or CrCl ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN)
    5. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    6. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
    7. Albumin >2.5 mg/dL
    8. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤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; 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 must be free of active brain metastases by contrast-enhanced CT/MRI scans within 2 weeks prior to starting the study drugs. If known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on MRI evaluation within 4 weeks from SRS or WBRT treatment.
  • Patients who have received radiation may be enrolled if the treating physician determines that they have recovered from radiation and are not experiencing radiation related clinically significant adverse events.
  • Female patients of child bearing potential must have a negative urine or serum pregnancy test within 7 days from the time of registration.
  • 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.
  • Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  • Male subjects should 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.

Exclusion Criteria:

  • Has a current confirmed diagnosis of type 1 diabetes or type 2 diabetes that has been diagnosed by an HbA1c ≥6.5, or is on any hypoglycemic medications (insulin, metformin, etc). Patients with a screening HbA1c 6.5-7.0 may be included after discussion with the principal investigator. Patients currently on metformin will be excluded.
  • 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 a known history of active TB (Bacillus Tuberculosis).
  • Hypersensitivity to pembrolizumab or any of its excipients.
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 (this excludes patients on anti-PD1) or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  • 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.
  • 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 two 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.
  • 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., thyroxineor physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  • Has an active infection requiring systemic IV antibiotic therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected). Note: Without known history, testing only needs to be performed if there is clinical suspicion for Hepatitis B or C.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03311308


Contacts
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Contact: Yana Najjar, MD 412-692-4724 najjaryg@upmc.edu
Contact: Amy Rose, RN 412-647-8587 kennaj@upmc.edu

Locations
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United States, Pennsylvania
Univ of Pittsburgh Medical Center Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Amy Rose, RN    412-647-8587      
Sponsors and Collaborators
Yana Najjar
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: Yana Najjar, Md Universtiy of Pittsburgh
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Responsible Party: Yana Najjar, Assistant Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03311308    
Other Study ID Numbers: 16-196
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: September 16, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Yana Najjar, University of Pittsburgh:
Melanoma
Unresectable
Stage III
Stage IV
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Metformin
Pembrolizumab
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents