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

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 maybe included on study after discussion with the Sponsor, given that the primaryendpoint of the study is Ki-67 of TIL (flow cytometry)

• Have biopsiable disease. Be willing to provide tissue from a newly obtained biopsyof a tumor lesion. Newly-obtained is defined as a specimen obtained up to 30 daysprior to initiation of treatment on Day 1.

• Patients may have received prior adjuvant therapy with anti-PD-1, anti-CTLA-4, orBRAF/MEK inhibitors.

• Patients may be immunotherapy treatment naïve in the advanced setting or may be onanti-PD-1 therapy with SD or PR for at least 12 weeks. Patients may have receivedipilimumab plus nivolumab in the metastatic setting with SD or PR for at least 12weeks 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 upperlimit of normal (ULN) (GFR can also be used in place of creatinine or CrCl ≥60mL/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 withtotal bilirubin levels > 1.5 ULN

6. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with livermetastases

7. Albumin >2.5 mg/dL

8. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unlesssubject is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants; Activated PartialThromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulanttherapy as long as PT or PTT is within therapeutic range of intended use ofanticoagulants

• Patients must be free of active brain metastases by contrast-enhanced CT/MRI scanswithin 2 weeks prior to starting the study drugs. If known to have prior brainmetastases, 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 physiciandetermines that they have recovered from radiation and are not experiencingradiation related clinically significant adverse events.

• Female patients of child bearing potential must have a negative urine or serumpregnancy test within 7 days from the time of registration.

• Female subject of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

• Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile, or abstain from heterosexual activity forthe 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 sterilizedor have not been free from menses for > 1 year.

• Male subjects should agree to use an adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of studytherapy.

Exclusion Criteria:

• Has a current confirmed diagnosis of type 1 diabetes or type 2 diabetes that hasbeen 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 afterdiscussion with the principal investigator. Patients currently on metformin will beexcluded.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to the first dose oftrial 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 studyDay 1 (this excludes patients on anti-PD1) or who has not recovered (i.e., ≤ Grade 1or at baseline) from adverse events due to agents administered more than 4 weeksearlier.

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapywithin 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or atbaseline) from adverse events due to a previously administered agent. Note: Subjectswith ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for thestudy. If subject received major surgery, they must have recovered adequately fromthe 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 ofthe skin that has undergone potentially curative therapy or in situ cervical cancer.

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by imaging for at leasttwo weeks prior to the first dose of trial treatment and any neurologic symptomshave 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. Thisexception does not include carcinomatous meningitis which is excluded regardless ofclinical stability.

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxineor physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) isnot considered a form of systemic treatment.

• Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

• Has an active infection requiring systemic IV antibiotic therapy.

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 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] isdetected). Note: Without known history, testing only needs to be performed if thereis 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 andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed.