The purpose of this study is to evaluate the effectiveness and safety of the combination of
Pembrolizumab (KEYTRUDA®) and the investigational drug, Metformin.
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
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
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
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.
- 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
- Patients may be treatment naïve in the advanced setting or may be on anti-PD-1 therapy
with SD or CR for at least 12 weeks.
- 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
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
- 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.
- Has a 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,
- 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
- 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 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
- Has a history of (non-infectious) pneumonitis that required steroids or current
- 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.