A Tissue Collection Study of Pembrolizumab (MK-3475) in Subjects With Resectable Advanced Melanoma
Condition: Malignant Melanoma
MeSH terms: Melanoma
Intervention: pembrolizumab
Intervention description: 200 mg Subjects will receive 1 dose of neoadjuvant pembrolizumab, followed by complete resection and then a year of adjuvant pembrolizumab
Intervention MeSH terms: Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 33.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Clinical stage III or resectable stage IV melanoma (MEL)

Summary:

      The main purpose of this trial is to evaluate the safety, tolerability and adverse event
      profile of pembrolizumab in subjects who have high risk melanoma before and after their
      standard of care surgical resection, and to collect tumor tissue from subjects before and
      after receipt of pembrolizumab to look at how the experimental drug interacts with tumor
      tissue. Subjects will receive 1 dose of neoadjuvant pembrolizumab, followed by complete
      resection and then a year of adjuvant pembrolizumab
    

Eligibility criteria:

        Inclusion Criteria:

          1. The subject must have clinical stage III or resectable stage IV MEL. Subject's may not
             have a diagnosis of uveal or mucosal melanoma.

          2. The subject must be expected to have an adequate amount of tumor burden to yield 2-4
             pre-operative research core biopsy (14-gauge needle) specimens or the equivalent
             amount of tissue (4-6 mm punch biopsy), in addition, to the tissue required for
             diagnostic purposes.

          3. The subject must be expected to have an adequate amount of residual tumor after their
             pre-operative research tumor tissue collection, such that their operative research
             tumor collection will also yield at least 4-6 research core biopsy specimens or the
             equivalent amount of tissue

          4. The subject must be willing to undergo the two paired tumor tissue biopsy procedures
             to obtain samples for biomarker analysis. Tissue obtained must not be previously
             irradiated.

          5. Either the subject or the subject's legal representative must be willing and able to
             provide written informed consent for the trial.

          6. The subject must be ≥ 18 years of age on day of signing informed consent.

          7. The subject must have a performance status of 0 or 1 on the ECOG Performance Scale.

          8. The subject must demonstrate adequate organ function as defined in Table 1, all
             screening labs must be performed within 10 days of treatment initiation.

             Table 1 Adequate Organ Function Laboratory Values System Laboratory Value
             Hematological Absolute neutrophil count (ANC)

               -  1500/mcL Platelets

               -  100,000/ mcL Hemoglobin

               -  9 g/dL or ≥5.6 mmol/L Renal Serum creatinine OR Measured or calculated creatinine
                  clearance (GFR can also be used in place of creatinine or CrCl)

                  ≤1.5 X upper limit of normal (ULN) OR

               -  50 mL/min for subject with creatinine levels > 1.5 X institutional ULN UPCC#
                  01615: Tissue Collection Study of Pembrolizumab in Advanced Melanoma Version
                  Date: 12/30/2014 Page 10 Hepatic Serum total bilirubin

                    -  1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels
                       > 1.5 ULN AST (SGOT) and ALT (SGPT)

                    -  2.5 X ULN OR

                    -  5 X ULN for subjects with liver metastases Coagulation International
                       Normalized Ratio (INR) or Prothrombin Time (PT) 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

                    -  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
                       aCreatinine clearance should be calculated per institutional standard.

          9. Female subject's of childbearing potential must have a negative serum pregnancy test
             within 72 hours prior to receiving the first dose of study medication.

         10. The subject must be willing to use protocol defined method(s) of contraception:

        Female subjects of childbearing potential must be willing to use 2 methods of
        contraception, or abstain from heterosexual sexual intercourse for two weeks before the
        time of the first dose of study medication, while on study, through 120 days after the last
        dose of study medication.

        Female subject's of childbearing potential are defined as those women who have not been
        surgically sterilized or have not been free from menses for > 1 year.

        Male subjects must agree to use an adequate method of contraception starting with the first
        dose of study medication, while on study, through 120 days after the last dose of study
        medication.

        Acceptable forms of birth control include condoms, diaphragms, cervical cap, an
        intra-uterine device (IUD), surgical sterility (tubal ligation or a partner that has
        undergone a vasectomy), or oral contraceptives, OR the subject must agree to completely
        abstain from heterosexual intercourse. Abstinence at certain times of the cycle only, such
        as during the days of ovulation, after ovulation and withdrawal are not acceptable methods
        of birth control

        Exclusion Criteria:

          1. Subject has unresectable disease; i.e. in the opinion of the surgical oncologist, all
             of the subject's melanoma cannot be completely removed with a clear margin.

          2. Subject is currently participating in or has participated in a study of an
             investigational agent or using an investigational device within 4 weeks of the first
             dose of study treatment.

          3. Subject has a known hypersensitivity to pembrolizumab or any of its ingredients.

          4. Subject has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
             or any other form of immunosuppressive therapy within 7 days prior to enrollment.

          5. Subject has had a prior monoclonal antibody 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.

          6. Subject has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,
             anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agents
             (including ipilimumab), interferon, high dose IL-1 or any other antibody or drug
             specifically targeting T-cell co-stimulation or checkpoint pathways.

          7. Subject has had prior chemotherapy, targeted small molecule therapy, 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

          8. For subject's who have received major surgery, the subject must have recovered
             adequately from the toxicity and/or complications from the intervention prior to
             starting study therapy.

          9. Subject has had radiation therapy to the tumor selected for research collection, or
             has had radiation therapy to any site within 4 weeks prior to study Day 1.

         10. Subject has received transfusion of blood products (including platelets or red blood
             cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or
             recombinant erythropoietin) within 4 weeks prior to study Day 1.

         11. Subject has a known additional malignancy that is progressing or requires active
             treatment.

         12. Subject has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis.

             Note: Subjects with previously treated brain metastases will be eligible to
             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.

         13. Subject has an active autoimmune disease requiring systemic treatment within the past
             3 months or a documented history of clinically severe autoimmune disease, or a
             syndrome that requires systemic steroids or immunosuppressive agents.

             Note: Subjects with vitiligo or resolved childhood asthma/atopy are an exception to
             this rule. Subjects that require intermittent use of bronchodilators or local steroid
             injections will not be excluded from the study. Subjects with hypothyroidism stable on
             hormone replacement or Sjorgen's syndrome will not be excluded from the study.

         14. Subject has evidence of interstitial lung disease or active, non-infectious
             pneumonitis.

         15. Subject has an active infection requiring systemic therapy, including active
             tuberculosis

         16. Subject 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.

         17. Subject has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         18. Subject is pregnant or breastfeeding, or expecting to conceive or father a child
             within the projected duration of the trial participation (from 2 weeks prior to the
             first dose of study treatment, while participating on the study and through 120 days
             after the last dose of trial treatment).

         19. Subject has severe cardiovascular disease, i.e. arrhythmias, requiring chronic
             treatment, congestive heart failure (NYHA Class III or IV) or symptomatic ischemic
             heart disease.

         20. Subject has hepatic decompensation (Child-Pugh score >6 [class B and C]).

         21. Subject has uncontrolled thyroid dysfunction

         22. Subject has uncontrolled diabetes mellitus

         23. Subject has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
             as determined by medical record review.

         24. Subject has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV
             RNA [qualitative] is detected) as determined by medical record review.

         25. Subject has received a live vaccine within 30 days prior to the first dose of trial
             treatment.