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
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.
