A Study to Evaluate the Safety and Effectiveness of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma Patients


About this study

The purpose of this 2-part study is to evaluate the safety and effectiveness of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design for up to 17 cycles. Participants who receive placebo or who stop treatment after receiving 17 cycles of pembrolizumab in Part 1, do not experience disease recurrence within 6 months of completing pembrolizumab in Part 1, and do not stop treatment with pembrolizumab for disease recurrence or intolerability, may be eligible to receive up to 35 additional cycles of pembrolizumab in Part 2 in an open-label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria: 

  • Male/female participants who are ≥ 12 years of age on the day of signing informed consent/assent [unless local regulations and/or institutional policies do not allow for participants < 18 years of age to participate; for those sites, the eligible population is ≥ 18  years of age] with surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per AJCC 8th edition guidelines.
    • Note: Participants must have T stage of T3b, T4a, or T4b with pathologically confirmed negative SLN biopsy, and no evidence of regional (N0) or distant metastatic disease (M0) per AJCC 8th edition guidelines. 
  • Participants must not have been previously treated for melanoma beyond complete surgical resection.
    • Note: Participants may not have been treated with radiation therapy for their melanoma prior to study entry.
  • No more than 12 weeks may elapse between final surgical resection and randomization. Treatment should start only after complete wound healing from the surgery. If there is a delay of 1 to 7 days exceeding 12 weeks due to unforeseen circumstances, the eligibility should be discussed with the Sponsor and the decision documented. A delay of 1 to 7 days for screening imaging requirements will be allowed if sponsor has allowed 1 week extension between surgical resection and randomization.
    • Note: Final surgical resection is defined in this protocol as complete resection of melanoma and a SLN biopsy. If the wide excision is followed by the SLN biopsy (i.e., they are not performed at the same time), no more than 12 weeks may elapse between the 2 surgical procedures. If a second wide excision needs to be completed after SLN biopsy, this date will be used to calculate final surgical resection date.
  • Have no evidence of metastatic disease on imaging as determined by investigator assessment. All suspicious lesions amenable to biopsy should be confirmed negative for malignancy.
  • Have a performance status of 0 or 1 on the ECOG Performance Scale at the time of enrollment, LPS score ≥50 (for participants ≤16 years old.), or a KPS score ≥50 (for participants >16 and <18 years old). (Appendix 8: Performance Status Scales).
  • Participant must have recovered adequately from toxicity and/or complications from surgery prior to starting study treatment.

Female participants:

  • A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    • Is not a woman of childbearing potential (WOCBP); OR
    • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year) or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at least 120 days after the last dose of study intervention.  The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention.
    • A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 72 hours before the first dose of study intervention.
    • If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    • Additional requirements for pregnancy testing during and after study intervention are located in Appendix 3.
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
    • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study and agrees to DMFS and OS data collection until these study endpoints are reached.  The participant provides consent/assent for future biomedical research. However, the participant may take part in the main study without participating in future biomedical research.
  • Have adequate organ function as defined below. Specimens must be collected within 10 days prior to the start of study treatment.
  • Adequate Organ Function Laboratory Values
  • System | Laboratory Value
    • Hematological
      • Absolute neutrophil count | (ANC) ≥ 1500/μL
      • Platelets | ≥ 100 000/μL
      • Hemoglobin | ≥.0 g/dL or ≥.6 mmol/L
    • Renal
      • Creatinine OR Measured or calculated2 creatinine clearance (GFR can also be used in place of creatinine or CrCl) | ≤ 1.5 × ULN OR ≥ 0 mL/min for participant with creatinine levels >1.5 × institutional ULN
    • Hepatic
      • Total bilirubin | ≤.5 × ULN OR direct bilirubin ≤LN for participants with total bilirubin levels >1.5 × ULN
      • AST (SGOT) and ALT (SGPT) | Part 1 ≤.5 × ULN
      • AST (SGOT) and ALT (SGPT) | Part 2 ≤.5 × ULN (<5 × ULN for participants with liver metastases)
    • Coagulation
      • International normalized ratio (INR) OR prothrombin time (PT)
      • Activated partial thromboplastin time (aPTT) | ≤.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
    • ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper limit of normal.
      • Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
      • Creatinine clearance (CrCl) should be calculated per institutional standard.
        • Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

Exclusion Criteria: 

Medical Conditions

  • Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years.
    • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
    • Note: Participants with a history of non-ulcerated cutaneous/acral primary melanoma <1 mm in depth with no nodal involvement are allowed in this trial. Participants with any previous melanoma that was ulcerated, ≥1 mm in depth, with nodal involvement, metastasis, or was treated beyond surgical resection (for example, radiation therapy) are not eligible for this trial. Participants with synchronous melanomas where lesions not under study are not ulcerated and <1 mm in depth are allowed on the study.  Participants with a history of mucosal or uveal melanoma are excluded from this trial even if diagnosis and treatment were completed > 5 years ago.
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
    • Note: The use of inhaled or topical steroids and systemic steroids at physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent with maximum dose of 10 mg daily) is allowed on study.
  • If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
  • A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    • Note: In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study medication.

Prior/Concomitant Therapy

  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
  • Has received prior systemic anti-cancer therapy for melanoma including investigational agents.
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

Prior/Concurrent Clinical Study Experience

  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
    • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

Diagnostic Assessments

  • Has severe hypersensitivity (≥Grade 3) to any pembrolizumab excipients.
  • Has an active autoimmune disease that has required systemic treatment in past 2 years (.i.e, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • Has an active infection requiring systemic therapy.
  • Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
    • Note: For Germany, HIV testing is mandatory.
  • Has a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known active Hepatitis C virus (defined as Hepatitis C virus RNA [qualitative] is detected) infection. No testing for Hepatitis B and Hepatitis C is required unless
  • mandated by local health authority.
    • Note: For Germany, France, and the UK, Hepatitis B and C testing is mandatory
  • Has a history of active tuberculosis (Bacillus tuberculosis).
    • Note: For Germany and the UK, Tuberculosis testing is mandatory.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.

Other Exclusions

  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.
  • Has had an allogeneic tissue/solid organ transplant.


Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Robert McWilliams, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Winston Tan, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information


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