A Study to Compare the Administration of Pembrolizumab After Surgery Versus Administration Both Before and After Surgery for High-Risk Melanoma
Condition: Acral Lentiginous Melanoma; Clinical Stage III Cutaneous Melanoma AJCC v8; Clinical Stage IV Cutaneous Melanoma AJCC v8; Mucosal Melanoma
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Biospecimen Collection; Computed Tomography; Magnetic Resonance Imaging; Pembrolizumab; Therapeutic Conventional Surgery
Intervention description: Undergo collection of blood; Undergo CT; Undergo MRI; Given IV; Undergo surgery
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 313.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how pembrolizumab works before and after surgery in treating
      patients with stage III-IV high-risk melanoma. Immunotherapy with monoclonal antibodies, such
      as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
      the ability of tumor cells to grow and spread. Giving pembrolizumab before and after surgery
      may work better compared to after surgery alone in treating melanoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must have clinically detectable stage
             III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or stage IV resectable
             melanoma. Patients with melanoma of mucosal or acral origin are eligible. Patients
             with melanoma of uveal origin are not eligible. Patients with a history of brain
             metastases are not eligible. Clinically detectable is defined as disease that is
             apparent and measurable via physical examination or radiographic imaging.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients are eligible for this trial either at
             initial presentation of their melanoma or at the time of the first detected nodal,
             satellite/in-transit, distant metastases, or recurrent disease in prior
             lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant
             metastases or disease in a prior complete lymphadenectomy basin must have been
             confirmed histologically by hematoxylin (H) & eosin (E) stained slides.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients with multiple regional nodal basin
             involvement are eligible. Gross or microscopic extracapsular nodal extension is
             permitted.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must have histologically proven stage
             IIIB or higher. This would entail pathologic confirmation beyond the primary or
             initial diagnosis of melanoma involving fine needle aspiration cytology or biopsy
             confirmation of any N-category or M-category resectable site.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received previous
             neoadjuvant treatment for their melanoma. Patients may have received prior
             non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy
             including, but not limited to ipilimumab, interferon alfa-2b, high dose interleukin
             (IL)-2, pegylated-interferon (PEG-IFN), anti-PD-1, anti-PD-L1 intra-tumoral, or
             vaccine therapies. Patients must not be planning to receive any of the prohibited
             therapies during treatment phases on the study.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not be planning to receive
             concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery,
             while on protocol therapy.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients may have received prior radiation
             therapy, including after prior surgical resection. All adverse events associated with
             prior surgery and radiation therapy must have resolved to =< grade 1 prior to
             randomization.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must be >= 18 years of age

          -  STEP 1 REGISTRATION (RANDOMIZATION): All patients must have disease status documented
             by a complete physical examination and imaging studies within 42 days prior to
             randomization. Imaging studies must include a CT of the chest, abdomen and pelvis with
             intravenous contrast (unless contraindicated). For patients with melanoma arising from
             the head and neck, dedicated neck imaging (CT with intravenous contrast is required.
             If the patient has unknown primary with disease in the axilla, neck imaging is
             required CT imaging must be done with intravenous contrast if there are no
             contraindications for it. Extremity melanomas must be imaged using CT with intravenous
             contrast or MRI with and without gadolinium

               -  Note: PET-CT scans are NOT acceptable to establish eligibility. Non-iodinated CT
                  scans that are part of common PET-CT imaging protocols do not provide contrast
                  for difficult to ascertain areas such as the neck and liver, and do not provide
                  enough CT detail to perform appropriate RECIST 1.1 measurements. As such, a
                  PET-CT with non-contrast CT or non-diagnostic quality CT images is considered
                  insufficient for the detection of melanoma.

          -  STEP 1 REGISTRATION (RANDOMIZATION): All patients must have a CT or magnetic resonance
             imaging (MRI) of the brain within 42 days prior to randomization. The brain CT or MRI
             should be performed with intravenous contrast (unless contraindicated).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Absolute neutrophil count (ANC) >=
             1,500/microliter (mcL) (within 42 days prior to randomization).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Platelets >= 100,000/mcL (within 42 days prior to
             randomization).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Hemoglobin >= 10 g/dL (within 42 days prior to
             randomization).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Total bilirubin =< 1.5 x institutional upper
             limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total
             bilirubin < 3.0 mg/dL) (within 42 days prior to randomization).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Serum glutamic-oxaloacetic transaminase (SGOT)
             (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT)
             (alanine aminotransferase [ALT]) =< 2 x IULN (within 42 days prior to randomization).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Alkaline phosphatase =< 2 x IULN (within 42 days
             prior to randomization).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must have lactate dehydrogenase (LDH)
             performed within 42 days prior to randomization.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must have adequate renal function as
             evidenced by calculated creatinine clearance > 30 mL/min. The creatinine level (mg/dL)
             used in the calculation must be obtained within 42 days prior to randomization.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must have Zubrod performance status =<
             2.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have a history of
             (non-infectious) pneumonitis that required steroids or current pneumonitis.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have an active infection
             requiring systemic therapy.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have 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
             (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
             adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
             treatment.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received live vaccines
             within 42 days prior to randomization. Examples of live vaccines include, but are not
             limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow
             fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal
             influenza vaccines for injection are generally killed virus vaccines and are allowed;
             however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines,
             and are not allowed.

               -  NOTE: The COVID-19 vaccines (currently available and those in the pipeline for
                  FDA emergency use authorization or FDA approval) do not contain live virus, and
                  therefore, COVID-19 vaccination does not affect or preclude eligibility for the
                  S1801 trial. For patients who have undergone lymphadenectomy, vaccines should be
                  delivered to a limb with an intact lymph node basin (Sentinel lymph node biopsy
                  in a limb is acceptable). The vaccine should not be administered in a limb that
                  has undergone lymphadenectomy.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients known to be human immunodeficiency virus
             (HIV) positive are eligible if they meet the following criteria within 30 days prior
             to randomization: stable and adequate CD4 counts (>= 350 mm^3), and serum HIV viral
             load of < 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they
             meet the CD4 count criteria.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have known active hepatitis B
             virus (HBV) or hepatitis C virus (HCV) infection prior to randomization. Note: No
             testing for hepatitis B and hepatitis C is required unless mandated by local health
             authority.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Prior malignancy is allowed providing it does not
             require concurrent therapy.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Women of childbearing potential must have a
             negative urine or serum pregnancy test within 28 days prior to randomization.
             Women/men of reproductive potential must have agreed to use an effective contraceptive
             method for the course of the study through 120 days after the last dose of study
             medication. Should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately. A woman is considered to be of "reproductive potential" if she has had
             menses at any time in the preceding 12 consecutive months. In addition to routine
             contraceptive methods, "effective contraception" also includes heterosexual celibacy
             and surgery intended to prevent pregnancy (or with a side-effect of pregnancy
             prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal
             ligation. However, if at any point a previously celibate patient chooses to become
             heterosexually active during the time period for use of contraceptive measures
             outlined in the protocol, he/she is responsible for beginning contraceptive measures.
             Patients must not be pregnant or nursing due to unknown teratogenic side effects.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must be deemed medically fit to undergo
             surgery by the treating medical/surgical team.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must be willing to submit the following
             surgical specimens: either all tissue blocks from the surgical specimen or two slides
             per block ([1] hematoxylin and eosin [H&E] slide and [1] unstained slide OR [2]
             unstained slides if H&E stained slides cannot be provided).

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must be offered the opportunity to
             participate in specimen banking.

          -  STEP 1 REGISTRATION (RANDOMIZATION): Patients must be informed of the investigational
             nature of this study and must sign and give written informed consent for this protocol
             in accordance with institutional and federal guidelines.

          -  STEP 1 REGISTRATION (RANDOMIZATION): As a part of the Oncology Patient Enrollment
             Network (OPEN) randomization process the treating institution's identity is provided
             in order to ensure that the current (within 365 days) date of institutional review
             board approval for this study has been entered in the system.

          -  STEP 2 REGISTRATION (SURGERY): Patients randomized to arm 2 (neoadjuvant arm) must be
             willing to submit tissue to determine pathologic response regardless of number of
             pre-operative doses of pembrolizumab (MK-3475) received. Determination of pathologic
             response cannot be done on less than the full surgical specimen.

          -  STEP 2 REGISTRATION (SURGERY): Patients must have disease assessments by CT
             chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head
             and neck melanoma, performed within 42 days (and no more than 49 days) before the
             planned date of surgery. MRI combined with non-contrast CT is an acceptable
             alternative for patients with CT contrast allergy, but imaging must encompass total
             body.

          -  STEP 2 REGISTRATION (SURGERY): Patients must register to step 2 within 17 days prior
             to planned date of surgery.

          -  STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must have undergone surgery prior to
             Step 3 registration. The Step 2 surgery must have completely resected their melanoma.

               -  Patients with gross positive residual disease following surgery do not qualify as
                  having disease-free status, and, therefore, such patients are not eligible to
                  register for adjuvant therapy.

               -  Patients with microscopic residual disease (i.e., positive margins) can be
                  treated with re-excision or radiation, per site discretion, to render the patient
                  disease-free prior to registration of adjuvant therapy.

               -  Disease-free status must be documented by a complete physical examination and
                  radiographic imaging studies within 42 days prior to Step 3 registration. Imaging
                  studies must include a CT of the chest, abdomen, and pelvis (unless
                  contraindicated). Extremity melanomas must be imaged using CT with intravenous
                  contrast or MRI with and without gadolinium. CT imaging must be done with
                  intravenous contrast if there are no contraindications for it.

               -  For patients with melanoma arising from the head and neck, dedicated neck imaging
                  (CT with IV contrast, unless contraindicated) is required.

               -  If the patient has had unknown primary with disease in the axilla, neck imaging
                  is required to assure the region is clear of cancer.

               -  Any other clinically indicated imaging studies if performed (e.g., bone scan)
                  must show no evidence of disease.

          -  STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must be registered to step 3 no more
             than 84 days after date of surgery.

          -  STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R0 or R1 resections must have
             disease-free status documented by a complete physical examination and imaging studies
             within 42 days prior to step 3 registration. These patients must have disease
             assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast
             if primary head and neck melanoma. MRI combined with non-contrast CT is an acceptable
             alternative for patients with CT contrast allergy, but imaging must encompass total
             body.

          -  STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R2 resections are not eligible
             for step 3 and must be removed from study treatment