A Phase II Randomized Study of Adjuvant versus Neoadjuvant Pembrolizumab for Clinically Detectable Stage III-IV High-risk Melanoma.

Disease Related Criteria
1. 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 (Section 10.1).
Note: Planned surgery must be documented on the S1801 Planned Surgery Form.
2. 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 H & E stained slides.
3. Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
4. Patients must have histologically proven Stage IIIB or higher (entails 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).
b. Prior/Concurrent Therapy Criteria
1. 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 IL-2, 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 listed in Section 7.2 during treatment phases on the study.
2. Patients must not be planning to receive concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery, while on protocol therapy.
3. 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 less than or equal to Grade 1 prior to randomization.
c. Clinical/Laboratory Criteria
1. Patients must be greater than or equal to18 years of age.
2. 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 total body PET-CT scan that is of diagnostic quality with iodine contrast-enhanced images (with or without brain) or a CT of the chest, abdomen and pelvis with intravenous contrast. For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous contrast or iodine contrast-enhanced PET-CT through the region) is required. If the patient has unknown primary with disease in the axilla, neck imaging is required CT imaging should be done with intravenous contrast if there are no contraindications for it.
3. All patients must have a CT or MRI of the brain within 42 days prior to randomization. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated).
4. Patients must have adequate bone marrow function as evidenced by all of the following: ANC greater than or equal 1,500/microliter (mcL); platelets greater than or equal 100,000/mcL; Hemoglobin greater than or equal 10 g/dL. These results must be obtained within 42 days prior to randomization.
5. Patients must have adequate hepatic function as evidenced by the following: total bilirubin less than or equal 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL), and SGOT (AST) and SGPT (ALT) and alkaline phosphatase less than or equal 2 x IULN. These results must be obtained within 42 days prior to randomization.
6. Patients must have LDH performed within 42 days prior to randomization.
7. Patients must have adequate renal function as evidenced by calculated creatine clearance greater than 30 mL/min. The creatinine level (mg/dL) used in the calculation must be obtained within 42 days prior to randomization.
Calculate creatinine clearance = (140-age) x wt (Kg) x 0.85 (if female)72 x creatinine (mg/dL)
8. Patients must have Zubrod Performance Status less than or equal 2 (see Section 10.14).
9. Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
10. Patients must not have an active infection requiring systemic therapy.
11. 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.
12. 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, 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.
13. Patients known to be HIV positive are eligible if they meet the following criteria within 30 days prior to randomization: stable and adequate CD4 counts (greater than or equal to 350 mm3), and serum HIV viral load of less than 25,000 IU/ml. Patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria.
14. 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.
15. Prior malignancy is allowed providing it does not require concurrent therapy.
16. 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.
17. Patients must be deemed medically fit to undergo surgery by the treating medical/surgical team.