Pembrolizumab Compared to Standard of Care Observation in Treating Patients with Completely Resected Stage I-III Merkel Cell Cancer

This phase III trial studies how well pembrolizumab works compared to standard of care observation in treating patients with stage I-III Merkel cell cancer that has been completely removed by surgery. 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.

Inclusion Criteria

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2 (Those patients who are wheel chair bound due to congenital or traumatic events more than one year before the diagnosis of Merkel cell carcinoma may be considered.)
• Women must not be pregnant or breast-feeding due to the unknown effects of the study drug in this setting. All women of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential, if receiving MK-3475 (pembrolizumab) or radiation therapy, and sexually active males must use an accepted and effective method of contraception or to abstain from sex from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment.
• Patient must have a histological confirmation of diagnosis of Merkel cell carcinoma (MCC), pathologic stages (American Joint Committee on Cancer [AJCC] version 8) I-IIIb. * Stage I patients with negative sentinel lymph node biopsy are ineligible. Patients who have a positive biopsy or for whom no biopsy was done are eligible. * Patients with distant metastatic disease (stage IV) are not eligible. * The primary tumor must have negative margins.
• Patients with all macroscopic Merkel cell carcinoma (either identified by physical exam or imaging) have been completely resected by surgery within 8 weeks before enrollment.
• All patients must have disease-free status documented by a complete physical examination and conventional imaging studies within 4 weeks prior to randomization.
• Patient must have no currently present metastases (as confirmed by standard imaging studies).
• Patient must have no previous systemic therapy or radiation therapy for Merkel cell carcinoma.
• Patients with inoperable disease who have received radiation are not eligible.
• White blood count >= 2000/uL (within 4 weeks prior to randomization).
• Absolute neutrophil count (ANC) >= 1000/Ul (within 4 weeks prior to randomization).
• Platelets >= 75 x 103/uL (within 4 weeks prior to randomization).
• Hemoglobin >= 8 g/dL (>= 80 g/L; may be transfused) (within 4 weeks prior to randomization).
• Creatinine =< 2.0 x upper limit of normal (ULN) (within 4 weeks prior to randomization).
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (within 4 weeks prior to randomization).
• Total bilirubin =< 2.0 x ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) (within 4 weeks prior to randomization).
• Patients who are human immunodeficiency virus (HIV)+ with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation.
• Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are eligible provided viral loads are undetectable. Patients on suppressive therapy are eligible.
• Patients must not be on active immunosuppression, have a history of life threatening virus, have had other (beside non-melanoma skin cancers, or recent indolent cancers e.g.: resected low grade prostate cancer) cancer diagnoses in the last two years, or have had immunotherapy of any kind within the last 2 years.
• Patients must not have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Operative notes from patient’s surgical resection must be accessible.

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) and recurrence free survival (RFS) as co-primary endpoints across the two arms.

SECONDARY OBJECTIVES:

I. To evaluate adverse events.

II. To evaluate distant metastasis free survival (DMFS).

III. To evaluate the impact of radiation on clinical outcomes (OS, RFS, DMFS).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. Patients may also undergo standard of care radiation therapy within 14 days of day 1, course 1.

ARM B: Patients receive standard of care observation for 17 courses. Patients may also undergo standard of care radiation therapy within 14 days of day 1, course 1.

After completion of study treatment, patients are followed up every 6 months for 4 years.

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Brian R. Gastman