Summary

This phase II trial investigates how well biomarkers on PET/CT imaging drive early discontinuation of anti-PD-1 therapy in patients with stage IIIB-IV melanoma that cannot be removed by surgery (unresectable). Anti-PD-1 therapy has become a standard therapy option for patients with unresectable melanoma. This trial is being done to determine if doctors can safely shorten the use of standard of care anti-PD1 therapy for melanoma by using biomarkers seen on PET/CT imaging and tumor biopsy.

Objectives

PRIMARY OBJECTIVE:
I. To determine the 12 month event free survival (EFS) rate following discontinuation of anti-PD-1 therapy in patients with disease control and negative fludeoxyglucose F-18 (FDG)- positron emission tomography (PET)/computed tomography (CT) scan or biopsy for residual disease after 9-13 months of anti-PD-1 therapy (Arm A).

SECONDARY OBJECTIVES:
I. To determine rates of pathologic response in patients with tumor biopsies where positive hypermetabolic activity was present on FDG-PET/CT scan after 9-13 months of anti-PD-1 therapy (Arm B).
II. To determine the overall 24 month EFS.
III. To determine overall survival from start of anti-PD-1 therapy.
IV. To determine percentage for patients who remain on treatment beyond 9-13 months because of positive FDG-PET/CT scan and positive biopsy for residual disease (or unable to obtain a biopsy).
V. To determine incidence rates of treatment-related adverse events beyond 9-13 months from start of treatment in patients who discontinue anti-PD-1 therapy (Arm A) and in patients who remain on anti-PD-1 therapy (Arm B).

EXPLORATORY OBJECTIVES:
I. To assess agreement in determining FDG-PET/CT positivity between the local site read and central review.
II. To determine if metabolic response on serial FDG-PET/CT from pre-therapy to step 1 registration (9-13 months of anti-PD-1 therapy), as determined centrally by various criteria, is associated with EFS.
III. To determine if metabolic response on serial FDG-PET/CT from step 1 registration (9-13 months on anti-PD-1 therapy) to week 49 on protocol (Arm B), as determined centrally by various criteria, is associated with EFS (Arm B).

BIOMARKER OBJECTIVE:
I. To bank tumor samples and peripheral blood for future biomarker studies.

OUTLINE: Patients continue their standard of care anti-PD-1 therapy and are then assigned to 1 of 2 arms.

STANDARD OF CARE: Treatment may consist of the following regimens: 1) nivolumab intravenously (IV) over 30 minutes every 2 weeks (Q2W) or every 4 weeks (Q4W); 2) pembrolizumab IV over 30 minutes every 3 weeks (Q3W) or every 6 weeks (Q6W); 3) nivolumab IV over 30 minutes and ipilimumab IV Q3W for 4 doses followed by nivolumab IV over 30 minutes Q2W or Q4W; or 4) pembrolizumab IV over 30 minutes and ipilimumab IV Q3W for 4 doses followed by pembrolizumab IV over 30 minutes Q3W or Q6W. Treatment continues until 39-56 weeks from start of standard of care anti-PD-1 therapy in the absence of disease progression or unacceptable toxicity.

ARM A: Patients with a negative FDG-PET/CT scan or a positive FDG-PET/CT scan but with a negative biopsy for viable tumor discontinue the anti-PD-1 therapy and undergo active surveillance.

ARM B: Patients with a positive FDG-PET/CT scan and positive biopsy for viable tumor or a positive FDG-PET/CT scan and biopsy not performed receive nivolumab IV over 30 minutes Q2W or Q4W, or pembrolizumab IV over 30 minutes Q3W or Q6W for 48 weeks in the absence of disease progression or unacceptable toxicity. Following the 48 weeks of treatment, patients undergo a second disease evaluation. Patients without disease progression are monitored off treatment. Patients with disease progression, or who are unable to undergo disease evaluation, have further therapy as determined by treating provider.

Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, and tumor biopsy throughout the study. Patients may optionally undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.