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Nivolumab

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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.

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 continue their standard of care anti-PD-1 therapy for 12 months in the absence of disease progression or unacceptable toxicity.

Patients continue their standard of care anti-PD-1 therapy. Treatment may consist of the following regimens: 1) nivolumab IV over 30 minutes Q2W or Q4W; 2) pembrolizumab IV over 30 minutes Q3W or 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 52 weeks from start of standard of care anti-PD-1 therapy in the absence of disease progression or unacceptable toxicity.

Patient Observation

Site Public Contact

Nicholas DiBella

Richard L. Deming

Jay W. Carlson

Sajjad A. Bhatti

Inderjit Mehmi

Geoffrey T. Gibney

Lynn G. Feun

Philip J. Stella

David H. Lawson

Howard A. Zaren

Bryan A. Faller

Sunandana Chandra

Howard M. Gross

Debra M. Prow

Joshua Lukenbill

Geoffrey T Gibney

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.

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 12 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 12 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 12 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 12 months from start of treatment in patients who discontinue anti-PD-1 therapy at 12 months and in patients who continue anti-PD-1 therapy beyond 12 months (Arm A versus \[vs.\] 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 12 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 12 to 24 months after start of anti-PD-1 therapy, as determined centrally by various criteria, is associated with EFS.

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 52 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 continue their standard of care anti-PD-1 therapy for 12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up through week 97 and then every 3 months for up to 5 years.

Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients With Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial

A Phase II Study of Biomarker Driven Early Discontinuation of Anti-PD-1 Therapy in Patients With Advanced Melanoma (PET-Stop)

Determining agreement between local and central review of FDG-PET/CT positivity

Metabolic response by serial FDG-PET/CT scan from baseline to 12 month time-point (Arm A) will be associated with EFS (Arm A) and with EFS (Arm B).

Metabolic response by serial FDG-PET/CT scan from the 12 month to 24 month time points (Arm B) will be associated with EFS (Arm A) and with EFS (Arm B).

Will bank tumor samples and peripheral blood for future biomarker studies.

Event is defined as recurrence, progression or melanoma-specific death. The distribution of EFS will be evaluated using the method of Kaplan-Meier.

Will be defined as the absence of residual viable melanoma in the resected metastasis site as assessed on local pathology review. Pathologic response rate will be estimated in patients with tumor biopsies where positive hypermetabolic activity was present on FDG-PET/CT scan after 12 month of anti-PD-1 therapy on Arm B. 95% confidence intervals (CIs) will be provided for all estimated rates.

The distribution of EFS will be evaluated using the method of Kaplan-Meier.

Overall 24 month EFS for patients in Arm B will be summarized.

Will determine the percentage of patients who remain on treatment beyond 12 months because of positive fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scan and positive biopsy for residual disease (or unable to obtain a biopsy).

95% CIs will be provided for all estimated rates.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients With Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial	NCT04462406	Advanced Melano... Clinical Stage ... Clinical Stage ... Melanoma of Unk... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Unresectable Ac... Unresectable Me... Unresectable Mu...	Ipilimumab Nivolumab Patient Observa... Pembrolizumab	18 Years -	Eastern Cooperative Oncology Group
Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients With Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial	NCT04462406	Advanced Melano... Clinical Stage ... Clinical Stage ... Melanoma of Unk... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Unresectable Ac... Unresectable Me... Unresectable Mu...	Ipilimumab Nivolumab Patient Observa... Pembrolizumab	18 Years -	Eastern Cooperative Oncology Group

Spots Global Cancer Trial Database for unresectable mucosal melanoma