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

• ClinicalTrials.gov Identifier: NCT04462406
• Recruitment Status: Recruiting
• First Posted: July 8, 2020
• Last Update Posted: August 31, 2020
• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

Tracking Information

• First Submitted Date: June 26, 2020
• First Posted Date: July 8, 2020
• Last Update Posted Date: August 31, 2020
• Actual Study Start Date: August 27, 2020
• Estimated Primary Completion Date: August 29, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 6, 2020)

Event free survival (EFS) rate (Arm A) [ Time Frame: At 12 months ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 6, 2020)

• Rates of pathologic response (Arm B) [ Time Frame: After 12 months of anti-PD-1 therapy ]
  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.
• EFS [ Time Frame: At 24 months ]
  The distribution of EFS will be evaluated using the method of Kaplan-Meier.
• Overall survival [ Time Frame: At 24 months ]
  Overall 24 month EFS for patients in Arm B will be summarized.
• Percentage of patients who remain on treatment beyond 12 months [ Time Frame: Up to 5 years ]
  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).
• Incidence rates of treatment-related adverse events -12 months from start of treatment in patients who discontinue anti-PD-1 therapy at 12 months (Arm A) and in patients who continue anti-PD-1 therapy beyond 12 months (Arm B) [ Time Frame: Up to 5 years ]
  95% CIs will be provided for all estimated rates.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 6, 2020)

• Determine FDG-PET/CT positivity between the local site read and central review [ Time Frame: Up to 5 years ]
  Determining agreement between local and central review of FDG-PET/CT positivity
• Metabolic response on serial FDG-PET/CT [ Time Frame: Baseline to 12 months of anti-PD-1 therapy ]
  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 on serial FDG-PET/CT [ Time Frame: 12 months to 24 months after start of anti-PD-1 therapy ]
  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).
• Banking samples for future biomarker studies [ Time Frame: Up to 5 years ]
  Will bank tumor samples and peripheral blood for future biomarker studies.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients With Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial
• Official Title: A Phase II Study of Biomarker Driven Early Discontinuation of Anti-PD-1 Therapy in Patients With Advanced Melanoma (PET-Stop)
• Brief 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Melanoma
• Clinical Stage III Cutaneous Melanoma AJCC v8
• Clinical Stage IV Cutaneous Melanoma AJCC v8
• Melanoma of Unknown Primary
• Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
• Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
• Pathologic Stage IIID Cutaneous Melanoma AJCC v8
• Pathologic Stage IV Cutaneous Melanoma AJCC v8
• Unresectable Acral Lentiginous Melanoma
• Unresectable Melanoma
• Unresectable Mucosal Melanoma

Intervention

• Biological: Ipilimumab
  Given IV
  Other Names:

  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy
• Biological: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
• Other: Patient Observation
  Undergo active surveillance
  Other Names:

  • Active Surveillance
  • deferred therapy
  • expectant management
  • Observation
  • Watchful Waiting
• Biological: Pembrolizumab
  Given IV
  Other Names:

  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Study Arms

• Experimental: Arm A (active surveillance)
  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.
  Intervention: Other: Patient Observation
• Active Comparator: Arm B (nivolumab, pembrolizumab, ipilimumab)
  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.
  Interventions:

  • Biological: Nivolumab
  • Biological: Pembrolizumab
• Standard of Care (nivolumab, pembrolizumab, ipilimumab)
  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.
  Interventions:

  • Biological: Ipilimumab
  • Biological: Nivolumab
  • Biological: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 6, 2020): 150
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 29, 2026
• Estimated Primary Completion Date: August 29, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• STEP 0 PRE-REGISTRATION INCLUSION CRITERIA
• Patient must have active advanced melanoma, defined as unresectable stage IIIB-IV by American Joint Committee on Cancer (AJCC) 8th edition
• Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosal primary sites. Patients with melanoma of unknown primary site are eligible. Patients must not have melanoma from an ocular primary site
• Patient must have had measurable disease by immune related Response Evaluation Criteria in Solid Tumors (imRECIST) prior to start of initial anti-PD-1 therapy

• Patient must be actively receiving standard of care anti-PD-1 therapy, currently be 52 weeks (+/- 2 weeks) from start of anti-PD-1 therapy, and have not experienced a toxicity that prevents them from continuing on therapy. Permitted systemic anti-PD-1 therapy regimens include:

  • Nivolumab 240 mg IV every (Q)2weeks or 480 mg IV Q4weeks
  • Pembrolizumab 200 mg IV Q3weeks or 400 mg IV Q6weeks
  • Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg IV Q3weeks induction x 4 doses, followed by nivolumab 240 mg IV Q2weeks or 480 mg IV Q4weeks maintenance
  • Nivolumab 3 mg/kg plus Ipilimumab 1 mg/kg IV Q3weeks induction x 4 doses, followed by nivolumab 240 mg IV Q2weeks or 480 mg IV Q4weeks maintenance
  • Pembrolizumab 2 mg/kg (or 200 mg flat dose) plus Ipilimumab 1 mg/kg IV Q3weeks induction x 4 doses, followed by pembrolizumab 200 mg IV Q3weeks or 400 mg IV Q6weeks maintenance
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients with detectable viral loads are excluded as it is unclear if these patients have a low risk of melanoma progression off anti-PD-1 treatment
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Patient must have experienced complete response, partial response, or stable disease on restaging CT scans by imRECIST that is maintained on restaging scans obtained at week 52 (+/- 2 weeks) from start of initial anti-PD-1 therapy

• Patient must have completed an FDG-PET/CT scan at week 52 (+/- 2 weeks) from start of initial anti-PD-1 therapy

  • Patients with PET/CT positive for hypermetabolic lesions: If a core needle, punch or excisional biopsy and pathological review of a representative lesion was not performed prior to pre-registration (Step 0) must either:

    • Be amenable to undergo a biopsy. Patient must not be on anticoagulation therapy or, if on anti-coagulation therapy, patient must be able to hold treatment for a biopsy procedure (core needle, punch or excisional biopsy). Anti-coagulation therapy is defined as low molecular weight heparin, warfarin, factor Xa inhibitor, or direct thrombin inhibitor
    • Have documentation of inability to perform the biopsy due to feasibility or safety concerns
• Leukocytes >= 3,000/mcL (obtained =< 4 weeks prior to protocol registration)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 4 weeks prior to protocol registration)
• Platelets >= 100,000/mcL (obtained =< 4 weeks prior to protocol registration)
• Total bilirubin =< institutional upper limit of normal (ULN) (patients with history of Gilbert's syndrome are permitted to have a total bilirubin > 1.5 x institutional ULN) (obtained =< 4 weeks prior to protocol registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 4 weeks prior to protocol registration)
• Creatinine =< 1.5 x institutional ULN (obtained =< 4 weeks prior to protocol registration)
• STEP 1 REGISTRATION INCLUSION CRITERIA
• Patient met all eligibility criteria outlined above
• Patient must register to Step 1 within 4 weeks of registration to Step 0

• Patients must meet one of the following criteria:

  • Patient had no positive hypermetabolic lesions on the week 52 FDG-PET/CT.

  • Patients with positive hypermetabolic lesion(s) on the week 52 FDG-PET/CT (positive hypermetabolic = standard uptake volume [SUV] > pooled mediastinal blood), one of the following must have occurred:

    • A representative lesion was biopsied (core needle, punch or excisional biopsy) within 14 days of registration to Step 0 and subsequent pathology review performed to determine the presence or absence of viable tumor
    • Documentation is present that the patient is not able to undergo biopsy of a hypermetabolic lesion due to feasibility or safety concerns, i.e., the lesion location that is not amenable to biopsy

Exclusion Criteria:

• STEP 0 PRE-REGISTRATION EXCLUSION CRITERIA
• Patient must not be receiving concurrent anti-tumor therapies in addition to the standard of care anti-PD-1 regimens. Patients who are receiving bisphosphonates and RANKL inhibitors for management of bone metastases are eligible
• Patient must not have brain metastases
• Women must not be pregnant or breast-feeding due to potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the anti-PD-1 regimens being used. All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A female of childbearing potential is defined as 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 and sexually active males must not conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of study registration and continuing until at least 5 months after the last dose of anti-PD-1 treatment for female patients and for at least 7 months after the last dose of anti-PD-1 treatment for male patients who are sexually active with a women of childbearing potential (WOCBP)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04462406
• Other Study ID Numbers: EA6192; NCI-2020-04463 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA6192 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA6192 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )
• Study Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Geoffrey T Gibney; ECOG-ACRIN Cancer Research Group

• PRS Account: Eastern Cooperative Oncology Group
• Verification Date: August 2020