Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients with Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial
18 Years and older, Male and Female
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.
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).
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).
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.
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 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.
After completion of study treatment, patients are followed up through week 97 and then every 3 months for up to 5 years.
- 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. Patients with mucosal melanoma defined as unresectable stage III or regional/distant metastatic disease are eligible
- 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 baseline brain metastases must have been treated with surgery and/or stereotactic radiosurgery and demonstrate disease control or response. Alternatively, patients with baseline brain metastases primarily treated with systemic therapy must demonstrate ongoing response/disease control. Patients with emergent or progressive brain metastases after start of systemic therapy are not eligible. Brain imaging (magnetic resonance imaging [MRI] with IV contrast preferred; non-contrast MRI or computed tomography [CT] scan are acceptable) at week 48 (+/- 6 weeks) to confirm disease control/response required
- 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 diagnostic restaging CT scan at week 48 (+/- 6 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 FDG 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 (ANC) >= 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
Treatment Sites in Georgia
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