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

Inclusion Criteria

• STEP 0 PRE-REGISTRATION INCLUSION CRITERIA
• Patient must be >= 18 years of age
• 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 modified 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 less than 56 weeks from start of anti-PD-1 therapy, and have not experienced a toxicity that prevents them from continuing on therapy. Patients are not required to complete all four induction doses of nivolumab/ipilimumab or pembrolizumab/ipilimumab if they continued to receive anti-PD-1 monotherapy. Weight based anti-PD-1 dosing is permitted in place of flat dosing. Permitted systemic anti-PD-1 therapy regimens include: * Nivolumab 240mg IV every (Q)2weeks or 480mg IV Q4weeks * Pembrolizumab 200mg IV Q3weeks or 400mg IV Q6weeks * Nivolumab 1mg/kg plus ipilimumab 3mg/kg IV Q3weeks induction x 4 doses, followed by nivolumab 240mg IV Q2weeks or 480mg IV Q4weeks maintenance * Nivolumab 3mg/kg plus Ipilimumab 1mg/kg IV Q3weeks induction x 4 doses, followed by nivolumab 240mg IV Q2weeks or 480mg IV Q4weeks maintenance * Pembrolizumab 2mg/kg (or 200mg flat dose) plus Ipilimumab 1mg/kg IV Q3weeks induction x 4 doses, followed by pembrolizumab 200mg IV Q3weeks or 400mg IV Q6weeks maintenance * Nivolumab 480mg / Relatlimab 160mg fixed-dose combination (FDC) IV Q4weeks
• 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 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 anti-PD-1 therapy are eligible for this trial
• Patients 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 patients of childbearing potential must have a blood test or urine study within 28 days prior to Step 0 pre-registration to rule out pregnancy. A second pregnancy test for patients registered to Arm A may be done as clinically indicated. A patient of childbearing potential is defined as anyone, 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)
• Patients 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 (for patients of childbearing potential) until at least 5 months after the last dose of anti-PD-1 treatment. Patients of childbearing potential must also not donate eggs during this same time period
• STEP 1 REGISTRATION INCLUSION CRITERIA
• Patient must meet all eligibility criteria outlined above. (HIV, HBV, and HCV viral load and pregnancy retesting is at the discretion of the treating provider)
• 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 (MRI with IV contrast preferred; non-contrast MRI or contrast enhanced CT scan are acceptable) at week 48 (+/- 6 weeks) to confirm disease control/response is required in patients with known brain metastasis history
• Patient must register to step 1 39-56 weeks from start of anti-PD-1 therapy regimen, and still be actively receiving treatment
• Patient must have experienced complete response, partial response, or stable disease on restaging scans by imRECIST that is maintained on the PET/CT scan 39-56 weeks from start of initial anti-PD-1 therapy
• Patient must have completed an FDG-PET/CT scan at 39-56 weeks from start of initial anti-PD-1 therapy * Patients with FDG-PET/CT positive for hypermetabolic lesion(s): If a core needle, punch or excisional biopsy, and pathological review of a representative lesion was not performed prior to pre-registration (step 0), patient 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
• Patient must meet one of the following criteria: * No positive hypermetabolic lesions on the FDG-PET/CT 39-56 weeks from start of initial anti-PD-1 therapy * Positive hypermetabolic lesion(s) on the FDG-PET/CT (positive hypermetabolic = standardized uptake value [SUV] > pooled mediastinal blood) 39-56 weeks from start of initial anti-PD-1 therapy, one of the following must have occurred: ** A representative lesion was biopsied (core needle, punch or excisional biopsy) within 90 days of the FDG-PET/CT scan 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
• Patient must register to Step 1 within 90 days of the FDG-PET/CT scan and biopsy/pathology report availability (if performed), and still be within 56 weeks from start of anti-PD-1 therapy