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 have active advanced melanoma, defined as unresectable stage IIIB-IV byAmerican Joint Committee on Cancer (AJCC) 8th edition

• Patient must have melanoma originating from cutaneous, acral-lentiginous, or mucosalprimary sites. Patients with melanoma of unknown primary site are eligible. Patientsmust not have melanoma from an ocular primary site

• Patient must have had measurable disease by immune related Response EvaluationCriteria 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 atoxicity that prevents them from continuing on therapy. Permitted systemic anti-PD-1therapy 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 Q3weeksinduction x 4 doses, followed by pembrolizumab 200 mg IV Q3weeks or 400 mg IVQ6weeks maintenance

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy 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 patientshave a low risk of melanoma progression off anti-PD-1 treatment

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Patient must have experienced complete response, partial response, or stable diseaseon restaging CT scans by imRECIST that is maintained on restaging scans obtained atweek 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 startof 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 lesionwas not performed prior to pre-registration (Step 0) must either:

• Be amenable to undergo a biopsy. Patient must not be on anticoagulationtherapy or, if on anti-coagulation therapy, patient must be able to holdtreatment for a biopsy procedure (core needle, punch or excisionalbiopsy). Anti-coagulation therapy is defined as low molecular weightheparin, warfarin, factor Xa inhibitor, or direct thrombin inhibitor

• Have documentation of inability to perform the biopsy due to feasibilityor safety concerns

• Leukocytes >= 3,000/mcL (obtained =< 4 weeks prior to protocol registration)

• Absolute neutrophil count >= 1,500/mcL (obtained =< 4 weeks prior to protocolregistration)

• Platelets >= 100,000/mcL (obtained =< 4 weeks prior to protocol registration)

• Total bilirubin =< institutional upper limit of normal (ULN) (patients with historyof Gilbert's syndrome are permitted to have a total bilirubin > 1.5 x institutionalULN) (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 protocolregistration)

• Creatinine =< 1.5 x institutional ULN (obtained =< 4 weeks prior to protocolregistration)

• 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 mediastinalblood), one of the following must have occurred:

• A representative lesion was biopsied (core needle, punch or excisionalbiopsy) within 14 days of registration to Step 0 and subsequent pathologyreview performed to determine the presence or absence of viable tumor

• Documentation is present that the patient is not able to undergo biopsy ofa hypermetabolic lesion due to feasibility or safety concerns, i.e., thelesion 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 thestandard of care anti-PD-1 regimens. Patients who are receiving bisphosphonates andRANKL 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 unbornfetus and possible risk for adverse events in nursing infants with the anti-PD-1regimens being used. All females of childbearing potential must have a blood test orurine study within 14 days prior to registration to rule out pregnancy. A female ofchildbearing potential is defined as any woman, regardless of sexual orientation orwhether they have undergone tubal ligation, who meets the following criteria: 1) hasachieved menarche at some point, 2) has not undergone a hysterectomy or bilateraloophorectomy; or 3) has not been naturally postmenopausal (amenorrhea followingcancer therapy does not rule out childbearing potential) for at least 24 consecutivemonths (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 orfather children by using accepted and effective method(s) of contraception or byabstaining from sexual intercourse from the time of study registration andcontinuing until at least 5 months after the last dose of anti-PD-1 treatment forfemale patients and for at least 7 months after the last dose of anti-PD-1 treatmentfor male patients who are sexually active with a women of childbearing potential (WOCBP)