Cryoablation+Ipilimumab+Nivolumab in Melanoma

Inclusion Criteria:

• Adult patients (age > 18) with unresectable melanoma who have progressed on immunecheckpoint inhibitor therapy (pembrolizumab, nivolumab, nivolumab-relatimab,atezolizumab, ipilimumab) and for whom their treating physician plans to initiatedual ICI with ipilimumab and nivolumab. Progression on adjuvant PD-1 inhibition ispermitted. PD-1 does not have to be the last therapy received. This is no limited onprior lines of ICI received. There is no wash-out period required from the time oftheir last therapy.

• Patients are medically eligible for dual checkpoint inhibition (i.e. nountreated/uncontrolled intercurrent medical issue including ongoing immune-relatedadverse event or need for systemic steroids >10mg PO prednisone or its equivalent,ECOG PS ≤2) with ipilimumab 3mg/kg and nivolumab 1mg/kg by their treating physician

• Must have a tumor amenable to percutaneous image-guided cryoablation based onroutine Interventional Radiology criteria.

• Patients must have measurable disease (by RECIST) independent of the lesion to beablated. Measurable disease is defined as at least one lesion that can be accuratelymeasured in at least one dimension (longest diameter to be recorded for non-nodallesions and short axis for nodal lesions) as ≥20 mm with conventional techniques oras ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 (Measurement of Effect) for evaluation of measurable disease.

• Prior radiation therapy to any site is allowed; with an exception of the target sitefor planned cryoablation

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Life expectancy of greater than 3 months

• Participants must have adequate organ and marrow function as defined below:

• Leukocytes ≥3,000/mcL

• Absolute neutrophil count ≥1,000/mcL

• Platelets ≥75,000/mcL

• Total bilirubin ≤3 institutional upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) ≤5 × institutional ULN

• CrCL > 30 ml/min

• Known Human immunodeficiency virus (HIV)-infected participants on effectiveanti-retroviral therapy with undetectable viral load within 6 months are eligiblefor this trial. (HIV testing not required at screening).

• For participants with known evidence of known chronic hepatitis B virus (HBV)infection, the HBV viral load must be undetectable on suppressive therapy, ifindicated. (HBV testing not required at screening).

• Participants with a history of known hepatitis C virus (HCV) infection must havebeen treated and cured. For participants with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load. (HCVtesting not required at screening).

• Participants with asymptomatic brain metastases are eligible.

• Participants with new or progressive asymptomatic brain metastases (active brainmetastases) or leptomeningeal disease are eligible if the treating physiciandetermines that immediate CNS specific treatment is not required and is unlikely tobe required during the first cycle of therapy.

• Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Lesion to undergo cryoablation cannot have had prior radiation therapy or otherlocoregional therapy

• Inability to hold systemic anticoagulation prior to cryoablation (if holdinganticoagulation is required by the operator)

• Participants who are receiving an investigational agent(s).

• Participants who are progressing on combination ipilimumab/nivolumab as their lastline of therapy

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual toxicities > Grade 1)

• Patients with symptomatic brain metastasis or LMD

• Participants on > 10mg of oral prednisone or its equivalent

• Participants with uncontrolled intercurrent illness.

• Pregnant women are excluded from this study because immune checkpoint inhibitorshave the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with immune checkpoint inhibitors, breastfeeding should bediscontinued.