Stereotactic Body Radiation Therapy, Ipilimumab, and Nivolumab for the Treatment of Metastatic Melanoma, The HAMMER I Study

Inclusion Criteria

• Adult patients (>= 18 years of age)
• Histologically or cytologically confirmed metastatic melanoma for which surgery is not recommended with liver metastases
• Disease must be measurable per Response Evaluation Criteria in Solid Tumors (RECIST)
• Patients must have a life expectancy of at least 6 months
• Patients must have a performance status of 0 - 2 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Allowable prior therapy: * Previous adjuvant or neoadjuvant treatment for melanoma is allowed, which may include molecularly-targeted agents, interferon (IFN)alpha, ipilimumab, nivolumab, and pembrolizumab, if it was completed at least 6 weeks before enrollment in the study * Patients who had experienced treatment-related adverse events from prior adjuvant or neoadjuvant treatment for melanoma are allowed if symptoms had returned to baseline or had stabilized * Prior stereotactic radiotherapy (SBRT) of extrahepatic metastases is permitted
• Patients must be willing to undergo multiple liver tissue biopsies
• Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days of enrollment)
• Platelets >= 100,000 / mcL (within 14 days of enrollment)
• Hemoglobin >= 9 g/dL without transfusion or erythropoietin (EPO) dependency (within 7 days of enrollment)
• Serum creatinine =< 2 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 45 mL/min for subject with creatinine levels > 2 X institutional ULN (within 14 days of enrollment) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X ULN (within 14 days of enrollment) * Direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X ULN for subjects with liver metastases (within 14 days of enrollment)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants (within 14 days of enrollment)
• Patients must be willing and able to sign an informed consent form
• Participants of childbearing potential * Female subject of childbearing potential should have a serum pregnancy test within 14 days of enrollment and 72 hours prior to receiving the first dose of I/N, and must be willing to use a highly effective method of contraception for the course of the study through 180 days after the last dose of I/N. (Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject) * Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 180 days after the last dose of study therapy. Sperm donation is prohibited while on study. (Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject)

Exclusion Criteria

• Diffuse involvement of liver by cancer on computed tomography (CT), positron emission tomography (PET), or magnetic resonance imaging (MRI)
• More than 4 liver metastases on CT scan at time of initial assessment. If a flare occurs during the initial I/N cycles, up to 8 metastases may be targeted if able to be targeted by a minimum of 8 Gy per fraction while meeting normal tissue constraints
• Diagnosis of underlying parenchymal end stage liver disease (cirrhosis) or biliary disease (primary biliary cirrhosis)
• Other locally advanced or metastatic invasive malignancy active within last 3 years, excluding in situ or localized cancers or malignancies which have been treated
• Patients who had received previous systemic anticancer therapy for unresectable or metastatic melanoma. Has known active carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least two weeks prior to enrollment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to enrollment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least two weeks prior to enrollment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to enrollment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) * Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Require daily corticosteroids > 10 mg of prednisone (or its equivalent) * Note: Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would NOT be excluded from the study * Note: Patients who require the use of topical steroids would not be excluded
• Has known psychiatric or substance use disorders that would interfere with safety or cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with informed consent through 180 days after the last dose of trial treatment
• Patient with known human immunodeficiency virus (HIV) infection are eligible if the CD4+ lymphocytes > 350 cells and there is no detectable viral load. HIV screening is not required to be eligible for this study
• Patient has received a bone marrow transplant or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment (not including the above exceptions)
• Has a known history of active TB (Bacillus Tuberculosis)
• Has known active hepatitis B or hepatitis C
• Prior Grade 3/4 life threatening immune related adverse event that is considered an unacceptable risk per the treating investigator
• Has received a live vaccine within 30 days of enrollment * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed * COVID vaccination acceptable; preferably all doses administered 7 days prior to start of immunotherapy
• Lacks insurance preapproval for SBRT
• Participation in another clinical study with an investigational product administered during the last 30 days
• Known hypersensitivity to nivolumab or ipilimumab or any of the excipients used in their products
• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
• Contraindication to MRI