Hepatic Ablation of Melanoma Metastases to Enhance Immunotherapy Response, a Phase I Clinical Trial (HAMMER I)

Study Overview
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Brief Summary
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The primary purpose of this study is to determine the feasibility of liver stereotactic body radiation therapy (SBRT) given in combination with systemic therapy (ipilimumab and nivolumab) in adults with metastatic melanoma with liver metastases who are at significant risk of not benefiting from systemic therapy alone.

Official Title
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Hepatic Ablation of Melanoma Metastases to Enhance Immunotherapy Response, a Phase I Clinical Trial (HAMMER I)

Conditions
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Melanoma, Ocular, Melanoma, Cutaneous, Metastatic Melanoma, Melanoma, Mucosal, Liver Metastases

Intervention / Treatment
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* Drug: Ipilimumab
* Drug: Nivolumab
* Procedure: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (≥18 years of age) with histologically or cytologically confirmed metastatic melanoma for which surgery is not recommended with liver metastases; disease must be measurable per RECIST criteria Patients must have a life expectancy of at least 6 months Patients must have a performance status of 0 - 2 on the ECOG Performance Scale. Allowable prior therapy: Previous adjuvant or neoadjuvant treatment for melanoma is allowed, which may include molecularly-targeted agents, 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 Patients must have adequate organ function per protocol Patients must understand and be willing to sign an informed consent form approved for this purpose by the Institutional Review Board (IRB) of the University of Michigan Medical Center indicating that they are aware of the investigational aspects of the treatment and the potential risks. Participants of childbearing potential Female subject of childbearing potential should have a serum pregnancy 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: Patients will be excluded from the trial if participants have the following: Diffuse involvement of liver by cancer on CT, PET, or MRI imaging 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 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 abuse disorders that would interfere with 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. Has a diagnosis of immunodeficiency (including Human Immunodeficiency Virus (HIV) or acquired immunodeficiency (AIDS)-related illness) or 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. Has a known history of active TB (Bacillus Tuberculosis). Has known active Hepatitis B or Hepatitis C. Prior Gr3/4 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 therapy Lacks insurance preapproval for SBRT

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipilimumab + Nivolumab + Stereotactic Body Radiation Therapy (SBRT)<br>Liver SBRT following the second cycle of ipilimumab + nivolumab, which will then be continued up to 4 total cycles prior to subsequent maintenance nivolumab for duration of clinical benefit and tolerance (standard of care systemic therapy) | Drug: Ipilimumab<br>* Ipilimumab administered IV over 85-100 minutes at 3 mg/kg (combined with nivolumab administered IV over 30-60 minutes at 1 mg/kg) every 3 weeks for a total of 4 doses or until progression or unacceptable toxicity.<br>Drug: Nivolumab<br>* Nivolumab administered IV over 30-60 minutes at 1 mg/kg (combined with ipilimumab administered IV over 85-100 minutes at 3 mg/kg) every 3 weeks for a total of 4 doses of the combination therapy or until progression or unacceptable toxicity. Subjects may receive maintenance dosing of nivolumab alone administered IV over 30-60 minutes at 240 mg every 2 weeks or 480 mg every 4 weeks for a maximum of 52 weeks or until progression or unacceptable toxicity.<br>Procedure: Stereotactic Body Radiation Therapy<br>* 24-45 Gy delivered in three fractions to up to 4 liver metastases<br>* Other names: SBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients who receive all planned radiotherapy. | Percentage of patients who receive all fractions of radiotherapy as planned following the second cycle of ipilimumab/nivolumab (I/N). Radiotherapy will be administered on C2D8 of I/N (±7days) | Up to 5 weeks after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who develop grade 3 or higher toxicity | Proportion of patients who develop grade three or higher toxicities within 60 days after treatment with SBRT or thirty days after the last cycle of I/N, whichever occurs later. Any serious adverse event that occurs after this time frame and is considered related to the study treatment will also be reported. | Up to 14 weeks after start of study treatment | 
| Overall survival (OS) | OS defined as the time from start of treatment to death. This will be analyzed using Kaplan-Meier curves and descriptive statistics. | Up to 2 years after end of study treatment | 
| Progression free-survival (PFS) | PFS defined as the time from start of treatment to date of radiological or clinical progression (leading to withdrawal from the study), or death from any cause, whichever comes first. Assessed Per RECIST v1.1; analyzed using Kaplan-Meier curves and descriptive statistics. | Up to 2 years after end of study treatment | 
| Proportion of patients with local control | Freedom from local progression (local control) is defined as the lack of progression of the tumors treated by RT, either by tumor size or enhancement. Progression or development of new tumors elsewhere in the liver or outside of the liver would not constitute a local control failure. Tumors which increase in size or demonstrate new or increasing enhancement are considered progression. Analyzed using Kaplan-Meier curves and descriptive statistics. | Up to 2 years after end of study treatment | 
| Objective response rate (ORR) | The percentage of patients whose disease decreases (Partial response - PR) and/or disappears (Complete response - CR) after treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Up to 2 years after end of study treatment | 
| Best overall response (BoR) | The best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). | Up to 2 years after end of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver SBRT, ipilimumab, nivolumab