Optune Device - TT Field Plus Nivolumab and Ipilimumab for Melanoma With Brain Metastasis

Study Overview
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Brief Summary
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This phase II study will evaluate the safety of combining intermediate frequency electric field (TT Field) with immunotherapy in melanoma patients with brain metastasis. The data of this study will also inform whether this combination will offer advantage in progression free survival (PFS) and overall survival.

Official Title
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Phase II Study of Optune Device - TT Field Plus Nivolumab and Ipilimumab for Melanoma With Brain Metastasis

Conditions
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Melanoma With Brain Metastasis

Intervention / Treatment
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* Device: Optune
* Biological: Nivolumab
* Biological: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed melanoma with metastasis to the brain. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. Candidate for treatment with immunotherapy. At least 18 years of age. Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Total bilirubin ≤ 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation, including at least 5 months (for women of childbearing potential) and at least 7 months (for men) after last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Received treatment in the metastatic setting Treated with whole brain radiation Receiving targeted therapy or on immunosuppressive agents (dexamethasone> 4mg/day) within 1 week of therapy. A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. Currently receiving any other investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, ipilimumab, or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. History of pre-existing immunodeficiency disorder or autoimmune condition requiring immunosuppressive therapy. This includes inflammatory bowel disease, ulcerative colitis, Crohn's disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatologic disease or any other medical condition or use of medication which might make it difficult for the patient to complete the full course of treatments or to generate an immune response to vaccines. Known sensitivity to conductive hydrogels. Skull defects such as missing bone or bullet fragments. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, vagus nerve stimulator, and other implanted electronic devices in the brain or spinal cord. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with nivolumab and/or ipilimumab. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

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: Optune + Ipilimumab + Nivolumab<br>Ipilimumab at 3 mg/kg IV over 90 minutes on Day 1 of each 21-day cycle for 4 cycles. Nivolumab at 1 mg/kg IV over 30 minutes on Day 1 of each 21-day cycle for 4 cycles, then at 240 mg IV over 30 minutes on Days 1 and 15 of each 28-day cycle for up to 20 doses Within 2 weeks of the start of ipilimumab (before or after), treatment with Optune will begin. All patients will be required to shave their heads to initiate array placement and Optune therapy. Treatment may continue for up to 1 year | Device: Optune<br>* -Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, perpendicular field directions at a maximal intensity of 707mARMS.<br>Biological: Nivolumab<br>* -Standard of care<br>* Other names: Opdivo;Biological: Ipilimumab<br>* -Standard of care<br>* Other names: Yervoy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Progression-free Survival | The PFS time will be calculated as the duration of time from the date of first dose of study treatment to the date of earliest intracranial progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | At 6 months (up to 184 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | -Defined as the duration of time from the date of first dose of study treatment to death from any cause. | At 6 months (up to 184 days) | 
| Best Intracranial Response Rate | Defined as the percentage of patients with a confirmed intracranial complete or partial response Using modified RANO criteria | Until disease progression or death whichever comes first (median follow-up 53 days (full range 15-91 days)) | 
| Best Extracranial Response Rate | Defined as the percentage of patients with a confirmed extracranial complete or partial response Using modified RANO criteria | Until disease progression or death whichever comes first (median follow-up 53 days (full range 15-91 days)) | 
| Extracranial Progression-free Survival | Defined as the duration of time from the date of first dose of study treatment to the date of earliest extracranial progression or death, whichever occurs first. Patients who neither progress nor die by the data cutoff date will be censored at the last follow up. Using modified RANO criteria | At 6 months | 
| Safety of the Treatment Regimen as Measured by Number of Participants With Treatment-related Grade 3 or Greater Adverse Events | -The descriptions and grading scales found in CTCAE version 5.0. | Through 100 days after completion of treatment (median follow-up 107.5 days, full range (25 days-190 days) | 
| Safety of the Treatment Regimen as Measured by Number of Participants With Discontinuations Due to Treatment Related Adverse Events. | -The descriptions and grading scales found in CTCAE version 5.0. | Through 100 days after completion of treatment (median follow-up 107.5 days, full range (25 days-190 days) |