This phase I trial finds out the side effects and possible benefits of stereotactic radiosurgery and immune checkpoint inhibitors with NovoTTF-100M for the treating of melanoma that has spread to the brain (brain metastases). Stereotactic radiosurgery is a type of external radiation therapy that uses special equipment to position the patient and precisely give a single large dose of radiation to a tumor. It is used to treat brain tumors and other brain disorders that cannot be treated by regular surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. NovoTTF-100M is a portable battery operated device which produces tumor treating fields in the body by means of surface electrodes placed on the skin. Tumor treating fields are low intensity, intermediate frequency electric fields that pulse through the skin to disrupt cancer cells' ability to divide. Giving stereotactic radiosurgery and immune checkpoint inhibitors with NovoTTF-100M may work better than stereotactic radiosurgery and immune checkpoint inhibitors.
PRIMARY OBJECTIVE: I. To determine the safety of combining tumor treating fields therapy (TTFields) to the two therapeutic backbones (stereotactic radiosurgery \[SRS\]+pembrolizumab and SRS+dual-checkpoint). SECONDARY OBJECTIVES: I. To evaluate skin toxicity (grade 1 \& 2 skin \> 20% and grade 3 \& 4 toxicity above 2% at 4-6 weeks and 3 months). (Skin AES include Dermatitis, Erosions, Infections, Ulceration). II. Control of the treated lesion in the brain with SRS+ immune checkpoint inhibitors (ICI) (i.e. local control), development of additional sites of disease in the brain that were not initially treated with SRS (i.e. anywhere intra-cranial failure), intra-cranial progression free survival (local control of the area that received SRS and anywhere intra-cranial failure), extra-cranial disease response (overall progression free survival), and overall survival. III. To evaluate treatment response at un-irradiated and extra-cranial sites (i.e. the abscopal effect) with all three arms. IV. To compare differences in potential serological and immune biomarkers, pretreatment, during treatment, and post treatment. V. Symptomatic radionecrosis rates at 3 and 6 months. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I: Patients receive standard of care pembrolizumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive standard of care nivolumab and ipilimumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 28 days.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Given IV
Given IV
Given IV
Undergo SRS
Undergo TTFields
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
The percentage of patients developing grade 3 CNS toxicity
Will be analyzed separately for arms 1 and 2. Radiation Therapy Oncology Group Grade 3 CNS toxicity will be measured using RTOG grade 3 CNS toxicity and reported as percentage of patients developing grad 3 CNS toxicity. Higher score means more patients developing toxicity. Lower score means less patients developing toxicity.
Time frame: At 3 months
Rates of skin toxicity
As measured by Common Terminology Criteria for Adverse Events (CTCAE) 5.0, will be reported using frequencies and percentages. Skin toxicity will be analyzed separately for arms 1 and 2.
Time frame: At 4-6 weeks and 3 months
Rates of alopecia
As measured by CTCAE 5.0, will be reported using frequencies and percentages. Alopecia will be analyzed separately for arms 1 and 2.
Time frame: At 4-6 weeks and 3 months
Time to progression
Will be defined as the time without evidence of tumor progression from time of stereotactic radiosurgery (SRS). Local control will be estimated using the Kaplan-Meier method. A 95% confidence interval for 6-month and 12-month local control will be estimated using the Greenwood formula. Local control will be analyzed separately for arms 1 and 2.
Time frame: At 6 and 12 months
Intracranial control
Will be defined as the time without evidence of tumor progression from time of SRS. Intracranial control will be estimated using the Kaplan-Meier method. A 95% confidence interval for 6-month and 12-month intracranial control will be estimated using the Greenwood formula. Intracranial control will be analyzed separately for arms 1 and 2.
Time frame: At 6 and 12 months
Progression free survival (PFS)
PFS will be estimated using the Kaplan-Meier method, and a 95% confidence interval for median PFS will be estimated using the Brookmeyer-Crowley approach. PFS will be analyzed separately for arms 1 and 2.
Time frame: From SRS to disease progression or death, assessed up to 2 years
Overall survival (OS)
OS will be estimated using the Kaplan-Meier method, and a 95% confidence interval for median OS will be estimated using the Brookmeyer-Crowley approach. OS will be analyzed separately for arms 1 and 2.
Time frame: From SRS to death, assessed up to 2 years
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