Summary

This phase I trial finds out the side effects and possible benefits of stereotactic radiosurgery and immune checkpoint inhibitors with NovoTTF-200M 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-200M 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-200M may work better than stereotactic radiosurgery and immune checkpoint inhibitors.

Objectives

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 dermatitis > 20% and grade 3 & 4 toxicity above 2% at 4-6 weeks and 3 months).
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-200M 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. Patients also undergo blood sample collection, magnetic resonance imaging (MRI), computed tomography (CT) and/or position emission tomography (PET) during screening and on study.

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-200M 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. Patients also undergo blood sample collection, MRI, CT and/or PET during screening and on study.

After completion of study treatment, patients are followed up for 28 days.

Eligibility

1. Be willing and able to provide written informed consent for the trial
2. Have a diagnosis of malignant melanoma
3. Be >= 22 years of age on the day of signing informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 or Karnofsky performance status >= 70%
5. Preference is for treatment naive patients that have not gotten previous immunotherapy. However, if approved by principal investigator (PI), patients that have gotten prior PD1 and/or dual immune checkpoint inhibitor therapy may be allowed on this trial if they have progressed intra-cranially or extra-cranially, and have very limited disease progression
6. Patient must be asymptomatic at time of getting SRS (day 0) on trial. Prednisone =< 20 mg/day (4 mg or less of dexamethasone equivalent) for at least 7 days prior to treatment is allowed
7. Patients with ocular, mucosal and unknown primary melanoma will also be eligible
8. Patients with 1-10 untreated brain metastases at time of initial brain metastases diagnosis (surgery to at least one of the brain lesions and/or biopsy of a lesion for diagnostic purposes and/or for standard of care purposes is acceptable). If patient has surgical removal of at least one lesion, we would wait for a reasonable time after surgery to start the TTFields, SRS and Immunotherapy. This is typically around 2-4 weeks after resection and clearance by neurosurgery to start the treatment. However, the exact time to start would depend on institutional standard of care practice pattern. Enrollment of patient can take place before or after planned surgery
9. Eligible for hypofractionation approach (9 Gy x 3 or 6 Gy x 5). 9 Gyx 3 is preferred approach, but 6 Gy x 5 fractions is acceptable
10. Eligible for immunotherapy and TTFields. The TTField wires will be removed immediately before the SRS delivery and then reconnected again immediately after SRS each session. The arrays will be left on the skin during SRS. This is to minimize any electrical discharge from the wires that may occur as a result of SRS beams going through the arrays and/or lead to any dose heterogeneity during SRS delivery and/or damage the electrical, battery operated equipment
11. Be willing to comply with NovoTTF-200M device treatment for at least 75% of the time
12. Must have caregiver or self support available to assist transducer array exchange
13. Prior radiation to the primary and/or regional radiotherapy for melanoma is acceptable
14. Baseline labs as within standard of care (complete blood count [CBC], comprehensive metabolic panel [CMP], lactate dehydrogenase [LDH], erythrocyte sedimentation rate [ESR], etc) are required within 28 days of enrollment
15. Have at least one measurable extra-cranial site of disease
16. Patients must have at least 14 days to recover from all prior treatment, including surgery, chemotherapy, immunotherapies, prior to enrollment on this protocol
17. Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 28 days of treatment initiation)
18. Platelets >= 100,000 / mcL (performed within 28 days of treatment initiation)
19. Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 28 days of treatment initiation)
20. Serum creatinine =< 1.5 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]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 28 days of treatment initiation)
21. Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
22. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 28 days of treatment initiation)
23. Albumin >= 2.5 mg/dL (performed within 28 days of treatment initiation)
24. International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 days of treatment initiation)
25. Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 28 days of treatment initiation)
26. Female subject of childbearing potential must have a negative urine or serum pregnancy within 2 weeks prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 year * Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Abstinence is acceptable, if this is the usual life style and preferred contraception for the patient

Treatment Sites in Georgia