REMASTer: REcurrent Brain Metastases After SRS Trial

• Radiation Therapy (Procedure): Post-op hypofractionated therapy or no radiation therapy
• Steroid Therapy (Drug): Best medical management with steroid therapy
• Laser Interstitial Thermal Therapy (Procedure): Minimally invasive technique to necrotize intracranial lesions using the NeuroBlate® System (NBS)

Primary outcomes

• Progressive Disease Cohort [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months]: Determine the effectiveness of LITT using the NeuroBlate® System with or without repeat SRS on recurrent brain metastases, as measured by freedom from local progression.
• Radiation Necrosis Cohort [Assessed for a three month period from time of randomization to steroid freedom without escalation of care.]: Determine the effectiveness of LITT using the NeuroBlate System versus standard medical management as measured by time to steroid independence without escalation of care, measured in days from LITT procedure, defined as freedom from steroids for a period of four weeks without escalation of care.

Secondary outcomes

• Progressive Disease Cohort: Overall Survival [Compare treatment approaches with respect to overall survival, defined as time from study biopsy to death or study exit, up to 24 months.]: Compare treatment approaches with respect to overall survival.
• Radiation Necrosis Cohort: Freedom from Local Progression (FFLP) or Neurological Death [Compare treatment approaches with respect to overall survival, defined as time from study biopsy to death or study exit, up to 24 months]: Compare treatment approaches with respect to FFLP or neurologic death

Sex: All, ages: 18 Years to any

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Patients with radiographically proven (by gadolinium-enhanced \[Gd-\] MRI) parenchymal brain metastases from histologically confirmed non-central nervous system (CNS) cancer
2. Patients with a "targetable", bi-dimensionally-measurable, intracranial lesion that is considered the first radiographic recurrence after upfront treatment with SRS +/- surgery (craniotomy or LITT). Prior whole brain radiation therapy (WBRT) is permitted provided the target lesion is at first progression following SRS +/- surgery, which would have occurred after WBRT. To classify a lesion as radiographically progressive, the lesion must demonstrate a ≥ 25% increase in size, relative to the post-nadir measurement following treatment with initial SRS, based on the Response Assessment in Neuro-Oncology criteria for CNS Tumors. To be "targetable" for this study, the lesion should be expected to be coverable through a planned single LITT trajectory and thus have a maximum perpendicular diameter (perpendicular to the laser trajectory) of 3 cm. An unanticipated intra-operative decision to utilize two trajectories is acceptable and patient may remain on study
3. Patient must be at least 3 months post initial SRS treatment of the target lesion
4. Target lesion must be amenable to undergo surgical biopsy and LITT treatment as determined by the treating neurosurgeon
5. Frozen pathology diagnosis must be attainable
6. Patient must be symptomatically stable for a minimum of 3 days prior to the procedure date on a max total daily steroid dose equivalent to 4 mg of Dexamethasone
7. ≥18 years of age
8. KPS ≥70
9. Patient is able and willing to complete study requirements
10. Patients with adequate hematologic parameters (all tests to be performed within <4 weeks of biopsy):

    1. ANC ≥ 1.5 X 109/L
    2. Platelet count ≥ 100 x 109/L
11. Blood chemistry laboratory value for serum creatinine < 1.5 x ULN (test to be performed within <4 weeks of biopsy)
12. Female patients must have a negative serum pregnancy test at screening. (Not applicable to patients with bilateral oophorectomy and/or hysterectomy or to those patients who are postmenopausal)
13. All patients of reproductive potential must agree to use an effective method of contraception during the study
14. Patients must be accessible for in-person follow-up

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Patients with greater than 3 progressing lesions at time of enrollment. To classify as a radiographically progressive, lesion must demonstrate a ≥ 25% increase in size, relative to the post-nadir measurement, following treatment based on the RANO criteria. Of note, there is no exclusion for total number of metastases. However, only one lesion can be selected to be the target lesion and this lesion alone may be ablated during the study procedure
2. Patients with concomitant newly diagnosed intracranial metastases (concurrent with the targetable radiographically progressive lesion), as these will require prioritized and different treatment approaches. There is no limit to the number of pre-existing or stable non-target metastases
3. Prior bevacizumab use within 4 weeks of study initiation
4. Patients with additional concurrent malignancies, outside of the primary cancer, requiring active treatment, except non-melanoma skin cancer, or in-situ cancer of the cervix e.g. patients with multiple types of cancer on active treatment
5. Patients with a serious active infection or other serious underlying medical conditions that would impair the ability of the patient to complete the protocol related QOL questionnaires and cognition assessments
6. Inability to tolerate or contraindication to steroid therapy (i.e., dexamethasone)
7. Deemed ineligible or unable to tolerate SRS therapy by treating neurosurgeon and/or radiation oncologist
8. Patients with any condition that would prohibit them from undergoing a surgical procedure, at the discretion of the treating physician team
9. Patients unwilling or unable to give consent for participation
10. Patients unable to comply with study requirements
11. Patients with diffuse leptomeningeal disease. Small focal areas of pachymeningeal disease that are considered "stable" are acceptable with approval from study Principal Investigator
12. Patients with rapidly progressing extracranial disease, with limited further treatment options

• Peter Fecci, MD, Principal investigator, University of Colorado, Denver