REMASTer: REcurrent Brain Metastases After SRS Trial

Study Overview
=================
Brief Summary
-----------------
Randomized, post-market multi-center study investigating the efficacy of two sets of treatment algorithms in brain metastases (BM) patients at the time of first intervention for radiographic progression after stereotactic radiosurgery (SRS), with or without surgery.

Official Title
-----------------
REMASTer: REcurrent Brain Metastases After SRS Trial

Conditions
-----------------
Brain Metastases, Radiation Necrosis, Recurrent Tumor, Recurrent Metastases

Intervention / Treatment
-----------------
* Procedure: Radiation Therapy
* Drug: Steroid Therapy
* Procedure: Laser Interstitial Thermal Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Patients with radiographically proven (by gadolinium-enhanced [Gd-] MRI) parenchymal brain metastases from histologically confirmed non-central nervous system (CNS) cancer. Patients with a targetable, bidimensionally-measurable, intracranial lesion that is radiographically recurrent after previous treatment with SRS +/- surgery (craniotomy or LITT). To classify a lesion as radiographically progressive, the lesion must demonstrate a ≥ 25% increase in size following treatment based on the Neuro-Oncology Criteria of Tumor Response for CNS Tumors. To be targetable for this study, the lesion should be coverable through a planned single LITT trajectory and thus have a maximum perpendicular diameter (perpendicular to the laser trajectory) of 3 cm. An intra-operative decision to utilize two trajectories is acceptable and patient may remain on study. Patient must be at least 3 months post initial SRS treatment of the target lesion Target lesion must be amenable to undergo surgical biopsy and LITT treatment as determined by the treating neurosurgeon. Frozen pathology diagnosis must be attainable. Patient must be symptomatically stable for a minimum of 3 days prior to the procedure date on a on a max total daily steroid dose equivalent to 4mg of Dexamethasone. ≥18 years of age KPS ≥70 Patient is able and willing to complete study requirements Patients with adequate hematologic parameters (all tests to be performed within <4 weeks of biopsy): ANC ≥ 1.5 X 109/L Platelet count ≥ 100 x 109/L Blood chemistry laboratory value for serum creatinine < 1.5 x ULN (test to be performed within <4 weeks of biopsy) 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) All patients of reproductive potential must agree to use an effective method of contraception during the study Patients must be accessible for follow-up Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: 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 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 targeted lesion and this lesion alone may be ablated during the study procedure. Patients with concomitant newly diagnosed intracranial metastases (concurrent with the targetable radiographically progressive lesion), as these will require prioritized and different treatment approaches. Prior bevacizumab use within 4 weeks of study initiation Patients with additional concurrent malignancies requiring active treatment, except non-melanoma skin cancer, or in-situ cancer of the cervix 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 Inability to tolerate or contraindication to steroid therapy (i.e., dexamethasone) Deemed ineligible or unable to tolerate SRS therapy by treating neurosurgeon and/or radiation oncologist Patients with any condition that would prohibit them from undergoing a surgical procedure, at the discretion of the treating physician team Patients unwilling or unable to give consent for participation Patients unable to comply with study requirements Patients with diffuse leptomeningeal disease Patients with rapidly progressing extracranial disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Recurrent Tumor<br>Receives Laser Interstitial Thermal Therapy (LITT) followed by surveillance or Receives Laser Interstitial Thermal Therapy (LITT) followed by hypofractionated radiation therapy (RT). | Procedure: Radiation Therapy<br>* Post-op hypofractionated therapy or no radiation therapy<br>Procedure: Laser Interstitial Thermal Therapy<br>* Minimally invasive technique to necrotize intracranial lesions using the NeuroBlate® System (NBS)<br>|
| Other: Radiation Necrosis<br>Receives Laser Interstitial Thermal Therapy (LITT) and best medical management with steroids or Receives best medical management with steroids. | Drug: Steroid Therapy<br>* Best medical management with steroid therapy<br>Procedure: Laser Interstitial Thermal Therapy<br>* Minimally invasive technique to necrotize intracranial lesions using the NeuroBlate® System (NBS)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progressive Disease Cohort | 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. | 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 | 
| Radiation Necrosis Cohort | 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. | Assessed for a three month period from time of randomization to steroid freedom without escalation of care. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progressive Disease Cohort: Overall Survival | Compare treatment approaches with respect to 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. | 
| Radiation Necrosis Cohort: Freedom from Local Progression (FFLP) or Neurological Death | Compare treatment approaches with respect to FFLP or neurologic death | Compare treatment approaches with respect to overall survival, defined as time from study biopsy to death or study exit, up to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Laser Interstitial Thermal Therapy, Stereotactic Radiosurgry, LITT, SRS, Radiation Necrosis, Brain Metastases