Study of Intraoperative Radiotherapy for Patients With Large Brain Metastases Treated With Neurosurgical Resection

Study Overview
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Brief Summary
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The primary purpose of this study is to establish a maximum tolerated dose (MTD) through a dose-escalation trial using intraoperative radiotherapy (IORT) following neurosurgical resection for large brain metastases, and to determine the progression-free survival rate as in the recurrence rate of treated brain metastasis.

Detailed Description
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The potential for delivering ablative doses of radiation to the tumor bed while simultaneously sparing normal brain parenchyma from significant doses of radiation and reducing the potential for tumor repopulation has led to interest in the use of intraoperative radiotherapy (IORT) for brain metastasis.

Official Title
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A Phase I/II Study of Intraoperative Radiotherapy for Patients With Large Brain Metastases Treated With Neurosurgical Resection

Conditions
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Brain Metastases

Intervention / Treatment
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* Radiation: intraoperative radiotherapy (IORT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be ≥ 18 years of age. Participants must have a Karnosfky performance status of ≥ 50%. Participants must not have had prior intracranial radiation. Participants must have a life expectancy greater than 3 months. Participants must have a preoperative MRI Brain T1-Gadolinum enhanced scan demonstrating a non-dural based lesion with greatest diameter ≥ 2.5 cm. Sufficient distance (≥ 2cm) of the intracranial lesion from optic structures (optic chiasm and bilateral optic nerves) and brainstem to meet established normal structure dose limits. Subject or subject's legal representative to provide signed/written informed consent to participate in the study protocol. Surface of balloon applicator must be ≥ 1cm from skin overlying closest portion of calvarium. Participants may remain on systemic therapy if they are receiving immunotherapy (anti-PD1, anti-PDL1, anti-CTLA-4), capecitabine, temozolomide, etoposide, vinorelbine, pemetrexed, lapatinib, traztuzumab, bevacizumab, mTor or ALK targeted agents with no break prior to initiating IORT. 9.1 Participants receiving cisplatin, methotrexate, taxanes, tyrosine kinase inhibitors, or BRAF targeted agents must have a seven day washout period prior to receiving IORT. 9.2 Participants receiving doxorubicin, T-DM1, or antibody-drug conjugates must have a fourteen day washout period prior to receiving IORT. 9.3. Participants receiving all other concurrent systemic agents will undergo consideration for a washout period prior to receiving IORT at the discretion of the study principal investigator. Exclusion Criteria: Participants may not be pregnant or breast-feeding. Patients must not have dural lesions or leptomeningeal disease. Patients must not have psychiatric or social conditions limiting adherence to protocol guidelines. Patients must not have contraindications to anesthesia, surgery, or MR imaging with Gadolinium injection. Patients must not have a frozen section diagnosis of small cell carcinoma, lymphoma, germinoma or non-malignant histology. Patients with additional unresected brain metastases must have a limited number of lesions/or volume of intracranial disease amenable to stereotactic radiotherapy at the discretion of the study principal investigator. Patients deemed to require postoperative whole brain radiotherapy should be excluded.

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: Sequential Assignment
Interventional Model Description: The resection procedure should be performed with image guidance (neuronavigation) with standard surgical technique. Optimal balloon applicator size will be selected with accordance to tumor bed/cavity geometry and adjacent normal brain parenchyma by the team of surgeons and radiation oncologists. The radiation oncologist will place the miniature x-ray source inside the balloon shaped catheter placed inside the tumor cavity. Radiotherapy will be initiated by the treating radiation oncologist for a defined time interval calculated by the machine planning software. After IORT has been delivered, the surgeon will remove the balloon applicator. Surgery will be continued in the regular fashion without additional requirements.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>intraoperative radiotherapy (IORT) arm | Radiation: intraoperative radiotherapy (IORT)<br>* intraoperative radiotherapy (IORT) during brain tumor resection to establish a maximum tolerated dose (MTD) through a dose-escalation trial using intraoperative radiotherapy (IORT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Established Maximum Tolerated Dose | Maximum tolerated dose will be determined by classical 3+3 dose-escalation design. Toxicity will be measured using the National Cancer Institute Common terminology criteria for adverse events (version 5.0). The first dose of 18Gy will be administered to the first 3 subjects, after 90 days from treatment a safety assessment for dose limiting toxicities will be done to determine if the next 3 subject will escalation to dose of 21Gy or receive 18Gy. If escalation to 21Gy is permitted, then after 90 days from treatment a safety assessment for dose limiting toxicities will be done to determine if next cohort of 3 subjects will escalate to a dose of 24Gy or receive 21Gy. The highest dose level to be administered will be 24 Gy if permitted by safety assessments. | Phase I cohorts; 90 days from treatments | 
| Number of Participants With Adverse Events | Number of adverse events reported per participant. | 12 months |