This is a Phase I dose escalation and expansion trial. The purpose of this study is to determine the maximum tolerated dose of radiation received during stereotactic radiosurgery in patients with brain metastases who have never received radiation to the brain before.

Inclusion Criteria:

• Clinically confirmed brain metastases by CT or MRI criteria. If there is evidence of extra-cranial metastatic disease, it is preferable that the lesions be pathologically confirmed (see section 4.2.5 for excluded histologies) and reviewed by a University of Utah or Huntsman Cancer Hospital pathologist if the initial review was done at an outside facility.

• Prior brain surgery is allowed, although a lesion situated in the operative bed would not be selected to receive an experimental dose of SRS treatment. SRS should be delivered 4-6 weeks post-surgery if the patient had a craniotomy for resection of a lesion. Enrollment of a patient with the goal of performing SRS outside of the 4-6 post-craniotomy window is at the PI's discretion.

• Patients must have 1-5 untreated brain metastases total.

• For patients planning to enroll in Cohort 1a (including expansion) or Cohort 1b: Tumor volume ≤ 4.1888 cm3 by CT or MRI measurement at the time of consultation/screening for the metastatic lesion on trial. Patients who have at least one additional lesion that is larger than the lesions eligible for the expansion cohort, but who are unable to find another open cohort, will have the eligible lesion(s) treated in the expansion cohort, and the remaining lesion(s) treated at the standard dose.

  • For patients enrolling in the expansion Cohort 1a: Up to five brain metastases with tumor volume ≤ 0.5237 cm3 by CT or MRI measurement at the time of consultation/screening will be treated on trial with the MTD. Brain metastases with volume > 0.5237 cm3 will be treated by standard of care SRS dosing.
  • For patients enrolling in Cohort 1b: Tumor volume of > 0.5237 cm3 and ≤ 4.1888 cm3 by CT or MRI measurement at the time of consultation/screening for the metastatic lesion on trial. All other brain metastases will be treated by standard of care SRS dosing.

• As of Protocol Version 9, Cohorts 2 and 3 are permanently closed to accrual. For patients planning to enroll in Cohort 2 or 3: Equivalent tumor diameter ≤ 40 mm by CT or MRI measurement at the time of consultation/screening for the metastatic lesion on trial. Equivalent tumor diameter </=40 mm by CT or MRI measurement for all lesions treated by standard of care SRS dosing.

• All metastatic lesions must be separated by a minimum of 3 cm as measured from the peripheral edges of the lesions that are in closest proximity to one another. If multiple lesions are present and are not all ≥ 3 cm away from each other, the patient will be deemed ineligible.

• Prior systemic therapy is allowed, although appropriate washout is required for patients who have been on BRAF inhibitors (at least 7 days).

• For subjects currently on active systemic cancer therapy, the treating medical oncologist should be consulted to ensure proper washout (if appropriate) periods prior to SRS.

• Patients must be at least 18 years of age.

• Karnofsky Performance Status (KPS) ≥ 60.

• Able to provide informed consent and have signed an approved consent form that conforms to federal and institutional guidelines.

• Women of child-bearing potential must have a negative pregnancy test within 10 days of study enrollment and must agree to use an acceptable method of birth control while receiving radiation and for 3 months after radiation. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for >1 year.

• Men who are able to father a child must agree to use an acceptable method of birth control while receiving radiation, and for 3 months after radiation.

Exclusion Criteria:

• Prior whole brain irradiation.
• Brain lesions with an equivalent diameter of > 40 mm in size on MRI imaging at the time of consultation/screening for protocol eligibility.
• Lesions located in anatomic regions that are not amendable to SRS (e.g., optic nerve)
• Brain lesions located in the brain stem.
• Radiographic or cytologic evidence of leptomeningeal disease
• Primary lesion with radiosensitive histology that includes the following: small cell carcinoma, germ cell tumors, lymphoma, leukemia, or multiple myeloma
• Women of child-bearing potential who are pregnant or breast feeding
• Patients with multiple lesions, which by size criteria would be enrolled in a cohort that is full at the time of enrollment and the 12-16 weeks DLT period has not yet been reached.