Stereotactic Radiosurgery Dose Escalation for Brain Metastases

Inclusion Criteria:

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

• Prior brain surgery is allowed, although a lesion situated in the operative bedwould not be selected to receive an experimental dose of SRS treatment. SRS shouldbe delivered 4-6 weeks post-surgery if the patient had a craniotomy for resection ofa lesion. Enrollment of a patient with the goal of performing SRS outside of the 4-6post-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 ofconsultation/screening for the metastatic lesion on trial. Patients who have atleast one additional lesion that is larger than the lesions eligible for theexpansion cohort, but who are unable to find another open cohort, will have theeligible 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. Forpatients planning to enroll in Cohort 2 or 3: Equivalent tumor diameter ≤ 40 mm byCT or MRI measurement at the time of consultation/screening for the metastaticlesion on trial. Equivalent tumor diameter </=40 mm by CT or MRI measurement for alllesions treated by standard of care SRS dosing.

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

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

• For subjects currently on active systemic cancer therapy, the treating medicaloncologist should be consulted to ensure proper washout (if appropriate) periodsprior 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 thatconforms to federal and institutional guidelines.

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

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

Exclusion Criteria:

• Prior whole/partial brain irradiation.

• Brain lesions with an equivalent diameter of > 40 mm in size on MRI imaging at thetime of consultation/screening for protocol eligibility.

• Lesions located in anatomic regions that are not amendable to SRS (e.g., opticnerve)

• Brain lesions located in the brain stem.

• Radiographic or cytologic evidence of leptomeningeal disease

• Primary lesion with radiosensitive histology that includes the following: small cellcarcinoma, 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 cohortwhich is full at the time of enrollment and the 12 weeks DLT period has not beenreached.