RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

This randomized phase I/II trial studies the side effects and the best dose of RO4929097 (gamma-secretase/Notch signalling pathway inhibitor RO4929097) when given together with whole-brain radiation therapy or stereotactic radiosurgery and to see how well it works compared to whole-brain radiation therapy or stereotactic radiosurgery alone in treating patients with breast cancer or other cancers (such as lung cancer or melanoma) that have spread to the brain. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Whole-brain radiation therapy uses high energy x-rays deliver radiation to the entire brain to treat tumors that can and cannot be seen. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether giving RO4929097 together with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.

PRIMARY OBJECTIVES: I. Determine the maximum-tolerated dose (MTD) and phase II dose of RO4929097 when combined with whole-brain radiation therapy (WBRT). (Phase I) II. Determine the safety profile of RO4929097 when combined with WBRT. (Phase I) III. Determine the MTD and phase II dose of RO4929097 when combined with stereotactic radiosurgery (SRS). (Phase I) IV. Determine the safety profile of RO4929097 when combined with SRS. (Phase I) V. Determine whether the addition of RO4929097 to WBRT or SRS significantly increases the percentages of estrogen receptor-negative breast cancer patients with brain metastases who achieve response (complete response \[CR\] + partial response \[PR\]) in the brain at the 12-week (3-month) time point after cranial radiotherapy. (Phase II) SECONDARY OBJECTIVES: I. Correlate responses and time to progression to: pre- and post-therapy tumor and archived tumor tissue expression of molecular and stem cell markers; pre- and post-therapy plasma biomarkers; changes in pre- and post-therapy tumor and archived tumor tissue expression of molecular and stem cell markers over the first 5 days of therapy and changes of pre- and post-therapy plasma biomarkers over the course of therapy; in Notch positive and Notch negative tumors, over the first 5 days of therapy with RO4929097, compare tumor tissue expression of molecular and stem cell markers. (Phase I and II) II. Determine progression free survival (PFS) in the brain for each treatment arm. (Phase II) III. Determine the percentage of patients alive and disease free (in the brain) at 6 months. (Phase II) IV. Determine local control rate (in the brain) at 24- and 48-week time point after cranial radiotherapy for each treatment arm. (Phase II) V. Determine distant failure rate (in the brain) at 24- and 48-week time point after cranial radiotherapy for each treatment arm. (Phase II) VI. Determine PFS in the body for each treatment arm. (Phase II) VII. Determine systemic response rate. (Phase II) VIII. Determine percentage of patients alive and without progression systemically at 6 months. (Phase II) IX. Further describe the safety profile of each treatment arm. (Phase II) X. Compare neurocognitive outcomes in each treatment arm. (Phase II) OUTLINE: This is a phase I, dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097 followed by a randomized phase II study. PHASE I: Patients with \>= 4 brain lesions receive RO4929097 orally (PO) once daily (QD) on days 1-3 weekly beginning 1 day prior to the first day of WBRT and continuing for 6 weeks (42 days) after the completion of radiation therapy. Patients with \>= 4 brain lesions also undergo whole-brain radiotherapy (WBRT) once daily, 5 days a week, for 2-4 weeks beginning on day 2. Patients with =\< 3 brain lesions receive RO4929097 PO QD on days 1-7 in weeks 1 and 2 and then days 1-3 in all subsequent weeks beginning 2 days prior to the first day of SRS and continuing for 6 weeks (42 days) after the completion of radiation therapy. Patients with =\< 3 brain lesions also undergo stereotactic radiosurgery (SRS) on day 4. Treatment continues in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients with \>= 4 brain lesions undergo WBRT as in phase I and patients with =\< 3 brain lesions undergo SRS as in phase I. ARM II: Patients with \>= 4 brain lesions receive RO4929097 and undergo WBRT as in phase I and patients with =\< 3 brain lesions receive RO4929097 and undergo SRS as in phase I. After completion of study treatment, patients are followed up every 12 weeks for up to 52 weeks.