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

PRIMARY OBJECTIVES:

I. Determine the maximum-tolerated dose and phase II dose of gamma-secretase inhibitor
RO4929097 (RO4929097) when combined with whole-brain radiotherapy (WBRT) or stereotactic
surgery (SRS) in patients with brain metastases secondary to estrogen receptor-negative
breast cancer. (Phase I) II. Determine the safety profile of these regimens in these
patients. (Phase I) III. Determine whether the addition of RO4929097 to WBRT or SRS
significantly increases the percentages of patients who achieve response (complete and/or
partial response) at the 12-week (3-month) time point after cranial radiotherapy. (Phase II)

SECONDARY OBJECTIVES:

I. Correlate response and time to progression with molecular, stem cell markers, and
biomarker expression in tumor tissue, archived tumor tissue, and plasma.

II. Compare changes over the first 5 days of therapy with changes over the course of
therapy.

III. Compare response and time to progression at the first 5 days of therapy with RO4929097
in Notch-positive and -negative tumor tissue expression of molecular and stem cell markers.

IV. Determine the progression-free survival of patients treated with these regimens. (Phase
II) V. Determine the percentage of patients alive and disease-free (in the brain) at 6
months. (Phase II) VI. Determine local control rate (in the brain) at 24- and 48-week time
point in these patients after cranial radiotherapy. (Phase II) VII. Determine distant
failure rate (in the brain) at 24- and 48-week time point in these patients after cranial
radiotherapy. (Phase II) VIII, Determine systemic response rate in patients treated with
these regimens. (Phase II) IX. Determine the percentage of patients alive and without
progression at 6 months. (Phase II) X. Further describe the safety profile of these regimens
in these patients. (Phase II) XI. Compare neurocognitive outcomes in patients treated with
these regimens. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor
RO4929097 followed by a phase II study.

PHASE I: Patients with >= 4 brain lesions receive oral gamma-secretase inhibitor RO4929097
(RO4929097) once daily on days 1-3 weekly for up to 10 weeks and 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 oral RO4929097 once daily on days 1-7,15-17, 22-24, 29-31,
and 36-38 and undergo stereotactic radiosurgery (SRS) on day 4. Courses with RO4929097
continue for up to 6 weeks after the completion of radiotherapy in the absence of disease
progression or unacceptable toxicity.

PHASE II: Patients are stratified according to HER2/neu status (positive vs negative), RPA
classification (I vs II), and number of brain metastases (1-3 vs >= 4). 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.

Patients may undergo plasma sample collection at baseline and periodically during study for
biomarkers (soluble markers of angiogenesis and circulating endothelial and precursor cells)
studies. Patients may also undergo tumor tissue sample collection periodically for molecular
(Notch activity) and stem cell marker analysis. Archived tumor tissue is also analyzed for
stem cell markers and Notch activity. Patients undergo neurocognitive testing (HVLT-R Free
Recall, Trail Making, Controlled Oral Word Associated, Grooved Pegboard Test [both hands],
HVLT-R: Delayed Recall, and HVLT- R: Delayed Recognition) at baseline and periodically
during study.

After completion of study therapy, patients are followed up for 52 weeks.

Inclusion Criteria:

- Must meet 1 of the following criteria:

- Histologically or cytologically confirmed breast or other cancer, such as lung
cancer, melanoma, etc., with newly diagnosed metastatic disease to the brain
(phase I)

- Patients who have available systemic therapeutic options with a
demonstrated survival benefit will not be eligible

- Histologically or cytologically confirmed breast cancer with newly diagnosed
metastatic disease to the brain

- Estrogen receptor-negative disease (phase II)

- Patients with newly diagnosed brain metastases who have received therapeutic regimens
with well-characterized, delayed toxicity (e.g., hematologic toxicity observed
following carmustine or mitomycin C) will not receive experimental therapy until the
patient has adequately recovered from all drug-related toxicities

- Measurable disease in the brain, defined as >= 1 lesion that can be accurately
measured in >= 2 dimensions (longest diameter and its longest perpendicular diameter
to be recorded)

- Tumor HER2/neu status positive or negative

- No leptomeningeal metastases

- Menopausal status not specified

- Karnofsky performance status (PS) 70-100%

- Recursive Partitioning Analysis (RPA) class I or II

- A small feasibility cohort of 10 RPA class III (Karnofsky PS < 70%) allowed,
however they will not be included in the efficacy analysis

- WBC >= 3,000/mm^3

- ANC >= 1,000/mm^3

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

- Total bilirubin normal

- AST (SGOT) =< 2.5 times upper limit of normal (ULN)

- ALT (SGPT) =< 2.5 times ULN

- Creatinine normal OR creatinine clearance >= 60 mL/min

- Fertile patients must use 2 forms of effective contraception (i.e., barrier
contraception and one other method of contraception) for the duration of study and
for >= 12 months after treatment

- Negative pregnancy test

- Not pregnant or nursing

- Able to swallow pills

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097

- No malabsorption syndrome or other condition that would interfere with intestinal
absorption

- Not known to be serologically positive for hepatitis A, B, or C, or have a history of
liver disease, other forms of hepatitis, or cirrhosis

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,
hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte
supplementation

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, and
hypokalemia

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure (NYHA class III or IV)

- Unstable angina pectoris

- A history of torsades de pointes or other significant cardiac arrhythmias

- Stable atrial fibrillation

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- Baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)

- No requirement for antiarrhythmics or other medications known to prolong QTc

- The use of oral or intravenous corticosteroids is allowed as needed for symptomatic
management of cerebral edema

- Typical doses of dexamethasone include 4 mg, up to four times daily,
administered either orally or intravenously

- Any type or number of prior therapies allowed

- No prior therapy with Notch inhibitors

- No prior cranial radiation

- Therapy-naive patients allowed

- At least 14 days since any prior experimental therapy, chemotherapy, or radiotherapy
and recovered to < grade 2 toxicities

- No other concurrent investigational agents

- No concurrent combination antiretroviral therapy in HIV-positive patients

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- No concurrent medications that are generally accepted by the QTdrugs.org Advisory
Board to carry a risk for Torsades de Pointes, including antiemetics

- No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4

- No concurrent medications or food that may interfere with the metabolism of
gamma-secretase inhibitor RO4929097, including ketoconazole and grapefruit juice

- No other concurrent anticancer agents or therapies