RO4929097 And Exemestane in Treating Pre- and Postmenopausal Patients With Advanced or Metastatic Breast Cancer

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose or the recommended phase II dose of
gamma-secretase inhibitor RO4929097 (RO4929097) in combination with exemestane in pre-
and postmenopausal patients with estrogen receptor-positive (ER+) advanced or
metastatic breast cancer. (Phase I)

- To determine the safety and tolerability of this regimen in these patients (Phase I)

- To determine the progression-free survival of patients treated with exemestane with vs
without RO4929097. (Phase II)

Secondary

- To determine the overall tumor response rate in patients treated with these regimens.
(Phase II)

- To determine the overall survival of patients treated with these regimens. (Phase II)

- To determine the safety of these regimens in these patients. (Phase II)

- To determine the quality of life of patients treated with these regimens. (Exploratory
phase II)

- To identify biomarkers of response to treatment or toxicity. (Exploratory phase II)

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

- Phase I: Patients receive oral exemestane* once daily on days 1-21 and oral
gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

- Phase II: Patients are stratified according to menopausal status (pre- vs
postmenopausal) and visceral disease (yes vs no). Patients are randomized to 1 of 2
treatment arms.

- Arm I: Patients receive exemestane* as in phase I and oral gamma-secretase
inhibitor RO4929097 at the MTD determined in phase I. Courses repeat every 21 days
in the absence of disease progression or unacceptable toxicity.

- Arm II: Patients receive exemestane* as in arm I. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

NOTE: *In addition to exemestane, pre-menopausal patients receive goserelin subcutaneously
every 28 days.

Patients may undergo blood and tissue sample collection for correlative studies.

Patients may complete quality-of-life questionnaires at baseline and periodically during
study using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B).

After completion of study therapy, patients are followed up for 4 weeks and then every 6
months thereafter.

DISEASE CHARACTERISTICS:

- Diagnosis of breast cancer

- Locally advanced or metastatic disease for which curative measures are not
effective

- Relapsed disease with (or within 6 months of discontinuation of) an
adjuvant nonsteroidal aromatase inhibitor or tamoxifen

- Progressive disease during treatment with first- or second-line hormonal
therapy that could include a nonsteroidal aromatase inhibitor, tamoxifen,
or fulvestrant

- Recurrent disease

- No locally recurrent resectable disease

- Histologically confirmed estrogen receptor-positive (ER+) by IHC

- Must have ≥ 5% strong staining for ER+ or ≥ 10% weak staining

- Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques OR
as ≥ 10 mm by spiral CT scan

- No HER2/neu-positive disease

- No known brain metastases

PATIENT CHARACTERISTICS:

- Pre- or postmenopausal status

- ECOG performance status 0-1

- Life expectancy ≥ 6 months

- WBC ≥ 3,500/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 2 mg/dL

- AST and ALT ≤ 2.5 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Able to swallow and retain oral medication

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for ≥ 12 months after
completion of study therapy

- More than 5 years since other invasive cancer except basal or squamous cell cancer of
the skin or cervical carcinoma in situ

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097 or other agents used in
the study

- No history of torsades de pointes

- No malabsorption syndrome or other condition that would interfere with intestinal
absorption (e.g., ulcerative colitis)

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

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or
hypokalemia

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

- Ongoing or active infection requiring parenteral antibiotics

- Impairment of lung function (e.g., chronic obstructive pulmonary disease or lung
conditions requiring oxygen therapy)

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

- Unstable angina pectoris, angioplasty, stenting, and or myocardial infarction
within the past 6 months

- Uncontrolled hypertension (systolic BP > 180 mm Hg or diastolic BP > 100 mm Hg
on 2 consecutive measurements separated by a 1-week period) despite adequate
medical support

- Clinically significant cardiac arrhythmia

- Multifocal premature ventricular contractions, bigeminy, trigeminy,
ventricular tachycardia that is symptomatic, or requiring treatment

- Uncontrolled diabetes (hyperosmolar state, ketoacidosis, etc.)

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

- No baseline QTcF > 450 msec (male) or > 470 msec (female)

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Fully recovered from all previous adverse events

- No prior exemestane for metastatic or recurrent breast cancer, or within the past 6
months in the adjuvant setting

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)

- At least 2 weeks since prior radiotherapy

- At least 2 weeks since prior and no other concurrent investigational agents

- No prior exposure to γ-secretase inhibitors

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

- No other concurrent CYP3A4 substrates, inducers, or inhibitors

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer agents or therapies, including chemotherapy,
radiotherapy, surgery, immunotherapy, hormonal therapy, or biologic therapy

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

- No concurrent antiarrhythmics or other medications known to prolong QTc