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

Conditions:Breast Cancer, Cancer
Therapuetic Areas:Oncology
Age Range:Any
Start Date:October 2010

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A Phase I Dose Escalation Trial of RO4929097 Administered in Combination With Exemestane in Pre- and Postmenopausal Patients With ER + Metastatic Breast Cancer / A Randomized Phase II Trial Comparing Exemestane in Combination With RO4929097 Compared With Exemestane Alone as Second or Third Line Hormonal Treatment of ER + Metastatic Breast Cancer in Pre- and Post-Menopausal Patients

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using
exemestane may fight breast cancer by lowering the amount of estrogen the body makes.
RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell
growth. Giving exemestane together with RO4929097 may kill more breast cancer cells.

PURPOSE: This partially randomized phase I/II trial is studying the side effects and the
best dose of RO4929097 when given together with exemestane and to see how well it works
compared to exemestane alone in treating premenopausal and postmenopausal patients with
advanced or metastatic breast cancer.



- 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)


- 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.


- Diagnosis of breast cancer

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

- 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


- 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

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

- 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)


- 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
We found this trial at
101 Manning Drive
Chapel Hill, North Carolina 27514
(919) 966-0000
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill One of the...
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Nashville, Tennessee 37232
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4117 East Fowler Avenue
Tampa, Florida 33612
(813) 745-4673
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida Moffitt Cancer...
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Egleston, GA
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