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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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

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Trial Information

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


PRIMARY OBJECTIVES:

I. 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.

II. Determine the safety and tolerability of this regimen in these patients. III. Determine
the progression-free survival of patients treated with exemestane with vs without RO4929097.

SECONDARY OBJECTIVES:

I. Determine the overall tumor response rate in patients treated with these regimens.

II. Determine the overall survival of patients treated with these regimens. III. Determine
the safety of these regimens in these patients. IV. Determine the quality of life of
patients treated with these regimens. V. Identify biomarkers of response to treatment or
toxicity.

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.

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.


Inclusion Criteria:



- 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

- 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, torsades de pointes, ventricular tachycardia
that is symptomatic, or requiring treatment)

- A requirement for antiarrthymics or other medications known to prolong QTC

- 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of treatment emergent adverse events (TEAEs) based on CTCAE version 3 grade (Phase I)

Outcome Description:

Will be summarized by body system, preferred term, verbatim of adverse event, intensity, and relationship to each study drug (BMS-936558 and/or the peptide vaccine).

Outcome Time Frame:

Up to 70 days

Safety Issue:

Yes

Principal Investigator

Julie Means-Powell

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2010-02181

NCT ID:

NCT01149356

Start Date:

October 2010

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male

Name

Location

H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Vanderbilt UniversityNashville, Tennessee  37232-6305
University of North CarolinaChapel Hill, North Carolina  27599
Emory UniversityAtlanta, Georgia  30322