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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01149356
First received: June 22, 2010
Last updated: September 23, 2013
Last verified: September 2013
  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. 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.


Condition Intervention Phase
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
Drug: exemestane
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Drug: goserelin acetate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of treatment emergent adverse events (TEAEs) based on CTCAE version 3 grade (Phase I) [ Time Frame: Up to 70 days ] [ Designated as safety issue: Yes ]
    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).

  • Time to relapse (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Time to relapse will be summarized using descriptive statistics.


Secondary Outcome Measures:
  • Overall survival (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

Enrollment: 30
Study Start Date: October 2010
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 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.
Drug: exemestane
Given orally
Other Names:
  • Aromasin
  • FCE-24304
  • PNU 155971
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given orally
Other Names:
  • R4733
  • RO4929097
Drug: goserelin acetate
Given subcutaneously to premenopausal patients
Other Names:
  • ICI-118630
  • ZDX
  • Zoladex
Active Comparator: Arm II
Patients receive exemestane as in arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: exemestane
Given orally
Other Names:
  • Aromasin
  • FCE-24304
  • PNU 155971
Drug: goserelin acetate
Given subcutaneously to premenopausal patients
Other Names:
  • ICI-118630
  • ZDX
  • Zoladex

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01149356

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Investigators
Principal Investigator: Julie Means-Powell H. Lee Moffitt Cancer Center and Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01149356     History of Changes
Other Study ID Numbers: NCI-2010-02181, NCI-2010-02181, MCC-8539, CDR0000675612, 8539, 8539, N01CM00100
Study First Received: June 22, 2010
Last Updated: September 23, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Exemestane
Goserelin
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014