Temsirolimus in Treating Patients With Locally Advanced or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well temsirolimus works in treating patients with breast cancer that has spread to other places in the body. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the overall activity (as defined by complete response [CR] + partial response [PR] + stable disease [SD] for >= 24 weeks) of a weekly 25 mg intravenous dose of temsirolimus in patients with locally advanced or metastatic breast cancer. II. To compare the activity of temsirolimus in patients with locally advanced or metastatic breast cancer whose primary tumors have mutations in the PIK3CA or PTEN gene with those whose tumors do not have a mutation in the PIK3CA gene. III. To examine correlations between antitumor activity of temsirolimus and alterations in expression of genes in the PI3K pathway in primary tumor biopsy specimens. OUTLINE: Patients receive temsirolimus intravenously (IV) over 30 minutes weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Official Title
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Phase II Trial of CCI-779 (Temsirolimus) in Patients With Locally Advanced or Metastatic Breast Cancer

Conditions
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Recurrent Breast Carcinoma, Stage III Breast Cancer AJCC v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed metastatic or recurrent breast cancer not amenable to local therapy (surgery and radiation) (histologic/cytologic confirmation of recurrence preferred, but not required) Either the primary or metastatic tumor must be positive for estrogen receptor (>= 1% by immunohistochemical staining) and/or progesterone receptor (>= 1% by immunohistochemical staining) and/or human epidermal growth factor receptor (HER2neu) (3+ immunohistochemical staining or fluorescence in situ hybridization [FISH] positive) Patients must have measurable disease; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan There are no limitations on the number of prior therapy regimens; however, patients who have had prior exposure to rapamycin or any other mechanistic target of rapamycin (mTOR) inhibitor are excluded from the trial Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin =< institutional upper limit of normal Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 times institutional upper limit of normal Creatinine =< 2.0 x normal institutional upper limit of normal Cholesterol =< 350 mg/dL (fasting) Triglycerides =< 400 mg/dL (fasting) Albumin >= 3.3 mg/dL Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; women of child-bearing potential must have a negative pregnancy test prior to treatment on study; breastfeeding should be discontinued if the mother is treated with temsirolimus Ability to understand and the willingness to sign a written informed consent document Tissue for correlative studies must be available and the subject must agree to use of tissue for these studies Exclusion Criteria: Patients must be off of hormonal agents used for the treatment of breast cancer for one week with the exception that premenopausal women who have been on a gonadotropin-releasing hormone (GnRH) agonist and subsequently progressed may, at the discretion of the treating physician, continue on the GnRH agonist Patients should have recovered from the adverse effects of prior chemotherapy; in general, this will mean that the patient would have been due or overdue for the next dose of the prior regimen: three weeks should have elapsed for a regimen administered once every three weeks, etc Radiotherapy should have been completed Three weeks should have elapsed since prior therapy with monoclonal antibodies Patients may not be receiving any other investigational agents or herbal preparations; patients may not be taking corticosteroids except in low doses as replacement for adrenal insufficiency or for short -term (less than 5 days) use for other reasons Patients with known brain metastases are not permitted on study unless the metastases have been controlled by prior surgery or radiotherapy, and the patient has been neurologically stable and off of steroids for at least 4 weeks Patients cannot be receiving enzyme-inducing antiepileptic drugs (enzyme-inducing antiepileptic drugs [EIAEDs]; e.g., phenytoin, carbamazepine, phenobarbital) nor any other CYP3A4 inducer such as rifampin or St. John's wort, as these may decrease temsirolimus levels; use of agents that potently inhibit CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited; CCI-779 can inhibit CYP2D6, and may decrease metabolism (and increase drug levels) of drugs that are substrates for CYP2D6, such as codeine; the appropriateness of use of such agents is left to physician discretion; if there is any doubt about eligibility based on concomitant medication, the study chair, Dr Fleming, should be contacted; all concomitant medications must be recorded Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled symptomatic cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study Patients with known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible for this trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (temsirolimus)<br>Patients receive temsirolimus IV over 30 minutes weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (Complete Response, Partial Response, or Stable Disease) | Response evaluation criteria in solid tumors (RECIST) criteria version 1.0 was used for response evaluation. Clinical benefit rate is defined as the proportion of subjects experiencing a complete response (CR), partial response (PR), or stable disease (SD) for at least 24 weeks. Evaluation of target lesions: Complete Response (CR)-- Disappearance of all target lesions; Partial Response (PR)-- At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; Stable Disease (SD)-- Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started; Evaluation of non-target lesions: Complete Response (CR)-- Disappearance of all non-target lesions and normalization of tumor marker level; Incomplete Response/ Stable Disease (SD)-- Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits | Up to 24 months |