Ph II Letrozole + OSI-774 (Tarceva) in Post-menopausal, w/ ER and/or PR-positive Met Breast Cancer.

Study Overview
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Brief Summary
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RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving letrozole together with erlotinib may kill more tumor cells. PURPOSE: This phase II clinical trial is studying how well giving letrozole together with erlotinib works in treating postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive locally recurrent or metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary To determine the rate of clinical benefit (complete response [CR], partial response [PR], and stable disease [SD] in patients with hormone-dependent locally recurrent or metastatic breast cancer treated with letrozole in combination with erlotinib hydrochloride. Secondary To determine the time to progression (TTP) in patients treated with this regimen. To evaluate the anti-tumor activity, as determined by CR and PR rates, of this regimen in these patients. To evaluate the safety of this regimen in these patients. To determine if tumors that are positive for epidermal growth factor receptor (EGFR) or Ser118 ER, or that overexpress human epidermal receptor (HER2) exhibit a longer TTP from the combination compared to tumors that do not express or overexpress these molecules. OUTLINE: This is a multicenter study. Patients are stratified according to prior hormone therapy (hormone-therapy naive/first-line therapy vs prior hormonal therapy with either tamoxifen or an aromatase inhibitor in the adjuvant or metastatic setting/second-line therapy) Patients receive oral letrozole and oral erlotinib hydrochloride once daily in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then yearly thereafter.

Official Title
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A Phase II Trial of Letrozole Plus OSI-774 (Tarceva) in Post-menopausal Women With ER and/or PR-Positive Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: letrozole
* Genetic: fluorescence in situ hybridization
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Patients must have estrogen (ER) and/or progesterone receptor (PgR)-positive, histologically confirmed adenocarcinoma of the breast with measurable (but not operable) locally recurrent disease, or measurable and/or evaluable metastatic disease (see protocol section 10.3), including isolated bone metastases. Patients with available paraffin tissue blocks from either the primary or the metastatic site must submit tissue blocks for retrospective EGFR and HER2 analysis. If tissue blocks cannot be submitted, 20 unstained slides from each paraffin block must be submitted. All patients must be post-menopausal females as defined by one of the following: Prior bilateral oophorectomy Prior bilateral ovarian irradiation No menstrual period for 12 months or longer If age 55 years or less and < 12 months from last menstrual period, patient must have a serum estradiol < or equal to 30 and an FSH level > 40. Patients must not have had more than 1 prior chemotherapy regimen for metastatic disease and have fully recovered from any grade 2-4 toxicities related to chemotherapy. No concurrent chemotherapy is allowed while on protocol therapy. Patients may have had 1 prior hormonal therapy for metastatic disease. This includes: tamoxifen, fulvestrant, anastrozole, exemestane, aminoglutethimide, megace, and letrozole. Patients may have received tamoxifen or aromatase inhibitors in the adjuvant setting. Patients must not have had prior therapy with EGF receptor inhibitors. Previous but not concomitant therapy with trastuzumab (Herceptin) is allowed. Patients must not have received Herceptin within 4 weeks of initiation of protocol therapy. Patients must have an ECOG performance status of 0, 1, or 2. Patients must have adequate hematologic, hepatic, and renal function as defined by the following within 2 weeks of initiation of therapy: Absolute neutrophils > or equal to 1,500/mm3 and platelets > or equal to 100,000/mm3. Bilirubin < than or equal to 1.5 upper limit of normal. SGOT and SGPT < or equal to 2.5 upper limit of normal. Creatinine < or equal to 1.5 upper limit of normal. INR, PTT and PT in the normal range. Must be 18 years of age or older. Patients must not have a history of central nervous system metastases or unevaluated CNS symptoms suggestive of possible brain metastases. Patients may receive concurrent radiation therapy to painful bone metastases or areas of impending bone fracture as long as radiation therapy is initiated prior to study entry and sites of evaluable disease outside the radiation port(s) are available for follow-up. Patients who have received prior radiotherapy must have recovered from toxicity induced by this treatment. Patients < 55 years of age must not have received Luteinizing hormone releasing hormone (LHRH) antagonists within 3 months prior to protocol therapy. Patients must not suffer from medical or psychiatric conditions that would interfere with ability to provide informed consent, communicate side effects, or comply with protocol requirements including maintenance of a compliance/pill diary. Patients must be disease-free of prior invasive cancers for > 5 years with the exception of basal or squamous cancer of the skin or cervical carcinoma in situ.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First line/hormone-therapy naive<br> | Drug: erlotinib hydrochloride<br>* OSI-774 150 mg/day<br>* Other names: Tarceva, OSI-774;Drug: letrozole<br>* Letrozole 2.5 mg/day<br>* Other names: Femara;Genetic: fluorescence in situ hybridization<br>* To determine HER2 gene amplification or excess copies of the HER2 gene<br>* Other names: None specified;Other: immunohistochemistry staining method<br>* to measure the epidermal growth factor receptors (EGFR)<br>* Other names: None specified;Other: laboratory biomarker analysis<br>* To determine if specific biomarkers exhibit a longer time to tumor progression after treatment with the study drugs<br>* Other names: none specified;|
| Experimental: Second-line/prev hormone-therapy tx<br> | Drug: erlotinib hydrochloride<br>* OSI-774 150 mg/day<br>* Other names: Tarceva, OSI-774;Drug: letrozole<br>* Letrozole 2.5 mg/day<br>* Other names: Femara;Genetic: fluorescence in situ hybridization<br>* To determine HER2 gene amplification or excess copies of the HER2 gene<br>* Other names: None specified;Other: immunohistochemistry staining method<br>* to measure the epidermal growth factor receptors (EGFR)<br>* Other names: None specified;Other: laboratory biomarker analysis<br>* To determine if specific biomarkers exhibit a longer time to tumor progression after treatment with the study drugs<br>* Other names: none specified;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Pathological Complete Response. | Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions | at 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression of Target Lesions | Time frame from study entry till discontinuation of treatment due to disease progression. Progression of target lesions is measured by RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions. | Every 12 weeks from on-study to disease progression | 
| Number of Patients With Anti-tumor Activity: Complete Response (CR) and Partial Response (PR) | Per RECIST criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions and partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions. | at 24 weeks | 
| Number of Patients With Worst-grade Toxicities Per Grade | Number of patients with worst-grade toxicities following NCI Common Toxicity Criteria: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, disabling, 5 = death | at 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage IV breast cancer