Tamoxifen Citrate in Treating Patients With Metastatic or Recurrent 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 tamoxifen citrate may fight cancer by blocking the use of estrogen by tumor cells. PURPOSE: This phase II trial is studying how well tamoxifen citrate works in patients with metastatic or recurrent breast cancer.

Detailed Description
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OBJECTIVES: Primary To correlate CYP2D6 (Cytochrome P450 2D6) score (0 vs 1-2) and progression-free survival (PFS) Secondary To correlate CYP2D6 score (0 vs 1 vs 2) and PFS To correlate CYP2D6 score (0 vs 1-2) and the proportion of these patients who are progression-free at 6 months. To correlate endoxifen concentration with response To correlate CYP2D6 with response To correlate the presence of candidate estrogen receptor (ESR) 1 and 2 variant alleles, UDP-glucuronosyltransferases (UGT) 7, sulfotransferases (SULT) 1A1, other candidate genes and biomarkers to PFS and other tamoxifen related outcomes OUTLINE: This is a multicenter study. Patients receive oral tamoxifen citrate once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities. Blood, plasma, and tissue samples are collected periodically for laboratory studies. After completion of study therapy, patients are followed up every 3-6 months for 5 years.

Official Title
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A Phase II Prospective Trial Correlating Progression Free Survival With CYP2D6 Activity in Patients With Metastatic Breast Cancer Treated With Single Agent Tamoxifen

Conditions
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Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: tamoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the breast Stage III (locally advanced), metastatic, or recurrent disease Deemed not resectable Estrogen-receptor and/or progesterone-receptor positive disease Receptor status is based on most recent results Measurable or non-measurable disease ECOG performance status 0-2 History of central nervous system (CNS) metastasis allowed provided it has been treated (surgery, radiotherapy, or radiosurgery) within the past 4 weeks and does not require medications to control symptoms Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases present) Negative pregnancy test Fertile patients must use effective nonhormonal contraception Disease-free of prior invasive malignancies for ≥ 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix Prior chemotherapy, trastuzumab, or bevacizumab in the adjuvant setting allowed provided it has been completed ≥ 4 weeks before study therapy; other prior non-hormonal investigational agents in the adjuvant setting must have been completed at least 4 weeks prior to study registration and should be discussed with the study PI Prior tamoxifen as adjuvant treatment is allowed as long as the patient did not have disease relapse or progression while on adjuvant tamoxifen or within 4 weeks of last dose Treatment in the advanced setting must have been completed at least 2 weeks prior to study initiation Prior aromatase inhibitors (e.g., anastrozole, letrozole, exemestane, aminoglutethamide) are allowed in the adjuvant or metastatic setting At least 2 weeks since prior and no concurrent medications that are strong to moderate inhibitors of CYP2D6 and may alter tamoxifen citrate metabolism including, but not limited to, any of the following: Paroxetine (Paxil) Fluoxetine (Prozac) Bupropion (Wellbutrin) Quinidine (Cardioquin) Concurrent radiotherapy to painful sites of bone disease or areas of impending fractures allowed provided the following criteria are met: Radiotherapy was initiated before study entry Sites of measurable or non-measurable disease are outside the radiotherapy port Recovered from prior radiotherapy Exclusion Criteria: Pregnant or nursing Concurrent chemotherapy Leptomeningeal disease Non-protocol concurrent hormonal therapy Medical or psychiatric conditions that would interfere with protocol compliance, the ability to provide informed consent, assessment of response, or anticipated toxicities Prior tamoxifen for advanced disease More than 2 lines of non-hormonal treatment in the locally advanced or metastatic setting, including trastuzumab (Herceptin), bevacizumab, or other biologics Starting bisphosphonate therapy while receiving treatment on this study Patients who have begun receiving bisphosphonate therapy prior to registration may continue at the same intervals used prior to study registration

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: Tamoxifen<br>Patients receive oral tamoxifen citrate once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicities. | Drug: tamoxifen<br>* PO<br>* Other names: NSC# 180973;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival by CYP2D6 Status in 2 Categories | Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Assessed every 3 months for 2 years, then every 6 months up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival by CYP2D6 Status in 3 Categories | Progression-free survival is defined as the time from registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Assessed every 3 months for 2 years, then every 6 months up to 5 years | 
| Proportion of Patients Progression-free at 6 Months | Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Assessed every 3 months for 6 months | 
| Proportion of Patients With Response | Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate response. Either complete response (CR) or partial response (PR) is considered as response. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Assessed every 3 months for 2 years, then every 6 months up to 5 years | 
| Endoxifen Concentration by Response | Endoxifen (ng/ml) was assessed at cycle 3. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate response. Either complete response (CR) or partial response (PR) is considered as response. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | Endoxifen was assessed at cycle 3; response was assessed every 3 months for 2 years, then every 6 months up to 5 years | 
| Progression-free Survival From 3 Months Post Registration | This is a landmark progression-free survival analysis at 3 months post registration. Only patients who were progression-free and alive at 3 months were included. Progression-free survival in this analysis is defined as the time from 3 months post registration to progression or death, whichever occurs first. Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) was used to evaluate progression. Progression is defined as appearance of one or more new lesions or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Assessed every 3 months for 2 years, then every 6 months up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, stage IV breast cancer