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Fulvestrant and Tamoxifen Citrate in Treating Patients with Estrogen Receptor Positive Metastatic Breast Cancer

Trial Status: Active

This randomized phase II trial studies how well fulvestrant and tamoxifen citrate work in treating patients with estrogen receptor positive breast cancer that has spread to other parts of the body. Estrogen can cause the growth of breast tumor cells. Hormone therapy using fulvestrant and tamoxifen citrate may fight estrogen receptor positive metastatic breast cancer by blocking the use of estrogen by the tumor cells.

Inclusion Criteria

  • Signed informed consent
  • Patients must have histologically or cytologically confirmed invasive breast cancer that is estrogen receptor positive (ER+) (> 1% staining) with radiographical or clinical evidence of metastatic disease * Measurable and/or non-measurable disease
  • Prior therapies: * Patients must have previously received an aromatase inhibitor in the adjuvant, neo-adjuvant or metastatic setting * The minimum duration of aromatase inhibitor (AI) in the adjuvant setting is 2 years * There is no minimum duration of AI in the metastatic setting or neoadjuvant setting * Patients may have been previously treated with a CDK 4/6 inhibitor or mTOR inhibitor or other investigational agent in addition to an aromatase inhibitor * Prior treatment with tamoxifen is allowed in the adjuvant setting provided that it was followed by a minimum of 2 years of an AI
  • Brain metastasis allowed if previously treated, stable and off steroids for a minimum of 56 days
  • Patients may be pre- or post-menopausal; pre-menopausal patients must be on ovarian suppression and must be adequately suppressed on luteinizing hormone-releasing hormone (LHRH) agonists with estradiol levels in the post-menopausal range * Premenopausal patients cannot be pregnant and must agree to adequate birth control in addition to ovarian suppression; agreement by the patient and/or partner to use highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception; contraception use should continue during the duration of study treatment and for at least 6 months after the last dose of study treatment
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Absolute neutrophil count (ANC) >= 1500 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 1.5 x ULN
  • Alanine aminotransferase (ALT) =< 2.5 x ULN
  • Alkaline phosphatase =< 2.5 x ULN with the following exception; alkaline phosphatase (ALP) =< 5 x ULN in patients with bone metastases
  • Adequate hemostatic function as determined by prothrombin time (PT), international normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.5 x ULN (unless on therapeutic coagulation, in which case the adequate level of anticoagulation will be determined by the investigator)
  • Adequate renal function, as indicated by creatinine =< 1.5 x ULN

Exclusion Criteria

  • Prior therapy exclusions: * Prior therapy with fulvestrant * Prior therapy with tamoxifen in the metastatic setting * More than 3 prior lines of endocrine therapy in the metastatic setting * More than one prior line of chemotherapy in the metastatic setting
  • Washout of 2 weeks is required for aromatase inhibitors; washout of 4 weeks is required for CDK 4/6 inhibitor, everolimus or other biological agent
  • Patients must not be receiving any other investigational agent
  • Patients with symptomatic, untreated central nervous system (CNS) metastases are not eligible
  • Patients may not have significant concurrent illness, infection, pregnancy or lactation
  • Patients must not have a different active malignancy, except for skin basal cell carcinoma, skin squamous cell carcinoma and cervical intraepithelial neoplasia


University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE
Contact: Shannon L. Puhalla
Phone: 412-641-5792


I. To compare progression-free survival (PFS) in fulvestrant and tamoxifen citrate (tamoxifen) arms in patients unselected by estrogen receptor (ESR1) mutation, and in the subset of patients with ESR1- mutation (mt) tumors assessed primarily from circulating tumor deoxyribonucleic acid (ctDNA) at enrollment.


I. Response rate compared between the tamoxifen and fulvestrant arms in the entire cohort and in the ESR1-mt.

II. Overall survival compared between the tamoxifen and fulvestrant arms in the entire cohort and in the ESR1-mt.

III. Safety and toxicity assessment.

IV. Clinical benefit rate (defined as complete response [CR]+ partial response [PR]+ stable disease at any tumor assessment) and clinical benefit rate at 6 months (CBR6) (defined as CR+PR+ stable disease for at least 6 months).


I. Assessment of concordance of ESR1 status in plasma and biopsy samples.

II. Assessment of longitudinal changes in circulating levels of ESR1-mt and correlation with response.

III. Assessment of concordance with metastatic biopsies and archived primary tumor samples, determination of ESR1 status at diagnosis in archived tumor samples.

IV. Assessment of the functionality of ESR1 in tumor biopsies collected prior to and following treatment with fulvestrant as assessed by ribonucleic acid sequencing (RNAseq).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive fulvestrant intramuscularly (IM) on days 1 and 15 of course 1, and on day 1 of each subsequent course. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive tamoxifen citrate orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Pittsburgh Cancer Institute (UPCI)

Principal Investigator
Shannon L. Puhalla

  • Primary ID UPCI 16-015
  • Secondary IDs NCI-2016-01578
  • ID NCT02913430