Z-Endoxifen Hydrochloride in Treating Patients With Metastatic or Locally Recurrent Estrogen Receptor-Positive Breast Cancer

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PRIMARY OBJECTIVES: l. To determine either the maximum-tolerated dose (MTD) of Z-endoxifen hydrochloride or the dose level associated with endoxifen steady state concentration (Css) of at least 2 uM in women with metastatic estrogen-receptor positive (ER+) breast cancer. (Dose Escalation Cohort) II....

PRIMARY OBJECTIVES: l. To determine either the maximum-tolerated dose (MTD) of Z-endoxifen hydrochloride or the dose level associated with endoxifen steady state concentration (Css) of at least 2 uM in women with metastatic estrogen-receptor positive (ER+) breast cancer. (Dose Escalation Cohort) II. To describe the safety profile of Z-endoxifen (Z-endoxifen hydrochloride) at each of the doses examined. (Dose Escalation Cohort) III. To evaluate changes in vision after 2 cycles of treatment. (Dose Escalation Cohort) IV. To gather preliminary data on the clinical benefit in terms of tumor response rate and progression-free survival. (Dose Escalation Cohort) V. To evaluate the changes in the frequency and severity of hot flashes after 2 cycles of treatment. (Expansion Cohort) VI. Evaluate changes in irritability scale using a validated irritability questionnaire. (Expansion Cohort) VII. To evaluate changes in markers of bone formation and absorption after 2 cycles of treatment. (Expansion Cohort) XIII. To evaluate changes in vision after 2 cycles of treatment. (Expansion Cohort). IX. To further characterize the safety profile of Z-endoxifen. (Expansion Cohort) SECONDARY OBJECTIVES: I. To characterize the plasma pharmacokinetics and urinary excretion of Z-endoxifen at each of the doses examined. II. For patients beginning in dose level 7 as well as the expansion cohorts, we will describe any changes in tumor expression of ER (both full length and truncated forms), progesterone receptor (PR), steroid receptor co-activator (SRC)1, SRC3, as well as the insulin-like growth factor receptor (IGF)1R/phosphatidylinositol 3 kinase (PI3K)/v-akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/mammalian target of rapamycin (mTOR) pathway and proliferation-related Ki-67 antigen (Ki67) after 1 cycle of treatment (approximately 28 days). III. To determine the frequency of estrogen receptor 1 (ESR1) mutations and the presence of antitumor activity (response rate and progression free survival [PFS]) in all patients whose tumors harbor ESR1 alterations. IV. To determine whether the ESR1 mutations identified in pre-treatment tumor biopsies can be detected in matched plasma cell free deoxyribonucleic acid (DNA) from the same patients. OUTLINE: This is a dose-escalation study followed by an expansion cohort study. Patients receive Z-endoxifen hydrochloride orally (PO) 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 for 30 days and then at 3 months.

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