Overview

This trial is active, not recruiting.

Conditions estrogen receptor positive, hot flashes, recurrent breast carcinoma, stage iiic breast cancer, stage iv breast cancer
Treatments laboratory biomarker analysis, pharmacological study, questionnaire administration, z-endoxifen hydrochloride
Phase phase 1
Sponsor National Cancer Institute (NCI)
Start date March 2011
End date January 2017
Trial size 62 participants
Trial identifier NCT01327781, 8821, CDR0000696902, MC093C, NCI-2011-00847, P30CA015083, U01CA069912, UM1CA186686

Summary

This phase I trial studies the side effects and the best dose of Z-endoxifen hydrochloride in treating patients with estrogen receptor-positive (ER+) breast cancer that has spread to other places in the body (metastatic) or has come back at or near the same place as the original tumor (locally recurrent). Estrogen can cause the growth of breast cancer cells. Hormone therapy using Z-endoxifen hydrochloride may fight breast cancer by blocking the use of estrogen by tumor cells.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Patients receive Z-endoxifen hydrochloride PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
laboratory biomarker analysis
Correlative studies
pharmacological study
Correlative studies
questionnaire administration
Ancillary studies
z-endoxifen hydrochloride Z-Endoxifen HCl
Given PO

Primary Outcomes

Measure
MTD defined as the highest dose level where at most 1 of 6 patients develops a dose limiting toxicity and 2 or more of the 3-6 patients treated at the next higher dose level develop a dose limiting toxicity
time frame: 28 days

Secondary Outcomes

Measure
Change in hot flash scores graded using a hot flash diary and the hot flash interference scale
time frame: Baseline to day 28
Overall survival
time frame: From study entry to death due to any cause, assessed up to 3 months
Progression-free survival
time frame: From study entry to the documentation of disease progression, assessed up to 3 months

Eligibility Criteria

Female participants at least 18 years old.

Inclusion Criteria: - Histologically confirmed diagnosis of metastatic or locally recurrent breast cancer - ER positive defined as > 1% nuclear staining on the biopsy that was obtained at the confirmation of metastatic or locally recurrent disease - Lesion type: Either evaluable or measurable disease - Pre- or post-menopausal female - For the expansion cohorts: tumor that is accessible for biopsy - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 - Life expectancy > 16 weeks - Capable of understanding investigational nature, potential risks and benefits of the study and able to provide written informed consent - Absolute neutrophil count (ANC) >= 1,000/uL - Platelet count >= 75,000/uL - Total bilirubin =< 1.5 times institutional upper limit of normal (IULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times IULN (< 5 times IULN if liver function test [LFT] elevations due to liver metastases) - Creatinine =< 1.5 times IULN - Women with human epidermal growth factor (HER)-2 positive disease must have received and progressed on at least one prior anti-HER-2 directed regimen (trastuzumab, lapatinib) for their metastatic disease - For dose escalation cohort: - Any number of prior systematic therapy regimens is allowed - NOTE: prior systematic therapy in the adjuvant setting is not required - At least one prior hormone containing regimen in the metastatic setting (tamoxifen if pre-menopausal; aromatase inhibitor if post-menopausal) - NOTE: exception: patients that fail (defined as the development of metastatic disease while receiving an adjuvant hormone containing regimen of tamoxifen for premenopausal and aromatase inhibitor for postmenopausal) are eligible and not required to receive additional hormonal containing regimens prior to enrollment - At least one prior chemotherapy containing regimen in adjuvant and/or metastatic setting - For the expansion cohort(s): - At least one prior hormone containing regimen in the metastatic setting (tamoxifen if pre-menopausal; aromatase inhibitor if post-menopausal) - NOTE: exception: patients that fail (defined as the development of metastatic disease while receiving an adjuvant hormone containing regimen of tamoxifen for premenopausal and aromatase inhibitor for postmenopausal) are eligible and not required to receive additional hormonal containing regimens prior to enrollment - NOTE: a prior hormone containing regimen in the adjuvant setting is not required; a hormonal regimen containing everolimus is allowed - Either 1 or 2 prior chemotherapy regimens are allowed but not required such that both are in the metastatic setting or one is in the adjuvant setting and one in the metastatic setting (note, an anthracycline and taxane based regimen delivered in the adjuvant setting would be considered one regimen) - Willingness to return to Mayo Clinic Rochester, Arizona, or Florida during treatment phase of the trial - Dose Escalation cohort only: - Mandatory Translational Research Components - Willingness to provide biologic specimens (blood and urine) - Dose Escalation cohorts beginning at 160 mg/day: Mandatory Translational Research Components - Willingness to provide biologic specimens (tissue) - Dose Expansion cohort(s): - Mandatory Translational Research Components - Willingness to provide biologic specimens (blood, tissue and urine) - Note: The goals of this study include assessment of the biologic effects on surrogate markers of Z-endoxifen and therefore, are contingent upon availability of the biologic specimens - Women of childbearing potential only: negative serum pregnancy test done =< 48 hours prior to registration - Capable of swallowing 20-mg capsules Exclusion Criteria: - Any of the following therapies prior to registration: - Chemotherapy =< 3 weeks - Immunotherapy =< 3 weeks - Biologic therapy =< 3 weeks - Hormonal therapy =< 3 weeks - Monoclonal antibodies =< 3 weeks - Radiation therapy =< 3 weeks - Anti-Her-2 directed therapy =< 3 weeks - Prior endoxifen therapy - Prior history of: - Stroke =< 6 months prior to registration - Seizures =< 3 months prior to registration - Deep vein thrombosis (DVT) or pulmonary embolism (PE) =< 12 months prior to registration - Two or more episodes of DVT and/or PE =< 5 years prior to registration - Crystalline retinopathy - Abnormal uterine bleeding =< 1 year prior to registration - Personal history of coagulopathy - Active DVT and/or PE requiring anti-coagulant therapy - Patients who are on anti-coagulant therapy for maintenance are eligible as long as the DVT and/or PE was > 12 months prior to enrollment and there is no evidence for active thrombosis (either DVT or PE) - Clinically symptomatic cataracts requiring imminent surgery - Patients that have cataracts that do not require surgery are eligible - Other invasive malignancy that has been diagnosed or has recurred < 2 years prior to registration except non-melanotic skin cancer or carcinoma-in-situ of the cervix - Any co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements - Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment; EXCEPTION: Neuropathies - if grade 2 neuropathies have been stable for at least 3 months since completion of prior treatment patient is eligible - Tumors involving the spinal cord or heart Note: tamoxifen has known estrogenic side-effects; while Z-endoxifen is considered a potent anti-estrogen and is not known to have estrogenic or agonist effects in vitro, the effect of Z-endoxifen in humans is unknown - Uncontrolled brain metastases Note: Brain metastases are not permitted on study unless the metastases have been treated by surgery or radiotherapy, and the patient has been neurologically stable and off steroids for >= 12 weeks - Plans to begin bisphosphonates or denosumab after registration or began a bisphosphonate or denosumab regimen < 90 days before registration Note: Patients on a stable dose of bisphosphonates or denosumab for > 90 days prior to registration are eligible - Any of the following: - Pregnant women - Nursing women - Women of childbearing potential who are unwilling to employ adequate contraception - Other concurrent chemotherapy or anti HER2 therapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)

Additional Information

Official title Phase I Study of Z-Endoxifen as a Hormonal Therapy for Breast Cancer
Principal investigator Matthew Goetz
Description 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. II. To describe the safety profile of Z-endoxifen (Z-endoxifen hydrochloride) at each of the doses examined. III. To evaluate changes in vision after 2 cycles of treatment. IV. To gather preliminary data on the clinical benefit in terms of tumor response rate and progression-free survival. 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 hydrochloride (Expansion cohort). SECONDARY OBJECTIVES: I. To characterize the plasma pharmacokinetics and urinary excretion of Z-endoxifen hydrochloride 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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).