Breast Cancer Clinical Trial
Z-Endoxifen Hydrochloride in Treating Patients With Metastatic or Locally Recurrent Estrogen Receptor-Positive Breast Cancer
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.
Full 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. (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.
Eligibility Criteria
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 of 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 x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (< 5 x institutional ULN if liver function test [LFT] elevations due to liver metastases)
Creatinine =< 1.5 x institutional ULN
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
Note: 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; EXCEPTIONS: 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
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)
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There are 3 Locations for this study
Scottsdale Arizona, 85259, United States
Jacksonville Florida, 32224, United States
Rochester Minnesota, 55905, United States
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