- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01327781
Z-Endoxifen Hydrochloride in Treating Patients With Metastatic or Locally Recurrent Estrogen Receptor-Positive Breast Cancer
Phase I Study of Z-Endoxifen as a Hormonal Therapy for Breast Cancer
Study Overview
Status
Conditions
Detailed 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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Arizona
-
Scottsdale, Arizona, United States, 85259
- Mayo Clinic in Arizona
-
-
Florida
-
Jacksonville, Florida, United States, 32224-9980
- Mayo Clinic in Florida
-
-
Minnesota
-
Rochester, Minnesota, United States, 55905
- Mayo Clinic in Rochester
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (Z-endoxifen hydrochloride)
Patients receive Z-endoxifen hydrochloride PO on days 1-28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
|
Correlative studies
Correlative studies
Ancillary studies
Given PO
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
Assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
The maximum grade of each type of toxicity will be recorded for each patient.
For each toxicity reported by dose level, the percentage of patients developing any degree of that toxicity as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
|
28 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression-free survival
Time Frame: From study entry to the documentation of disease progression, assessed up to 3 months
|
From study entry to the documentation of disease progression, assessed up to 3 months
|
|
Overall survival
Time Frame: From study entry to death due to any cause, assessed up to 3 months
|
From study entry to death due to any cause, assessed up to 3 months
|
|
Change in hot flash scores graded using a hot flash diary and the hot flash interference scale
Time Frame: Baseline to day 28
|
The number and severity of hot flashes will be examined.
Times series plots of hot flash scores will be constructed to visually assess changes across time within a dose level and between dose levels.
In particular, for each expansion dose level, a 90% confidence interval will be constructed for the proportion of patients whose hot flash scores increase at least 2 fold from baseline after one course of treatment.
|
Baseline to day 28
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in tumor expression levels of SRC3
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of SRC1
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of IGF1R
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of PI3K
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of AKT
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of mTOR
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of phosphorylated ribosomal protein S6 kinase kinase
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of epidermal growth factor receptor
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of HER2
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of p42/p44 mitogen-activated protein kinase
Time Frame: Baseline up to day 28
|
A grid (similar to a heat map) will be constructed where columns represent the proteins and the rows represent individual patients.
This grid will be visual inspected for differences between expansion dose levels as well as tendencies of protein level shifts than seem to behave similarly.
|
Baseline up to day 28
|
Change in tumor expression levels of Ki-67
Time Frame: Baseline up to day 56
|
For Ki-67 by expansion dose level, a 90% binomial confidence interval for the mean change in the percentage of positive cells after 2 courses of treatment from pre-Z-endoxifen treatment levels will be determined.
Also, Spearman rank correlation coefficients will be used to examine the strength of the association between the change in ER positivity, PR positivity, and Ki-67 positivity.
|
Baseline up to day 56
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Matthew P Goetz, Mayo Clinic
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Breast Diseases
- Breast Neoplasms
- Physiological Effects of Drugs
- Antineoplastic Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Hormone Antagonists
- Bone Density Conservation Agents
- Estrogen Antagonists
- Selective Estrogen Receptor Modulators
- Estrogen Receptor Modulators
- Tamoxifen
Other Study ID Numbers
- NCI-2011-00847 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- P30CA015083 (U.S. NIH Grant/Contract)
- U01CA069912 (U.S. NIH Grant/Contract)
- P50CA116201 (U.S. NIH Grant/Contract)
- UM1CA186686 (U.S. NIH Grant/Contract)
- CDR0000696902
- MC093C
- 8821 (Other Identifier: CTEP)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Recurrent Breast Carcinoma
-
City of Hope Medical CenterNational Cancer Institute (NCI)CompletedRecurrent Fallopian Tube Carcinoma | Recurrent Ovarian Carcinoma | Recurrent Primary Peritoneal Carcinoma | Recurrent Uterine Corpus Carcinoma | Recurrent Breast Carcinoma | Triple-Negative Breast CarcinomaUnited States
-
National Cancer Institute (NCI)CompletedRecurrent Fallopian Tube Carcinoma | Recurrent Ovarian Carcinoma | Recurrent Primary Peritoneal Carcinoma | Recurrent Breast Carcinoma | Estrogen Receptor Negative | HER2/Neu Negative | Progesterone Receptor Negative | Triple-Negative Breast Carcinoma | Male Breast Carcinoma | Stage IV Breast Cancer AJCC...United States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)TerminatedRecurrent Breast Carcinoma | Stage IV Breast Cancer AJCC v6 and v7 | Malignant Chest Wall Neoplasm | Recurrent Inflammatory Breast Carcinoma | Stage IV Inflammatory Breast CarcinomaUnited States
-
National Cancer Institute (NCI)NRG OncologyActive, not recruitingUnresectable Breast Carcinoma | Stage IV Breast Cancer AJCC v6 and v7 | Stage III Breast Cancer AJCC v7 | Metastatic Breast Adenocarcinoma | Metastatic HER2-Positive Breast Carcinoma | Recurrent Breast Adenocarcinoma | Recurrent HER2-Positive Breast Carcinoma | Unresectable HER2-Positive Breast CarcinomaUnited States, Canada
-
Mayo ClinicRecruitingBreast Carcinoma | Recurrent Breast Carcinoma | Metastatic Breast CarcinomaUnited States
-
Northwestern UniversityBristol-Myers Squibb; National Cancer Institute (NCI)TerminatedStage IV Breast Cancer | HER2/Neu Negative | Recurrent Inflammatory Breast Carcinoma | Stage IV Inflammatory Breast CarcinomaUnited States
-
National Cancer Institute (NCI)WithdrawnRecurrent Fallopian Tube Carcinoma | Recurrent Ovarian Carcinoma | Recurrent Primary Peritoneal Carcinoma | Recurrent Breast Carcinoma | Estrogen Receptor Negative | HER2/Neu Negative | Progesterone Receptor Negative | Triple-Negative Breast Carcinoma | Ovarian Serous Adenocarcinoma | Primary Peritoneal... and other conditions
-
National Cancer Institute (NCI)Active, not recruitingRecurrent Breast Carcinoma | Triple-Negative Breast Carcinoma | HER2-Negative Breast Carcinoma | Bilateral Breast Carcinoma | Localized Breast CarcinomaUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingRecurrent Fallopian Tube Carcinoma | Recurrent Ovarian Carcinoma | Recurrent Primary Peritoneal Carcinoma | Recurrent Uterine Corpus Carcinoma | Endometrial Adenocarcinoma | Recurrent Breast Carcinoma | Estrogen Receptor Negative | HER2/Neu Negative | Progesterone Receptor Negative | Triple-Negative Breast... and other conditionsUnited States
-
National Cancer Institute (NCI)RecruitingAnatomic Stage III Breast Cancer AJCC v8 | Recurrent Fallopian Tube Carcinoma | Recurrent Ovarian Carcinoma | Recurrent Primary Peritoneal Carcinoma | Anatomic Stage IV Breast Cancer AJCC v8 | Advanced Malignant Solid Neoplasm | Locally Advanced Malignant Solid Neoplasm | Unresectable Malignant Solid... and other conditionsUnited States, Puerto Rico
Clinical Trials on Laboratory Biomarker Analysis
-
ECOG-ACRIN Cancer Research GroupNational Cancer Institute (NCI)CompletedProstate Cancer
-
National Cancer Institute (NCI)Recruiting
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)Not yet recruitingLynch Syndrome | Recurrent Uterine Corpus Carcinoma | Stage I Uterine Corpus Cancer | Stage II Uterine Corpus Cancer | Stage III Uterine Corpus Cancer | Stage IV Uterine Corpus CancerUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)Not yet recruitingRecurrent Uterine Corpus Carcinoma | Stage III Uterine Corpus Cancer | Stage IV Uterine Corpus CancerUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)RecruitingStage IIIA Ovarian Cancer | Stage IIIB Ovarian Cancer | Stage IIIC Ovarian Cancer | Stage IV Ovarian CancerUnited States
-
Ohio State University Comprehensive Cancer CenterActive, not recruitingLung Cancer | Radiation Toxicity | Adult Brain TumorUnited States
-
National Cancer Institute (NCI)Active, not recruitingMalignant NeoplasmUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Askin TumorUnited States, Canada, Puerto Rico, Australia, New Zealand, Switzerland
-
Alliance for Clinical Trials in OncologyNational Cancer Institute (NCI)Completed
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Osteosarcoma | Metastatic Osteosarcoma | Localized OsteosarcomaUnited States