Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer
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|ClinicalTrials.gov Identifier: NCT02311933|
Recruitment Status : Active, not recruiting
First Posted : December 9, 2014
Last Update Posted : June 12, 2018
|Condition or disease||Intervention/treatment||Phase|
|Estrogen Receptor Positive HER2/Neu Negative Recurrent Breast Carcinoma Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Stage IV Breast Cancer AJCC v6 and v7||Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Tamoxifen Citrate Drug: Z-Endoxifen Hydrochloride||Phase 2|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||80 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Randomized Phase II Trial of Tamoxifen Versus Z-Endoxifen HCL in Postmenopausal Women With Metastatic Estrogen Receptor Positive, HER2 Negative Breast Cancer|
|Actual Study Start Date :||March 6, 2015|
|Estimated Primary Completion Date :||July 1, 2019|
Experimental: Arm I (z-endoxifen hydrochloride)
Patients receive z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Z-Endoxifen Hydrochloride
Other Name: Z-Endoxifen HCl
Experimental: Arm II (tamoxifen citrate)
Patients receive tamoxifen citrate PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression and bone metastases may cross over to Arm I and receive z-endoxifen hydrochloride starting no later than 28 days after documentation of disease progression.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Tamoxifen Citrate
- Progression free survival (PFS) [ Time Frame: The time from registration to documentation of local, regional or distant disease progression or death without progression of disease, assessed up to 5 years ]Estimates will be determined using nonparametric maximum likelihood estimation for interval censored data. The generalized log-rank test for interval censored data will be used to assess whether PFS differs between the treatment arms. A secondary analysis of the primary clinical endpoint will follow the approach proposed by Freidlin et al.
- Incidence of adverse events, per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ]For a given adverse event (AE), the proportion of patients on each treatment arm who report developing a grade 2-5 of this AE will be determined.
- Tumor response rate by study arm, defined as the number of patients with a complete or partial response [ Time Frame: Up to 5 years ]Defined by Response Evaluation Criteria in Solid Tumors on 2 consecutive evaluations at least 6 weeks apart, divided by the total number of eligible patients who began study treatment. A 90% binomial confidence interval will be constructed for the true response rate.
- Overall survival distribution by study arm [ Time Frame: The time from registration to death due to any cause, assessed up to 5 years ]The distribution of survival times will be estimated using the method of Kaplan-Meier.
- Deoxyribonucleic acid (DNA) alterations as measured by Foundation medicine [ Time Frame: Baseline ]Data will be returned as presence or absence of various DNA alterations, along with description of type and location of the alteration. The nature of alterations in each pathway and gene will be described in tabular format. Association of presence or absence of DNA alterations with PFS will be assessed overall, by pathway, and by gene via Cox regression with the goal of evaluating hazard ratio estimates and confidence intervals. Alterations will be considered together as well as by type. Model fit and stability evaluated, and exact methods used if needed. Performed for both arms and within arms.
- Nuclear receptor coactivator 3 (SRC3) immunohistochemistry expression levels [ Time Frame: Baseline ]Within each treatment arm, a point and interval estimate of the difference in tumor response rate between those with metastatic SRC3-positive disease and those with metastatic SRC3-negative disease will be constructed using the properties of the binomial distribution. Also, a point and interval estimate of the odds of disease progression among those with metastatic SRC3-positive disease relative to those with metastatic SRC3-negative disease will be ascertained from the parameter estimates of fitting a proportional hazard model to the progression data.
- Change in biochemical markers of bone turnover [ Time Frame: Baseline to week 8 (after course 2) ]For each of the markers of bone formation, the percent change after 2 courses of treatment from pre-treatment levels will be determined. A two-sided alpha = 0.01 z-test will be used to assess whether the percent change in a given bone absorption biomarkers differs with respect to treatment.
- Z-endoxifen hydrochloride area under curve (AUC) [ Time Frame: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9 ]A population PK will be developed using the software program NONMEM, Version 7. The model will be parameterized in terms of AUC (the primary endpoint), as well as clearance and volume of distribution. Criteria for model selection will include the likelihood ratio test, shrinkage estimates, reasonableness of parameter estimates, as well as goodness-of-fit plots. Attempts will be made to identify the covariates that affect drug behavior or those that explain variability in this patient population.
- Pharmacokinetic (PK) data [ Time Frame: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9 ]Examined in an exploratory and hypothesis-generating fashion. Pharmacokinetic-pharmacodynamic (PD) relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.
- Pharmacogenetic data [ Time Frame: Baseline ]Examined in an exploratory and hypothesis-generating fashion.
- Pharmacodynamic data [ Time Frame: Baseline, 2-4, and 4-6 hours post-administration day 1 of course 1; baseline day 2 of course 1; pre-administration day 1 of course 3; pre-administration day 1 of course 9 ]PK/PD relationships will be explored for effects of endoxifen on efficacy-related, adverse events or laboratory parameters of clinical interest. Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by model-based analyses. The data may be pooled with data from other/future studies for additional population PK/PD analyses.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02311933
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|Principal Investigator:||Matthew Goetz||Alliance for Clinical Trials in Oncology|