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Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02311933
Recruitment Status : Active, not recruiting
First Posted : December 9, 2014
Results First Posted : September 28, 2021
Last Update Posted : May 3, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
This randomized phase II trial studies how well tamoxifen citrate works compared with z-endoxifen hydrochloride in treating patients with breast cancer that has spread to nearby tissue or lymph nodes or other parts of the body and has estrogen receptors but not human epidermal growth factor receptor 2 (HER2) receptors on the surface of its cells. Estrogen can cause the growth of tumor cells. Hormone therapy using tamoxifen citrate or z-endoxifen hydrochloride may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether tamoxifen citrate or z-endoxifen hydrochloride is more effective in treating patients with breast cancer.

Condition or disease Intervention/treatment Phase
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 Drug: Endoxifen Hydrochloride Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Tamoxifen Citrate Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Primary Completion Date : November 6, 2020
Estimated Study Completion Date : May 25, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
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.
 Drug: Endoxifen Hydrochloride
Given PO
Other Names:
  • Z-Endoxifen HCl
  • Z-Endoxifen Hydrochloride

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies
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
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Tamoxifen Citrate
Given PO
Other Names:
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Soltamox
  • TAM
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide


Outcome Measures
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Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Assessed up to 5 years ]
    The primary endpoint is progression-free survival (PFS) defined as the time from randomization to documentation of local, regional or distant disease progression or death without progression of disease.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Pharmacogenetic Data [ Time Frame: Baseline ]
    Examined in an exploratory and hypothesis-generating fashion.

  7. 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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION ELIGIBILITY CRITERIA
  • Women who agree to undergo a standard of care core biopsy of recurrent or metastatic breast cancer to confirm the ER+ (>= 10% nuclear staining) and HER2 negative status

  • Patient must have been previously treated with an aromatase inhibitor (either letrozole, anastrozole or exemestane) either in the adjuvant or metastatic setting, and have one of the following types of primary or secondary endocrine resistant disease

    • Primary clinical resistance is defined as one of the following:

      • Recurrence within the first 2 years of adjuvant endocrine therapy while on aromatase inhibitor therapy
      • Progression within first 6 months of initiating first-line endocrine therapy (either aromatase inhibitor or fulvestrant containing regimen) for the treatment of metastatic breast cancer

    • Secondary clinical resistance is defined as one of the following:

      • Recurrence after year 2 while receiving adjuvant aromatase inhibitor therapy, or within 12 months of completing adjuvant aromatase inhibitor therapy
      • Progression occurring 6 or more months after initiating the first endocrine therapy for metastatic disease (either fulvestrant or aromatase inhibitor containing regimen)
  • Patients with a history of measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with non-measurable disease and bone metastases are eligible
  • No history of tumors involving spinal cord or heart
  • No current evidence of visceral crisis or lymphangitic spread
  • No known brain metastases

  • Women must be postmenopausal

    • Postmenopausal status is verified by:

      • Prior bilateral surgical oophorectomy, or
      • Age >= 60 years, or
      • Age < 60 with no menses for > 1 year with follicle-stimulating hormone (FSH) and estradiol levels within post menopausal range, according to institutional standard

  • Prior treatment

    • No more than two prior chemotherapy regimens in the metastatic setting
    • Prior treatment with an aromatase inhibitor (either anastrozole, letrozole or exemestane), either in the adjuvant or metastatic setting is required
    • Unlimited prior endocrine regimens in the metastatic setting, which may have included an everolimus or cyclin dependent kinase (CDK) 4/6 inhibitor (such as palbociclib, abemaciclib or ribociclib) containing regimen
    • Prior tamoxifen treatment is allowed in the adjuvant setting, but patients must not have experienced relapse within 1 year of stopping tamoxifen
    • No prior treatment with tamoxifen in the metastatic setting
    • No prior treatment with endoxifen

    • Patients who have not fully recovered from acute, reversible effects of prior therapy regardless of interval since last treatment are not eligible to participate in this study

      • EXCEPTION: neuropathies-if grade 2 neuropathies have been stable for at least 3 months since completion of prior treatment patient is eligible
  • Not receiving any medications or substances that are strong inhibitors of cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6)
  • Not receiving any other investigational agents

  • No uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Uncontrolled symptomatic cardiac arrhythmia
    • Uncontrolled hypertension (defined as blood pressure > 160/90)

  • None of the following co-morbid conditions:

    • Cataracts of grade 2 or greater as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    • Retinopathy of grade 2 or greater as per CTCAE version 4.0

      • Note: patients that have cataracts that do not require surgery are eligible
      • Note: serious adverse events will be reported on CTEP-Adverse Event Reporting System (AERS) using CTCAE version (v)5.0

    • Deep vein thrombosis/pulmonary embolism (DVT/PE) within the past 6 months

      • Note: patients that are on anticoagulant therapy for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment, and there is no evidence for active thrombosis (either DVT or PE)
  • No other active second malignancy other than non-melanoma skin cancers within 3 years of pre-registration; a second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for at least 3 years prior to pre-registration
  • Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
  • Able to swallow oral formulation of the study agent
  • Hemoglobin >= 9 g/dL
  • Platelet count >= 75,000/mm^3
  • Creatinine =< 1.5 x upper limits of normal (ULN)
  • Total bilirubin =< 1.5 x upper limits of normal (ULN)
  • Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN); for patients with liver metastasis: =< 5 x upper limits of normal (ULN)
  • REGISTRATION ELIGIBILITY CRITERIA

  • Patients with either measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with both non-measurable disease and bone metastases are eligible

    • Non-measurable bone only disease: Non-measurable bone only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft-tissue component, or mixed lytic-blastic bone lesions without a measurable soft-tissue component
    • Lytic bone lesions, with an identifiable soft tissue component, evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), can be considered as measurable lesions if the soft tissue component otherwise meets the definition of measurability previously described
  • No tumors involving spinal cord or heart
  • No visceral crisis, lymphangitic spread or known brain metastases: visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease
  • Histologic confirmation, from the A011203 pre-registration biopsy, by institutional/local pathologist of either locally advanced or metastatic breast cancer that is estrogen receptor positive and HER2 negative; those patients with bone only disease with either no tumor or insufficient tumor for ER/progesterone receptor (PR) and HER2 staining after the bone biopsy are still eligible to participate in this study
  • Estrogen receptor positive disease is defined as > 10% nuclear staining

  • HER2 negative disease as per 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, one of the following must apply:

    • 0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization (ISH)
    • 0 or 1+ by IHC and ISH not done
    • 2+ by IHC and not amplified by ISH or
    • IHC not done and not amplified by ISH

  • None of the following therapies are allowed prior to registration:

    • Chemotherapy =< 2 weeks
    • Immunotherapy =< 2 weeks
    • Biologic therapy =< 2 weeks
    • Hormonal therapy =< 2 weeks
    • Monoclonal antibodies =< 2 weeks
    • Radiation therapy =< 2 weeks

    • Anti-Her-2 or other "targeted" (e.g. mammalian target of rapamycin [mTOR]) therapy =< 2 weeks

      • NOTE : Any toxicities derived from these therapies must be =< grade 2 prior to starting study therapy
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

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


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Matthew P Goetz Alliance for Clinical Trials in Oncology
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):
Study Protocol and Statistical Analysis Plan  [PDF] April 24, 2018

More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02311933    
Other Study ID Numbers: NCI-2014-02409
NCI-2014-02409 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A011203
A011203 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A011203 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: December 9, 2014    Key Record Dates
Results First Posted: September 28, 2021
Last Update Posted: May 3, 2023
Last Verified: February 2023
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Tamoxifen
Estrogen Antagonists
Hormone Antagonists
 Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents