Clinical Trials /

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

NCT02311933

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-02409
  • SECONDARY ID: NCI-2014-02409
  • SECONDARY ID: A011203
  • SECONDARY ID: A011203
  • SECONDARY ID: A011203
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT02311933

Conditions

  • 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

Interventions

DrugSynonymsArms
Tamoxifen CitrateApo-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, ZemideArm II (tamoxifen citrate)
Z-Endoxifen HydrochlorideZ-Endoxifen HClArm I (z-endoxifen hydrochloride)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess whether progression-free survival with z-endoxifen hydrochloride (HCl) relative
      to that with tamoxifen (tamoxifen citrate) is prolonged in postmenopausal women with local
      advanced or metastatic estrogen receptor (ER) positive/Her2 negative breast cancer.

      SECONDARY OBJECTIVES:

      I. To assess the safety profile of each of these agents in this patient population.

      II. To assess whether the tumor response rate (as determined using the Response Evaluation
      Criteria in Solid Tumors [RECIST] criteria) among those randomized to z-endoxifen HCl differs
      from that among those randomized to tamoxifen.

      III. To estimate the median progression-free survival time for those who receive z-endoxifen
      HCl after disease progression with tamoxifen.

      TERTIARY OBJECTIVES:

      I. To examine whether ER alpha alterations (defined as either ER activating mutations or ER
      amplification) are associated with longer progression-free survival (PFS) or higher response
      rates in the z-endoxifen HCl arm compared to the tamoxifen arm.

      II. To determine changes in lipid profiles comparing tamoxifen and z-endoxifen HCl.

      III. For each treatment, to evaluate changes in markers of bone formation and absorption
      after 12 weeks (4 cycles) of treatment.

      IV. For all patients and by treatment arm, to determine whether progression-free survival
      differs with respect to the sensitive to endocrine therapy (SET) index.

      V. To examine whether deoxyribonucleic acid (DNA) alterations as measured by Foundation
      medicine in all coding exons of 287 cancer-related genes as well as 78 polymorphisms in 34
      absorption, distribution, metabolism, and excretion (ADME)-related genes are associated with
      longer PFS or higher response rates in the z-endoxifen HCl arm compared to the tamoxifen arm.

      VI. To assess whether the molecular characteristics identified in the tumor biopsies are
      detectable in the circulating tumor cells (CTCs) and/or cell-free DNA (cfDNA).

      VII. For each treatment arm: to examine changes in ER expression on CTCs, changes in estrogen
      receptor (ESR) mutations or amplification in CTCs or CfDNA and explore the impact of these
      changes on PFS and response rates.

      VIII. To further characterize pharmacokinetics, pharmacogenetics and metabolism of
      z-endoxifen HCl and tamoxifen.

      IX. To determine the impact of the concentrations of tamoxifen and its metabolites on PFS in
      the tamoxifen arm.

      X. To determine the impact of the concentrations of z-endoxifen HCl and its metabolites on
      PFS in the endoxifen arm.

      XI. To determine the impact of genetic variation in the enzymes responsible for tamoxifen and
      z-endoxifen HCl metabolism.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive z-endoxifen hydrochloride orally (PO) on days 1-21. Courses repeat
      every 21 days in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive tamoxifen citrate PO once daily (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.

      After completion of study treatment, patients are followed up yearly for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (z-endoxifen hydrochloride)ExperimentalPatients receive z-endoxifen hydrochloride PO on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Z-Endoxifen Hydrochloride
Arm II (tamoxifen citrate)ExperimentalPatients 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.
  • Tamoxifen Citrate

Eligibility 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

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events, per CTCAE version 4.0
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Overall survival distribution by study arm
Time Frame:The time from registration to death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of survival times will be estimated using the method of Kaplan-Meier.
Measure:Tumor response rate by study arm, defined as the number of patients with a complete or partial response as defined by RECIST on 2 consecutive evaluations at least 6 weeks apart, divided by the total number of eligible patients who began study treatment
Time Frame:Up to 5 years
Safety Issue:
Description:A 90% binomial confidence interval will be constructed for the true response rate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 8, 2018