Clinical Trials /

Testing an Active Form of Tamoxifen (4-hydroxytamoxifen) Delivered Through the Breast Skin to Control Ductal Carcinoma in Situ (DCIS) of the Breast

NCT02993159

Description:

This randomized phase IIB trial studies how well tamoxifen or afimoxifene works in treating patients with estrogen receptor positive breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate or afimoxifene may fight breast cancer by blocking the use of estrogen by the tumor cells.

Related Conditions:
  • Ductal Carcinoma In Situ
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing an Active Form of Tamoxifen (4-hydroxytamoxifen) Delivered Through the Breast Skin to Control Ductal Carcinoma in Situ (DCIS) of the Breast
  • Official Title: Phase IIB Pre-Surgical Trial of Oral Tamoxifen Versus Transdermal 4-hydroxytamoxifen in Women With DCIS of the Breast

Clinical Trial IDs

  • ORG STUDY ID: NCI 2015-06-04
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2016-01911
  • SECONDARY ID: N01-CN-2012-00035
  • SECONDARY ID: NCI 2015-06-04
  • SECONDARY ID: NWU2015-06-04
  • SECONDARY ID: N01CN00035
  • NCT ID: NCT02993159

Conditions

  • Ductal Breast Carcinoma In Situ
  • Estrogen Receptor Positive

Interventions

DrugSynonymsArms
Afimoxifene4-Hydroxy-Tamoxifen, 4-Hydroxytamoxifen, 4-OHTArm I (afimoxifene, placebo)
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 (placebo, tamoxifen citrate)

Purpose

This randomized phase IIB trial studies how well tamoxifen or afimoxifene works in treating patients with estrogen receptor positive breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate or afimoxifene may fight breast cancer by blocking the use of estrogen by the tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To demonstrate that 2 mg once daily per breast of 4-hydroxytamoxifen (4-OHT) topical gel
      results in a reduction in the Ki-67 labeling index of ductal breast carcinoma in situ (DCIS)
      lesions that is not inferior to that seen with 20 mg daily oral tamoxifen citrate (TAM) for
      8±2 weeks weeks weeks, when comparing the base-line diagnostic core biopsy to the therapeutic
      surgical excision sample.

      SECONDARY OBJECTIVES:

      I. To compare post-therapy changes in the oncotype DCIS-score between arms (this is a
      validated reverse transcriptase-polymerase chain reaction [RT-PCR] assay for Ki67, STK15,
      survivin, cyclin B1, MYBL2, PR, GSTM1).

      II. To compare between-group post-therapy changes in immunohistochemistry (IHC) markers:
      CD-68 macrophage marker as a surrogate for response to therapy, p16 and COX-2.

      III. To compare post-therapy changes in breast density, quantitative estimate, between arms.

      IV. To compare post-therapy breast tissue and plasma levels of TAM and its metabolites
      (N-desmethyl tamoxifen [NDT], [E] and [Z] isomers of 4-hydroxytamoxifen [4-OHT],
      N-desmethyl-4-hydroxytamoxifen [endoxifen]).

      V. To compare post-therapy breast tissue and plasma levels of estradiol and progesterone
      between arms (optional).

      VI. To compare the post-therapy fraction of participants demonstrating "no residual DCIS".

      VII. To compare post-therapy changes in plasma proteins involved in coagulation: factors VIII
      and IX, von Willebrand factor, total protein S between arms.

      VIII. To compare post-therapy changes in plasma markers of systemic estrogenic effect (IGF-1,
      SHBG).

      IX. To compare post-therapy changes in symptoms as captured in the breast cancer prevention
      trial (BCPT) Eight Symptom Scale (BESS) questionnaire and skin reactions to 4-OHT gel.

      OUTLINE: Patients are randomized into 1 of 2 arms.

      ARM I: Patients apply afimoxifene gel to both breasts and receive placebo orally (PO) daily
      for 8±2 weeks in the absence of disease progression or unexpected toxicity.

      ARM II: Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO
      daily for 8±2 weeks in the absence of disease progression or unexpected toxicity.

      After completion of study treatment, patients are followed up at 1-2 weeks and 1 month after
      surgery.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (afimoxifene, placebo)ExperimentalPatients apply afimoxifene gel to both breasts and receive placebo PO daily for 8±2 weeks in the absence of disease progression or unexpected toxicity.
  • Afimoxifene
Arm II (placebo, tamoxifen citrate)Active ComparatorPatients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for 8±2 weeks in the absence of disease progression or unexpected toxicity.
  • Tamoxifen Citrate

Eligibility Criteria

        Inclusion Criteria:

          -  Screen-detected, estrogen receptor (ER) positive DCIS of the breast proven on core
             needle biopsy, defined as 10% positive cells; the presence of a focus suspicious for
             microinvasion will be allowed; the size of the DCIS in the core biopsy sample must
             total 5 mm (multiple cores can be summed) and must be estimated on the deepest step
             section (if step sections are taken)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Participants must have acceptable organ and marrow function as defined below:

        Baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a
        minimal panel will therefore be appropriate.

          -  Leukocytes >= 3,000/microliter

          -  Absolute neutrophil count >= 1,500/microliter

          -  Platelets >= 100,000/microliter

          -  Total bilirubin within "≤1.5 x institutional upper limit of normal (ULN)institutional
             limits

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 1.5 x institutional upper limit of normal (ULN)

          -  Creatinine within "≤1.5 x institutional upper limit of normal (ULN) institutional
             limits

          -  Women of childbearing potential and their male partners must agree to use TWO
             effective forms of birth control (abstinence is not an allowed method) prior to study
             entry and for the duration of study participation, and for two months following the
             last dose of study medications; effective birth control methods are: copper IUD
             [intrauterine device], diaphragm/cervical cap/shield, spermicide, contraceptive
             sponge, condoms; women of childbearing potential must have a negative urine pregnancy
             test within seven days before starting study medications; should a woman become
             pregnant or suspect she is pregnant while participating in this study, she should
             inform her study physician immediately

          -  Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.
             tanning beds) for the duration of the study

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  DCIS presentation as a palpable mass

          -  Exogenous sex steroid use within 4 weeks prior to core needle biopsy

          -  Prior ipsilateral breast cancer radiotherapy will be excluded; prior contralateral
             breast cancer therapy within 2 years will also be excluded

          -  Skin lesions on the breast that disrupt the stratum corneum (eg eczema, ulceration)

          -  History of endometrial neoplasia

          -  History of thromboembolic disease (history of varicose veins and superficial phlebitis
             is allowed)

          -  Current smokers

          -  Current users of potent inhibitors of tamoxifen metabolism must be able to discontinue
             their use and switch to an alternative medication for the duration of participation,
             under the advice of their physician; if the physician feels that an alternative
             medication is not appropriate for the subject and the current medication is medically
             necessary, the subject will not be eligible; the drugs are listed below; many of these
             are not in clinical use at the moment; bupropion, celecoxib, chlorpheniramine,
             chlorpromazine, cimetidine, citalopram, clemastine, clomipramine, clozapine, cocaine,
             delavirdine, desipramine, diphenhydramine, doxepin, duloxetine, escitalopram,
             fluoxetine, haloperidol, halofantrine, hydroxyzine, imipramine, isoniazid,
             ketoconazole, methadone, methimazole, mibefradil, miconazole, nicardipine, paroxetine,
             pergolide, perphenazine, pioglitazone, pyrimethamine, quinidine, quinine, ranitidine,
             ritonavir, ropinirole, sertraline, terbinafine, thioridazine, ticlopidine,
             tranylcypromine, trazodone, tripelennamine

          -  Prior use of SERMS or AIs including tamoxifen, raloxifene, anastrozole, letrozole, or
             exemestane for prevention or therapy within 5 years

          -  Participants may not be receiving any other investigational agents within 30 days of
             enrollment or during this study

          -  History of allergic reactions attributed to tamoxifen or compounds of similar chemical
             or biologic composition

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued by
             nursing mothers who agree to participate in the study

          -  Men are excluded from this study since DCIS of the breast is exceedingly rare in men,
             and there are no data regarding skin penetration of 4-OHT though male chest wall skin
             (which is thicker and hairier than female chest wall skin)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Ki67 labeling assessed by standard immunohistochemistry
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:

Secondary Outcome Measures

Measure:CD68, p16, and COX2 assessed by IHC
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:Estradiol and progesterone levels in breast tissue and plasma assessed by liquid chromatography/tandem mass spectrometry
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:Fraction of subjects with "no residual DCIS" in surgical sample assessed by core needle biopsy
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:Oncotype DCIS-score assessed by RT-PCR
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:Pathologic complete response defined as absence of residual DCIS or residual DCIS responded completely to therapy
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:
Measure:Plasma markers of systemic estrogenic effect (IGF-1, SHBG)
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:Plasma proteins involved in coagulation (factors VIII and IX, von Willebrand factor, and total protein S)
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:Symptoms assessed by BESS questionnaire
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Will evaluate hot flashes, vaginal discharge/dryness, skin reactions to afimoxifene gel. Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.
Measure:TAM and its metabolites levels in breast tissue and plasma
Time Frame:Up to 1 month after surgery
Safety Issue:
Description:Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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