Phase IIB Pre-Surgical Trial of Oral Tamoxifen Versus Transdermal 4-hydroxytamoxifen in Women With DCIS of the Breast
Overview
- Phase
- Phase 2
- Intervention
- Afimoxifene
- Conditions
- Ductal Breast Carcinoma In Situ
- Sponsor
- Northwestern University
- Enrollment
- 100
- Locations
- 6
- Primary Endpoint
- Change in Ki-67 Labeling Index
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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 4-10 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 4-10 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 4-10 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.
Investigators
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
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
Arms & Interventions
Arm I (afimoxifene, placebo)
Patients apply afimoxifene gel to both breasts and receive placebo PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity.
Intervention: Afimoxifene
Arm I (afimoxifene, placebo)
Patients apply afimoxifene gel to both breasts and receive placebo PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity.
Intervention: Laboratory Biomarker Analysis
Arm I (afimoxifene, placebo)
Patients apply afimoxifene gel to both breasts and receive placebo PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity.
Intervention: Placebo
Arm II (placebo, tamoxifen citrate)
Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity.
Intervention: Laboratory Biomarker Analysis
Arm II (placebo, tamoxifen citrate)
Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity.
Intervention: Placebo
Arm II (placebo, tamoxifen citrate)
Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity.
Intervention: Tamoxifen Citrate
Outcomes
Primary Outcomes
Change in Ki-67 Labeling Index
Time Frame: baseline to up to 10 weeks
Change in the Ki-67 labelling index of DCIS lesions evaluated using immunohistochemistry
Secondary Outcomes
- Change in Oncotype DCIS-Score(baseline to up to 10 weeks)
- Post-therapy Breast Tissue Levels of Tamoxifen and Its Metabolites(up to 10 weeks)
- Post-therapy Plasma Levels of Tamoxifen and Its Metabolites(up to 10 weeks)
- Ki-67 Labelling Index in the Terminal Duct Lobular Units (TDLUs)(baseline to up to 10 weeks)
- Change in Plasma Proteins Involved in Coagulation(baseline to up to 10 weeks)
- Change in Plasma Markers of Systemic Estrogenic Effect (SHBG)(baseline to up to 10 weeks)
- Change in Plasma Markers of Systemic Estrogenic Effect (IGF-1)(baseline to up to 10 weeks)
- Change in Symptoms as Captured in the Breast Cancer Prevention Trial (BCPT) Eight Symptom Scale (BESS) Questionnaire and Skin Reactions to 4-OHT Gel.(baseline to up to 10 weeks)