Clinical trial NCT06184750: Finding the Best Tamoxifen Dose for Breast Cancer Risk Reduction in Premenopausal Women, RENAISSANCE Trial
Official title: Refining Tamoxifen Dose for Premenopausal Breast Cancer Risk Reduction (RENAISSANCE): A Phase II Single Arm Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Carcinoma
Breast Ductal Carcinoma In Situ
Breast Lobular Carcinoma In Situ
Estrogen Receptor-Positive Breast Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2023-12-28
Enrollment: 200
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This phase II trial evaluates response-guided low-dose tamoxifen for reducing breast density in women who are at higher than average risk for breast cancer. Increasing breast density is a well established risk factor for breast cancer. Tamoxifen is a selective estrogen receptor modulator. It works by blocking the effects of the hormone estrogen in the breast. Tamoxifen has been shown to reduce breast density, even at reduced dosages, and is approved for the prevention of breast cancer.

Detailed description: PRIMARY OBJECTIVE:

I. To evaluate whether the overall proportion of premenopausal tamoxifen responders (defined by absolute dense area reduction on mammogram of \> 10%) can be increased through a strategy of within-individual dose escalation among non-responders from 5 mg per day to 10 mg per day.

SECONDARY OBJECTIVES:

I. To assess the association of plasma levels of major tamoxifen metabolites with tamoxifen dose and breast density changes from baseline.

II. To evaluate longitudinal change from baseline in serum biomarkers of tamoxifen response at each dose level: sex hormone binding globulin (SHBG), insulin like growth factor 1 (IGF-1) and C-reactive protein (CRP).

III. To assess the association of baseline dense area (continuous variable) with tamoxifen response.

IV. To evaluate the impact of tamoxifen dose on participant-reported symptoms (Breast Eight Symptom Scale, BESS).

V. To evaluate the impact of tamoxifen dose on adherence to final tamoxifen dose.

EXPLORATORY OBJECTIVES:

I. To evaluate breast tissue-based biomarkers (in research biopsy samples) that associate with tamoxifen response at six months, comparing within-person change in responders and non-responder.

II. To assess the association between single nucleotide polymorphisms that overlap between risk of breast cancer and dense are of breasts; and others that relate to efficiency of tamoxifen metabolism.

III. To evaluate change in breast cancer risk estimates from baseline to 18 months, as assessed by an AI (artificial intelligence) tool and compare changes by dose group.

OUTLINE: This is a within-participant dose-escalation study of tamoxifen.

Participants receive tamoxifen 5mg orally (PO) once daily (QD) for 6 months. Participants with absolute dense area reduction (aDAR) \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.

After completion of study intervention, patients are followed up at 4 weeks.

Eligibility criteria: Inclusion Criteria:

* Premenopausal women at the time of enrollment defined by any of the following:

  * Age under 50 years and regular menstruation (most recent period within the past 3 months)
  * Age under 50 years and continuous hormonal contraception use and at least one intact ovary
  * Women who are not postmenopausal based on serum hormone levels (estradiol =\< 30 pg/mL, follicle-stimulating hormone \[FSH\] \>= 30 IU/mL)
* Women with any of the following:

  * A history of unilateral estrogen receptor (ER) positive ductal carcinoma in situ (DCIS) with local therapy completed (as determined by treating physician recommendation and patient acceptance) at least 1 month prior to study entry. (The untreated breast will be the study breast, for both imaging and optional biopsy)
  * Recent or prior lobular carcinoma in situ (LCIS), or any form of epithelial atypia
  * Are risk eligible for preventive medication based on a five-year risk of 1.7% or greater, estimated with a validated model: the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool, Tyrer-Cusick, Breast Cancer Surveillance Consortium. If the Tyrer-Cuzick model is used a ten-year risk of 3.4% or greater is acceptable
  * Are tamoxifen-eligible by American Society of Clinical Oncology (ASCO) guidelines (\>= 2-fold increased risk compared to peer if age \>= 45 years, and \>= 4-fold increased risk if age \< 45 years)
  * A history of mantle radiotherapy
  * A moderate penetrance germline pathogenic variant
* Participants ≥ 18 and ≤ 55 years old will be enrolled. Our trial objectives are not relevant to females under 18 years of age since breast cancer is extraordinarily rare in this age group, and there are no guidelines regarding use of tamoxifen in children, even if know to be at very high risk for breast cancer when older. Because no dosing or adverse event (AE) data are currently available on the use of tamoxifen in participants \< 18 years of age
* Eastern Cooperative Oncology Group (ECOG) performance status must be =\< 2 (Karnofsky \>= 60%)
* Human immunodeficiency virus (HIV)-infected patients are eligible to participate if they are on effective anti-retroviral therapy with undetectable viral load within the prior 6 months
* Women with evidence of chronic hepatitis B virus (HBV) infection, are also eligible if the HBV viral load is undetectable; they may be on suppressive therapy, if indicated
* Women with a history of hepatitis C virus (HCV) infection are eligible if treated and cured. For those who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Women with herpes simplex virus (HSV) infection are eligible if on chronic or as needed (due to a flare) suppressive antiviral therapy
* Hormonal contraceptive users are eligible and should maintain the same oral contraceptive preparation throughout the duration of the trial. For women who have a levonorgestrel-coated intra-uterine device, removal for medical reasons will be allowed
* The effects of tamoxifen on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because tamoxifen is known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Breast Imaging Reporting and Data System (BIRADS) breast density category A on most recent mammogram
* History of selective estrogen receptor modulator (SERM) use within the past 5 years unless:

  * Use was less than 6 months duration in the past 5 years and not used in the 1 year prior to enrollment OR
  * Use was no greater than 2 months duration in the past 1 year and not used in the 6 months prior to enrollment
* History of invasive breast cancer
* Prior bilateral breast surgery (mastectomy or breast augmentation surgery including breast implants)
* Women with "mosaic mammographic screening views", i.e., whose larger breast size precludes being imaged within a single mammographic screening view
* Current use of a strong CYP3A4 inducer or a strong CYP2D6 inhibitor unless willing and able to discontinue use and switch to an alternative medication for the duration of participation, under the advice of their physician. If the physician believes the current medication cannot be replaced, the participant will not be eligible
* Current use of Warfarin
* Planning to become pregnant within the next two years. Potential study participants will be questioned about this and excluded if they are planning pregnancy over the next 20 months
* History of thromboembolism. A history of superficial thrombophlebitis is allowed
* History of uterine cancer or atypical uterine hyperplasia with uterus intact
* Participants may not be receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen
* Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant women are excluded from this study because tamoxifen a category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with tamoxifen. Breastfeeding should be discontinued if the mother is treated with tamoxifen

Primary outcomes:
measure: Proportion of women who have a response at any time point
timeFrame: At 6, 12, and 18 months
Secondary outcomes:
measure: Plasma levels of major tamoxifen (TAM) metabolites
timeFrame: At 6, 12, and 18 months
measure: Longitudinal change in serum biomarkers of tamoxifen response
timeFrame: From baseline up to 18 months
measure: Baseline dense area
timeFrame: Up to 18 months
measure: Patient-reported symptoms
timeFrame: At baseline, 6, 12, and 18 months
measure: Adherence to final tamoxifen dose
timeFrame: Up to 18 months
Other outcomes:
measure: Breast tissue-based biomarkers
timeFrame: At 6 months
measure: Single nucleotide polymorphisms (SNPs)
timeFrame: Up to 18 months
measure: Change in breast cancer risk estimates
timeFrame: From baseline to 18 months
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - Prevention Research Clinic
state: Arizona
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois College of Medicine - Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: Northwestern University
name: Seema A Khan
role: PRINCIPAL_INVESTIGATOR
References: