Phase 2 Randomized Double-Blind Trial of Low-Dose Exemestane Versus Low-Dose Tamoxifen in Postmenopausal Women at High Risk for Breast Cancer

Trial ID: 2024-520004-26-00
Protocol: BabyTEARS
Sponsor: Ente Ospedaliero Ospedali Galliera Di Genova

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Diseases & Conditions

Lobular breast carcinoma in situ Intraductal proliferative breast lesion

Objectives

The primary objective of this randomized double-blind phase 2 trial is to compare the efficacy of low-dose **exemestane** (babyexe) versus low-dose **tamoxifen** (babytam) in terms of changes in the quality of life, as measured by the overall score of the Menopause-Specific Quality of Life Questionnaire (MENQOL), from baseline to 12 months. This is clinically relevant as it aims to assess the impact of these treatments on the quality of life in postmenopausal women at high risk for breast cancer, potentially guiding therapeutic decisions.

Secondary objectives include:

Comparing differences between babyexe and babytam on sex hormones (free estradiol, estradiol/SHBG) and the IGF system (IGF-I, IGFBP-3, and their ratio) at 6 and 12 months.
Determining differences in overall MENQOL domains at 6 months.
Evaluating individual domains of MENQOL (physical, sexual, psychosocial, vasomotor) at 6 and 12 months.
Assessing the toxicity profile according to NCICTC AE version 5.
Investigating pill adherence, joint pain and stiffness, and C-telopetide levels at 6 and 12 months.
Evaluating patient uptake through satisfaction and reasons for trial acceptance or refusal in all screened subjects.
Comparing the toxicity of babyexe with full-dose historical controls treated in the adjuvant setting.

Participants

The clinical trial involves a total of **70 participants** who are exclusively **female** and postmenopausal, with an age range corresponding to categories 3 and 4, which typically includes middle-aged to older adults. The study population was selected based on specific criteria, including a recent histologic diagnosis of estrogen receptor-positive ductal carcinoma in situ (ER+ve DCIS) or a significant risk of developing **breast cancer** as determined by established risk models. Participants are required to have a negative gynecological examination and a mammography performed within six months prior to the trial consent form signature. They must also have a life expectancy of at least 10 years and normal liver function tests and blood cell count. The trial excludes male subjects and does not involve a vulnerable population. Participants are expected to be in good general health, as indicated by an Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) of 0-1, and must be able to swallow oral medications. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the effects of low-dose **exemestane** versus low-dose **tamoxifen citrate** in postmenopausal women at high risk for **breast cancer**. The primary objective is to assess changes in the quality of life, as measured by the Menopause-Specific Quality of Life Questionnaire (MENQOL), from baseline to 12 months. The trial will also evaluate secondary endpoints, including differences in sex hormones, IGF system markers, and safety profiles between the two treatment arms over a 12-month period.

Participants will be involved in the study for a maximum of 12 months, with the trial expected to conclude by October 2027. The study will commence with a screening visit to confirm eligibility based on criteria such as postmenopausal status, recent gynecological examination, and performance status. Eligible participants will then be randomized to receive either **exemestane** or **tamoxifen citrate**, both administered orally. The trial includes follow-up visits at 6 and 12 months to monitor treatment effects, adherence, and safety. The end-of-study visit will coincide with the 12-month follow-up, where final assessments will be conducted.

Participants may be withdrawn from the study if they experience adverse events that compromise safety, fail to adhere to the study protocol, or if the investigator deems it necessary for any other reason. The trial's double-blind design ensures that neither participants nor investigators are aware of the treatment allocation, maintaining the integrity of the study results. The trial's duration and structured visits are designed to comprehensively evaluate the comparative effects of the two hormonal treatments on quality of life and other health parameters in the target population.

Treatment

The clinical trial involves the administration of two experimental medications, **Exemestane** and **Tamoxifen Citrate**, both of which are utilized in a double-blind, randomized study to assess their effects on post-menopausal women at high risk for breast cancer. **Exemestane** is administered in an oral pharmaceutical form, with a maximum daily dose of 25 mg. The treatment period for **Exemestane** is set for a duration of 12 months. The medication is chemically derived and classified under the ATC code L02BG06. The administration of **Exemestane** is conducted under a masked protocol to maintain the integrity of the double-blind study design.

**Tamoxifen Citrate** is also administered orally, with a maximum daily dose of 10 mg. Similar to **Exemestane**, the treatment period for **Tamoxifen Citrate** is 12 months. This medication is chemically derived and classified under the ATC code L02BA01. The administration of **Tamoxifen Citrate** is likewise conducted under a masked protocol to ensure the study remains double-blinded. Both medications are not formulated for pediatric use and are categorized as hormonal treatments. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the difference between the mean changes of individual scores on the overall Menopause-Specific Quality of Life Questionnaire (MENQOL) between the two treatment arms, measured from baseline to 12 months. This will provide insight into the impact of low-dose **exemestane** versus low-dose **tamoxifen** on the quality of life in post-menopausal women at high risk for breast cancer.

Secondary endpoints include the evaluation of sex hormones, specifically the ratio of free estradiol to estradiol/SHBG, and the IGF system components (IGF-I, IGFBP-3, and their ratio) after 12 months. Additionally, the difference in the overall MENQOL score after 6 months of treatment will be assessed. The trial will also measure the difference between arms in each of the four individual MENQOL domain scores (physical, vasomotor, sexual, and psychosocial) at both 6 and 12 months. Other secondary endpoints include the assessment of toxicity and safety profiles according to CTCAE v.5, the Promise Medication Adherence Scale (PMAS) for pill adherence, the Brief Pain Inventory (BPI), and C-telopetide levels at 6 and 12 months. Patient uptake at the screening/baseline phase will be measured with a questionnaire addressing breast cancer worry and lifestyle risk factors, along with participant satisfaction regarding study explanation. The toxicity of low-dose exemestane will also be compared with historical controls treated in the adjuvant setting.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post- menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. In addition, any of the following criteria must be met: a. Recent (within 12 months from date of consent form signature) histologic diagnosis of ER+ve (>5%) DCIS or diagnosis within 3 years of HRL (ADH, LCIS, ALH), or: b. At least 3% breast cancer risk at 5 years (or 5% risk at 10 yrs) per one of the following risk models: the Breast Cancer Surveillance Consortium risk calculator V3 and Tyrer-Cuzick model V8, or: c. Known carriers of a germline pathogenic/likely pathogenetic variant within 5 years in the following moderate penetrance genes (CHEK2 or ATM), or women with chest wall irradiation before age of 30 years.
Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) 0-1.
Able to swallow oral medications.
Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Specifically, all cancers diagnosed since 3 years or longer except for breast and endometrial are eligible.
Ability to understand and willingness to sign a written informed consent document.
Mammography performed up to 6 months before the trial consent form signature.
DEXA performed up to 12 months before the trial consent form signature.
Patients with life expectancy >= 10 years.
Patients with normal liver function tests and blood cell count.
Negative gynecological examination performed up to 6 months before the trial consent form signature.

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Exclusion Criteria

Pre/perimenopausal women
History of DVT or PE.
Endometrial cancer.
Macular disorders.
Inability to comply with study procedures.
Prior use of antiestrogens within 12 months from the date of the trial consent form signature.
Use of hormone replacement therapy (HRT) within 3 months from the date of the trial consent form signature.
Severe osteoporosis (T score <-2.5 at either spine or hip), or recent vertebral fracture (within 6 months) not treated with zolendronic acid or denosumab.
Use of terbinafine, quinidine, cinacalcet, rifampicin, phenytonin, carbamazepine, phenobarbital, and St. John’s wort, warfarin, erythromycin, cyclosporin, nifepidine and any concomitant type of coumarin-type of anticoagulant therapy.
Patients with moderate or severe renal impairment.
Patients with a known hypersensitivity to study drugs.