Randomized Phase 3 Trial on Personalized Tamoxifen Dosing for Adjuvant Therapy in Breast Cancer: Impact on Discontinuation and Efficacy

Trial ID: 2025-522240-40-00
Sponsor: Karolinska Institutet

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Diseases & Conditions

Breast cancer female

Objectives

The primary objective of the POWER trial is to evaluate the effect of **personalised dosing** of tamoxifen on the discontinuation rates in patients with **breast cancer**. This is compared to the standard regimen of 20 mg per day. The clinical relevance of this objective lies in potentially reducing discontinuation rates, which can enhance treatment adherence and improve therapeutic outcomes in breast cancer management.

Secondary objectives include comparing the effect of personalised dosing on various clinical and patient-centered outcomes:

Patient reported outcomes (PROM)
Quality of life
Levels of tamoxifen metabolites
Breast cancer outcomes
Overall survival (OS)
Breast density
Health economic aspects

These secondary objectives aim to provide a comprehensive understanding of the broader impacts of personalised dosing, beyond discontinuation rates, potentially influencing future treatment guidelines and patient care strategies.

Participants

The clinical trial focuses on **Breast Cancer** and involves a study population consisting exclusively of female participants. The age range for the participants is 18 years and older, specifically targeting premenopausal or perimenopausal women. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, indicating they are in relatively good health. The trial does not include a vulnerable population. Participants must adhere to non-hormonal contraception during the trial, and a pregnancy test is recommended for women of child-bearing potential who are sexually active and not using reliable contraceptive methods. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on their diagnosis of primary breast cancer and recommendation for adjuvant tamoxifen treatment, with or without concomitant goserelin. Participants must be able and willing to undergo blood sampling and provide written consent to participate in the trial. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized**, two-armed, open-label, phase 3 study to evaluate the impact of personalized dose optimization of **tamoxifen** in patients with **breast cancer**. The primary objective is to assess the effect of varying doses of tamoxifen (10 mg, 20 mg, or 40 mg per day) on the discontinuation rate compared to the standard regimen of 20 mg per day. The trial is expected to commence recruitment on October 1, 2025, and conclude by June 30, 2036, with an estimated participant involvement of up to 60 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, menopausal status, and performance status. Eligible participants are women aged 18 years or older, premenopausal or perimenopausal, with an ECOG WHO performance status of 0 to 2. They must be recommended for adjuvant tamoxifen treatment, with or without concomitant goserelin, and must agree to use non-hormonal contraception during the trial. Following the screening, participants will be randomized to receive one of the specified tamoxifen doses.

Subsequent follow-up visits will be scheduled to monitor the primary endpoint of tamoxifen discontinuation and secondary endpoints, including quality of life assessments, plasma metabolite concentrations, and survival outcomes. The trial will also evaluate mammographic breast density, cost-effectiveness, and genetic polymorphisms. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted.

Participants may be withdrawn from the study early if they experience adverse effects that necessitate discontinuation of the study drug, fail to comply with the study protocol, or withdraw consent. The trial is categorized as low intervention, ensuring that the safety and well-being of participants are prioritized throughout the study duration.

Treatment

The clinical trial involves the use of **Tamoxifen**, marketed as Tamoxifen Viatris 20 mg tabletter, as the experimental medication. Tamoxifen is administered in the form of a **tablet** and is taken **orally**. The trial explores personalised dosing regimens, with participants receiving either 10 mg, 20 mg, or 40 mg of Tamoxifen per day. The maximum daily dose is set at 40 mg, and the total maximum dose over the treatment period is 72,000 mg. The treatment period is limited to a maximum of 60 days. The active substance, Tamoxifen, is of chemical origin and is classified under the ATC code L02BA01. The pharmaceutical product is manufactured by Viatris Limited and is not a paediatric formulation.

The trial is designed to compare the personalised dosing of Tamoxifen against the standard-of-care therapy, which involves a fixed daily dose of 20 mg. This standard regimen serves as the comparator treatment in the study. The primary objective is to assess the impact of personalised dosing on the discontinuation rates of Tamoxifen therapy in patients with breast cancer. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in the clinical trial titled "The POWER trial: A randomised, two-armed open label phase 3 clinical trial on personalised dose optimisation with adjuvant tamoxifen therapy after breast cancer to investigate the impact on discontinuation and efficacy compared to standard of care" will be assessed using a variety of endpoints. The primary endpoint is the discontinuation of **tamoxifen**. Secondary endpoints include assessments using the BESS plus (2007) scale and subscales, the POWER symptom questionnaire, and a quality of life questionnaire. Additionally, the concentration of circulating plasma metabolites will be measured, along with invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), breast cancer-specific survival (BCSS), and overall survival (OS). Other secondary endpoints include mammographic breast density, cost-effectiveness and use of healthcare resources, genetic polymorphisms in germline DNA, and biomarkers used for therapeutic drug monitoring.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients with primary breast cancer, recommended for adjuvant tamoxifen treatment with or without concomitant goserelin
Women aged >18 years to ≤ 75 years
ECOG WHO PS 0 – 2
Participants must use non-hormonal contraception during the trial. A pregnancy test is recommended for women of child-bearing potential who are sexually active and not using reliable contraceptive methods before inclusion
Able and willing to undergo blood sampling according to study protocol
Able and willing to give their written consent to participate in the trial
More than 2.5 years left of planned tamoxifen treatment if switching from aromatase inhibitors.

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Exclusion Criteria

Previous or ongoing use of tamoxifen or endoxifen. Could be allowed after discussion with Sponsor E.g. treatment with tamoxifen for previous primary breast cancer
Ongoing treatment with adjuvant CDK4/6 inhibitors or capecitabine or trastuzumab emtansin. Previous treatment with CDK4/6 inhibitors, capatecitabine or trastuzumab emtansin is allowed.
Previous medical history of: Deep venous thrombosis or pulmonary embolism if not on life-long anticoagulant treatment with DOAC. A history of previous PICC-line or subcutaneous venous port associated thrombosis or superficial thrombophlebitis is allowed. Bleeding disorder or coagulopathy. Macular disorders, retinal disorder, severe cataract or glaucoma.
Current use of warfarin. Antiaggregants’ and direct oral anticoagulants are allowed
Not willing to abstain from strong and moderate CYP2D6 inhibitors or CYP3A4 inducers during the tamoxifen treatment
Strong and moderate inhibitors of CYP2D6 not allowed in the trial: Bupropion (Zyban), Duloxetin (Cymbalta), Fluoxetin (Fontex), Levemopromazin (Nozinan), Mirabegron (Betmiga), Paroxetin (Seroxat), Terbinafin (Lamisil) for systemic use.
CYP3A4 inducers not allowed in the trial (D-interactions in “Janusmedicin” janusmed.se): Efavirenz, Fenobarbital, Fenytoin, Johannesört, Karbamazepin, Primidon, Rifampicin, rifamycin.
Current pregnancy, breastfeeding, or already at start of tamoxifen planning to become pregnant within the next two years
Use of systemic menopausal hormonal therapy (MHT) and all types of systemic hormonal contraception. Local treatment is acceptable
Uncontrolled intercurrent physical or psychiatric illness, or social situations that would limit compliance with protocol requirements
Prior invasive malignancy during the last five years. Prior or current in situ cancers are allowed
Participation in another clinical drug trial
Inability to understand the study related information