Therapeutic Dose Monitoring (TDM) of Tamoxifen

Breast Cancer Clinical Trial

Official title:

Therapeutic Dose Monitoring (TDM) of Tamoxifen and Its Active Metabolites in Combination With Patient-reported Symptom Scores Among Patients With Breast Cancer Receiving Adjuvant Tamoxifen Treatment

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05133674
• Other study ID #: TDM of TAM
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 4, 2022
• Est. completion date: March 1, 2023

Study information

• Verified date: May 2022
• Source: Karolinska University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Tamoxifen is a potent and effective drug reducing the risk of dying from breast cancer in the adjuvant setting. Although more modern drugs have partly replaced tamoxifen, it is helpful in the neoadjuvant and metastatic settings as a single drug. Despite that, in the adjuvant setting, it is a valuable drug.

This study aims to validate and study the feasibility of serial assessments, including therapeutic drug monitoring of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen by capillary blood sampling, combined with patient-reported symptom scores. This will provide preliminary data to allow us to develop a future multicentre randomised clinical trial of personalised dose monitoring and adjustment of adjuvant tamoxifen therapy to enhance the quality of life and breast cancer outcomes.

Description:

This repeated-measures, prospective, open-label, single-centre study is designed for women with stage 0-3 breast cancer receiving adjuvant tamoxifen 20 mg/day.

Inclusion criteria:

1. Female patients aged ≥ 18 years with hormone-positive stage 0-3 breast cancer.

2. Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.

3. Ongoing daily adjuvant tamoxifen minimum of 2 months ± gonadotropin-releasing hormone (GnRH) analogues ± radiation therapy (RT) for stage 3 breast cancer.

4. Locally recurrent disease, previously treated with adjuvant tamoxifen.

5. Able to use software applications developed specifically for small, wireless computing devices, such as smartphones and tablets.

6. Have small, wireless computing devices, such as smartphones and tablets.

Exclusion Criteria:

1. Fulfilling any of the contraindications for tamoxifen.

2. Metastatic (stage IV) breast cancer.

3. Included in other clinical studies receiving not approved investigational medicinal drug.

4. Ongoing pregnancy or lactation.

5. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

No. Of Subjects: 40 female subjects.

Measured components: Tamoxifen, 4-hydroxytamoxifen and Z-endoxifen

Study design: Blood samples for measurement of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen will be drawn capillary in total at 4-time points, at inclusion (baseline), and after 1, 2, and 3 weeks for each participant; and venously in total at 2-time points, at inclusion (baseline), and after 3 weeks for each participant.

At each time, participants will be asked to leave 2 vials of capillary blood (50ul x2) using the rhelise™ kit and 2 samples of conventional venous blood for blood and plasma (5 ml x 2).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: March 1, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Female patients aged = 18 years with hormone-positive stage 0-3 breast cancer.

2. Performance status ECOG 0-2.

3. Ongoing daily adjuvant tamoxifen minimum of 2 months ± GnRH analogues ± RT for stage 3 breast cancer.

4. Locally recurrent disease, previously treated with adjuvant tamoxifen.

5. Able to use software applications developed specifically for small, wireless computing devices, such as smartphones and tablets.

6. Have small, wireless computing devices, such as smartphones and tablets.

Exclusion Criteria:

1. Fulfilling any of the contraindications for tamoxifen.

2. Metastatic (stage IV) breast cancer.

3. Included in other clinical studies receiving not approved investigational medicinal drug.

4. Ongoing pregnancy or lactation.

5. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Carcinoma
• Breast Neoplasms
• Breast Tumors
• Cancer of Breast
• Malignant Neoplasm of Breast
• Neoplasms

Intervention

Drug:
• Tamoxifen 20 mg
i) a self-testing capillary kit, the rhelise™ kit for measuring the concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen and ii) a patient interactive digital tool (app) mBraze to collect data about symptoms and guide breast cancer patients on adjuvant tamoxifen.

Locations

Country	Name	City	State
Sweden	Karolinska University Hospital	Stockholm

Sponsors (1)

Lead Sponsor	Collaborator
Karolinska University Hospital

Country where clinical trial is conducted

Sweden, 

References & Publications (14)

Bergqvist J, Lundström S, Wengström Y. Patient interactive digital support for women with adjuvant endocrine therapy in order to increase compliance and quality of life. Support Care Cancer. 2021 Jan;29(1):491-497. doi: 10.1007/s00520-020-05476-z. Epub 2020 May 13. — View Citation

Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, Jin Y, Storniolo AM, Nikoloff DM, Wu L, Hillman G, Hayes DF, Stearns V, Flockhart DA. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006 Jul;80(1):61-74. — View Citation

Cronin-Fenton DP, Damkier P. Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics. Adv Pharmacol. 2018;83:65-91. doi: 10.1016/bs.apha.2018.03.001. Epub 2018 May 7. Review. — View Citation

Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011 Aug 27;378(9793):771-84. doi: 10.1016/S0140-6736(11)60993-8. Epub 2011 Jul 28. — View Citation

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015 Oct 3;386(10001):1341-1352. doi: 10.1016/S0140-6736(15)61074-1. Epub 2015 Jul 23. — View Citation

Eriksson M, Eklund M, Borgquist S, Hellgren R, Margolin S, Thoren L, Rosendahl A, Lång K, Tapia J, Bäcklund M, Discacciati A, Crippa A, Gabrielson M, Hammarström M, Wengström Y, Czene K, Hall P. Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial. J Clin Oncol. 2021 Jun 10;39(17):1899-1908. doi: 10.1200/JCO.20.02598. Epub 2021 Mar 18. — View Citation

Fabian CJ. Will a Low-Dose Option Improve Uptake of Tamoxifen for Breast Cancer Risk Reduction? J Clin Oncol. 2019 Jul 1;37(19):1595-1597. doi: 10.1200/JCO.19.00656. Epub 2019 May 13. — View Citation

Ferraldeschi R, Newman WG. The Impact of CYP2D6 Genotyping on Tamoxifen Treatment. Pharmaceuticals (Basel). 2010 Apr 15;3(4):1122-1138. Review. — View Citation

He W, Fang F, Varnum C, Eriksson M, Hall P, Czene K. Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer. J Clin Oncol. 2015 Jul 10;33(20):2262-9. doi: 10.1200/JCO.2014.59.3673. Epub 2015 Jun 1. — View Citation

Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005 Jan 5;97(1):30-9. — View Citation

Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, Nikoloff DM, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011 May;89(5):718-25. doi: 10.1038/clpt.2011.32. Epub 2011 Mar 23. — View Citation

Sanchez-Spitman AB, Swen JJ, Dezentjé VO, Moes DJAR, Gelderblom H, Guchelaar HJ. Effect of CYP2C19 genotypes on tamoxifen metabolism and early-breast cancer relapse. Sci Rep. 2021 Jan 11;11(1):415. doi: 10.1038/s41598-020-79972-x. — View Citation

Smith SG, Sestak I, Forster A, Partridge A, Side L, Wolf MS, Horne R, Wardle J, Cuzick J. Factors affecting uptake and adherence to breast cancer chemoprevention: a systematic review and meta-analysis. Ann Oncol. 2016 Apr;27(4):575-90. doi: 10.1093/annonc/mdv590. Epub 2015 Dec 8. Review. — View Citation

Thorén L, Lindh JD, Ackehed G, Kringen MK, Hall P, Bergh J, Molden E, Margolin S, Eliasson E. Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles. Br J Clin Pharmacol. 2021 Mar;87(3):1243-1252. doi: 10.1111/bcp.14500. Epub 2020 Aug 9. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To validate the rhelise™ kit for monitoring tamoxifen, 4-hydroxytamoxifen and Z-endoxifen among patients recommended or who have ongoing adjuvant tamoxifen.	Blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen at baseline, two weeks, 1, 2, and 3 weeks by capillary and venous blood sampling (whole blood/plasma).	At at inclusion (baseline) for each participant.
Primary	To validate the rhelise™ kit for monitoring tamoxifen, 4-hydroxytamoxifen and Z-endoxifen among patients recommended or who have ongoing adjuvant tamoxifen.	Blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen at baseline, two weeks, 1, 2, and 3 weeks by capillary and venous blood sampling (whole blood/plasma).	At week 3 after inclusion for each participant.
Secondary	To test the correlations of concentrations found in the capillary sample (rhelise™ kit) and the venous blood sample (gold standard).	Correlations of blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen between venous blood samples and capillary blood samples (Sensitivity and specificity).	At 4-time points, at inclusion (baseline), and after 1, 2, and 3 weeks for each participant.
Secondary	To validate user acceptability and feasibility of self-testing the capillary kit.	Capillary blood test concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen were taken by the patient and the research nurse.	At 4-time points, at inclusion (baseline), and after 1, 2, and 3 weeks for each participant.
Secondary	Symptom distresses scores measured by the patient interactive digital tool (application) mBraze.		at baseline and 3 weeks.
Secondary	To compare and correlate blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen with patient-reported outcome measures and the application mBraze for symptom self-monitoring.	Correlations between tamoxifen, 4-hydroxytamoxifen and Z-endoxifen concentrations and symptom distress score ((fatigue, insomnia, pain, body image, and systemic therapy side-effect and cognitive-, emotional-, role-, sexual and social functioning).; Correlations between tamoxifen, 4-hydroxytamoxifen and Z-endoxifen concentrations and symptom distress in the same patient.	at baseline and 3 weeks
Secondary	To validate the user experience of the mBraze app.	- The interview on user acceptability and attitudes toward mBraze.	at 3 weeks.
Secondary	To validate the usability of the mBraze app.	- Self-reported usability and user experience of the mBraze app measured with system usability scale (SUS).	at 3 weeks.
Secondary	To determine user acceptability and attitudes toward self-testing.	- The interview on user acceptability and attitudes toward self-testing.	at 3 weeks.