A Study to Evaluate Exemestane Tablets Combined With Ovarian Function Suppression/Ablation in Treatment of Premenopausal Breast Cancer Patients With CYP2D6*10 Mutations （STEP）

NCT03137368 | Unknown Phase 3 DMC FDA Drug

• 1 other identifier: CH-BC-059
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

This is a multicenter, randomized, open-label, parallel, active-controlled superiority clinical study conducted in early premenopausal estrogen-receptor positive breast cancer patients with CYP2D6\*10 mutations. The efficacy and safety of Exemestane Tablets combined with ovarian function suppression/ablation and Tamoxifen Tablets combined with ovarian function suppression/ablation in the treatment of early premenopausal estrogen-receptor positive breast cancer patients with CYP2D6\*10 mutations are compared.

Conditions

CYP2D6 Polymorphism

Keywords

ovarian function suppression/ablation; breast cancer; Exemestane; Tamoxifen; CYP2D6*10 mutations

Outcome Measures

Primary Outcomes (1)

• Disease free survival (DFS)

  It is defined as the time from randomization to the first breast cancer local/distant recurrence, the new breast cancer of the contralateral breast, second primary cancer and the death caused by any reason

  the first breast cancer local/distant recurrence, the new breast cancer of the contralateral breast, second primary cancer and the death caused by any reason in 5 years

Secondary Outcomes (3)

• Recurrence rate (local or distant)

  It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

• Overall survival (OS)

  It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

• Incidence of Treatment-Emergent Adverse Events

  It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

Other Outcomes (4)

• Breast cancer free survival

  It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

• Distant relapse free survival

  It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

• The occurrence rate of the contralateral breast cancer

  It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

Study Arms (2)

treatment group

EXPERIMENTAL

Exemestane Tablets combined with ovarian function suppression/ablation

Drug: Exemestane Tablets; Other: ovarian function suppression/ablation; Genetic: CYP2D6*10 gene test

control group

ACTIVE COMPARATOR

Tamoxifen Tablets combined with ovarian function suppression/ablation

Other: ovarian function suppression/ablation; Genetic: CYP2D6*10 gene test; Drug: Tamoxifen

Interventions

Exemestane Tablets DRUG

drug therapy

treatment group

ovarian function suppression/ablation OTHER

Gonadotropin-releasing hormone analogue Goserelin Injection 3.6mg or Leuprorelin Injection 3.75 mg, a subcutaneous injection should be done every 28±2 days; or Bilateral ovariectomy.

control group; treatment group

CYP2D6*10 gene test GENETIC

CYP2D6\*10 gene test

control group; treatment group

Tamoxifen DRUG

drug therapy

control group

Eligibility Criteria

• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Providing informed consent forms voluntarily before screening evaluation;
• For Chinese premenopausal women, her estradiol level must be within the premenopausal level, or the patient meet the following 4 criteria in the prior 6 months: No chemotherapy, Regular menstruation, No use of hormonal, contraceptives, No use of hormone for treatment or for temporary amenorrhea caused by chemotherapy, the estradiol level tested within 8 months after the last dose of chemotherapeutics is within the premenopausal level;
• Patients with invasive breast cancer which has been confirmed by histological examination;
• Complete removal of tumor by surgery without local residual;
• Neoadjuvant chemotherapy before surgery is permitted if the surgery for primary breast cancer is performed within 12 weeks without any further adjuvant chemotherapy, or adjuvant chemotherapy is completed within 8 months;
• Estrogen receptor (ER) and/or progesterone receptor (PR) positive: If the patient has more than one breast tumor lesions, each tumor lesion should be ER and/or PR positive.
• Her-2 negative;
• Genotyping test performed by the central laboratory designated by sponsor with the results confirmed as CYP2D6\*10T/T gene mutation.
• Women of childbearing age with negative serum pregnancy test result, and agreeing to adopt highly efficient non-hormonal contraception measure throughout the study;
• Subject without major organ dysfunction, and with normal heart, liver, kidney, lung and other major organ function.

You may not qualify if:

• Inflammatory breast cancer;
• Breast cancer patients with supraclavicular lymph nodes metastasis;
• Patients with enlarged internal mammary lymph nodes (except for patients with negative pathologic findings);
• Ovariectomy which is not specified in the study;
• Patients with ovary protection during the chemotherapy;
• Concomitant use of other aromatase inhibitors (not Exemestane);
• Received major surgery which was unrelated to breast cancer within four weeks before randomization, or the patients had not yet fully recovered from such surgery;
• Pregnant or lactating women;
• Known active hepatitis B or hepatitis C or HIV;
• Having difficulty in swallowing oral preparations and gastrointestinal dysfunction;
• Recently had severe and uncontrolled systemic diseases (e.g.: cardiovascular disease, lung disease, or metabolic disease, venous thrombosis with clinical significance);
• Currently or previously suffering from other malignant tumors (except for skin basal cell carcinoma or squamous cell carcinoma, carcinoma in situ of cervix which had been fully treated), unless a radical treatment had been done with the evidence of no-recurrence or metastasis in nearly five years;
• Allergic to any study drug or any ingredients of drug;
• Patient with poor compliance or other conditions which makes the patient unsuitable to participate in this study judged by the investigator.

Sponsors & Collaborators

• Cancer Institute and Hospital, Chinese Academy of Medical Sciences: lead
• Pfizer: collaborator

Study Sites (1)

CancerIHCAMS

Beijing, Beijing Municipality, 100010, China

Location

Related Publications (20)

• Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009 Oct 7;302(13):1429-36. doi: 10.1001/jama.2009.1420.

  PMID: 19809024 BACKGROUND

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29. doi: 10.3322/caac.21254. Epub 2015 Jan 5.

  PMID: 25559415 RESULT

• Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, Glanville J, Gray A, Harris A, Johnston K, Lodge M. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy. Health Technol Assess. 2006 Sep;10(34):iii-iv, ix-xi, 1-204. doi: 10.3310/hta10340.

  PMID: 16959170 RESULT

• Gansler T, Ganz PA, Grant M, Greene FL, Johnstone P, Mahoney M, Newman LA, Oh WK, Thomas CR Jr, Thun MJ, Vickers AJ, Wender RC, Brawley OW. Sixty years of CA: a cancer journal for clinicians. CA Cancer J Clin. 2010 Nov-Dec;60(6):345-50. doi: 10.3322/caac.20088.

  PMID: 21075954 RESULT

• Buzdar A. The place of chemotherapy in the treatment of early breast cancer. Br J Cancer. 1998 Sep;78 Suppl 4(Suppl 4):16-20. doi: 10.1038/bjc.1998.757.

  PMID: 9741784 RESULT

• Dezentje VO, Guchelaar HJ, Nortier JW, van de Velde CJ, Gelderblom H. Clinical implications of CYP2D6 genotyping in tamoxifen treatment for breast cancer. Clin Cancer Res. 2009 Jan 1;15(1):15-21. doi: 10.1158/1078-0432.CCR-08-2006.

  PMID: 19118028 RESULT

• Blackburn HL, Ellsworth DL, Shriver CD, Ellsworth RE. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy. Cancer Causes Control. 2015 Mar;26(3):319-32. doi: 10.1007/s10552-014-0519-7. Epub 2015 Jan 3.

  PMID: 25554091 RESULT

• Brauch H, Schroth W, Eichelbaum M, Schwab M, Harbeck N; in cooperation with the AGO TRAFO Comission. Clinical Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast Cancer. Breast Care (Basel). 2008;3(1):43-50. doi: 10.1159/000114642. Epub 2008 Feb 22.

  PMID: 20824020 RESULT

• 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. doi: 10.1093/jnci/dji005.

  PMID: 15632378 RESULT

• Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005 Dec 20;23(36):9312-8. doi: 10.1200/JCO.2005.03.3266.

  PMID: 16361630 RESULT

• Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007 Nov 20;25(33):5187-93. doi: 10.1200/JCO.2007.12.2705.

  PMID: 18024866 RESULT

• Thompson AM, Johnson A, Quinlan P, Hillman G, Fontecha M, Bray SE, Purdie CA, Jordan LB, Ferraldeschi R, Latif A, Hadfield KD, Clarke RB, Ashcroft L, Evans DG, Howell A, Nikoloff M, Lawrence J, Newman WG. Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy. Breast Cancer Res Treat. 2011 Jan;125(1):279-87. doi: 10.1007/s10549-010-1139-x. Epub 2010 Sep 1.

  PMID: 20809362 RESULT

• Margolin S, Lindh JD, Thoren L, Xie H, Koukel L, Dahl ML, Eliasson E. CYP2D6 and adjuvant tamoxifen: possible differences of outcome in pre- and post-menopausal patients. Pharmacogenomics. 2013 Apr;14(6):613-22. doi: 10.2217/pgs.13.47.

  PMID: 23570465 RESULT

• Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics. 2002 Mar;3(2):229-43. doi: 10.1517/14622416.3.2.229.

  PMID: 11972444 RESULT

• Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics. 2007 Feb;17(2):93-101. doi: 10.1097/01.fpc.0000239974.69464.f2.

  PMID: 17301689 RESULT

• Qian JC, Xu XM, Hu GX, Dai DP, Xu RA, Hu LM, Li FH, Zhang XH, Yang JF, Cai JP. Genetic variations of human CYP2D6 in the Chinese Han population. Pharmacogenomics. 2013 Nov;14(14):1731-43. doi: 10.2217/pgs.13.160.

  PMID: 24192122 RESULT

• Xu Y, Sun Y, Yao L, Shi L, Wu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, He L, Li P, Xie Y. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008 Aug;19(8):1423-1429. doi: 10.1093/annonc/mdn155. Epub 2008 Apr 11.

  PMID: 18407954 RESULT

• Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015 Jan 29;372(5):436-46. doi: 10.1056/NEJMoa1412379. Epub 2014 Dec 11.

  PMID: 25495490 RESULT

• Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Lang I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. doi: 10.1056/NEJMoa1404037. Epub 2014 Jun 1.

  PMID: 24881463 RESULT

• Janni W, Hepp P. Adjuvant aromatase inhibitor therapy: outcomes and safety. Cancer Treat Rev. 2010 May;36(3):249-61. doi: 10.1016/j.ctrv.2009.12.010. Epub 2010 Feb 4.

  PMID: 20133065 RESULT

MeSH Terms

Conditions

Breast Neoplasms

Interventions

exemestane; Tamoxifen

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy Director of Medical Oncology

Model Details: randomized, open-label, parallel, active-controlled superiority clinical study

Study Record Dates

• First Submitted: April 24, 2017
• First Posted: May 2, 2017
• Study Start: August 9, 2018
• Primary Completion: October 30, 2023
• Study Completion: October 30, 2023
• Last Updated: October 31, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)