MORE-T: Higher Dose Preoperative taMOxifen in Premenopausal bREast Cancer Patients
Study Details
Study Description
Brief Summary
MORE-T trial is designed to investigate the effect of Tamoxifen 40mg (vs. Tamoxifen 20mg) for 2wks in presurgical setting.
The greater reduction in Ki-67 might be observed in Tamoxifen 40mg arm compared to the Tamoxifen 20mg arm.
Open Label, Phase 2, Randomized with 1:1 allocation
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Tamoxifen
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Selective estrogen receptor modulator
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It has been the main endocrine treatment for decades
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Tamoxifen is a major endocrine treatment option, particularly for women who still have a significant ovarian estrogenic activity that cannot be controlled by aromatase inhibitors.
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The prospective clinical trials have shown that tamoxifen 20mg has comparable efficacy against tamoxifen 40mg with fewer toxicities in breast cancer patients. However, most of the trials comparing tamoxifen 20mg and 40mg were done in postmenopausal women.
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Previous studies have suggested that the higher dose of tamoxifen can induce higher serum levels of the drugs, and increasing tamoxifen dose up to 40mg can induce clinical responses in tumors resistant to 20mg of tamoxifen. A recent prospective trial demonstrated that increasing the dose of tamoxifen from 20 mg to 40 mg can compensate for the reduced endoxifen level in intermediate or poor metabolizer tamoxifen metabolizers based on CYP2D6 genotyping.
Ki-67
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Ki-67 antigen, a nuclear antigen, and marker of cell proliferation, is expressed during all cell-cycle phases except for G0, with levels peaking during mitosis.
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Reduction in Ki67 expression is reported to correlate with treatment response to endocrine therapy in ER+ breast cancer, and Ki-67 in short-term neoadjuvant studies has been shown to predict outcome in long-term adjuvant trials.
As the investigators have a higher proportion of young aged, premenopausal breast cancer patients in Korea, the investigators had an opportunity to examine the prognostic impact of young age in breast cancer recurrences and survivals. The institutional database and the Korean nationwide breast cancer registry data have all shown that the poor prognostic effect of a young age was exclusively seen in women with hormone receptor-positive breast cancers, and the effect was potentially due to the resistance to the tamoxifen. As therapeutic options diversify, studies on factors predictive of sensitivity to various endocrine therapies are needed to help select the appropriate treatment for young premenopausal breast cancer patients.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Tamoxifen 40mg Tamoxifen 20mg b.i.d - Participants will be treated for 14 days. |
Drug: Tamoxifen Oral Product
Experimental arm will have tamoxifen 40mg and active comparator arm will have tamoxifen 20mg for 14 days.
Other Names:
Diagnostic Test: Assessment of Ki-67
Paired biopsies (before and after tamoxifen therapy) will be required for the assessment of Ki-67.
Procedure: Surgery
The surgery date should be fixed before randomization. The surgery is to be performed within 1 day after the last dose of study treatment.
|
| Active Comparator: Tamoxifen 20mg Tamoxifen 10mg b.i.d - Participants will be treated for 14 days. |
Drug: Tamoxifen Oral Product
Experimental arm will have tamoxifen 40mg and active comparator arm will have tamoxifen 20mg for 14 days.
Other Names:
Diagnostic Test: Assessment of Ki-67
Paired biopsies (before and after tamoxifen therapy) will be required for the assessment of Ki-67.
Procedure: Surgery
The surgery date should be fixed before randomization. The surgery is to be performed within 1 day after the last dose of study treatment.
|
Outcome Measures
Primary Outcome Measures
- Changes in Ki-67 level [After 14-day of tamoxifen treatment]
Change in Ki67 (percentage of positive tumor cells tested by immunohistochemistry [IHC] - digital Image Analysis ) after a 14-day treatment period compared to baseline.
Secondary Outcome Measures
- Changes in Ki67 according to CYP2D6 genotyping [After 14-day of tamoxifen treatment]
Change in Ki67 (percentage of positive tumor cells tested by immunohistochemistry [IHC]) after a 14-day treatment period compared to baseline according to CYP2D6 genotyping.
- The proportion of participants with relative decrease from baseline of Ki-67 ≥50% [After 14-day of tamoxifen treatment]
The proportion of participants with relative decrease from baseline of Ki-67 (% positive tumor cells) ≥50%.
- AE [After 14-day of tamoxifen treatment]
Adverse events
- SAE [After 14-day of tamoxifen treatment]
Serious adverse events
- PEPI (Preoperative Endocrine Prognostic Index) score [After 14-day of tamoxifen treatment]
The PEPI score (ranged 0 to 12, lower score mean a better outcome) is the sum of the risk points of the pathological tumor (pT) stage, the pathological node (pN) stage, Ki67 levels and ER status (Allred score).
- RFS [5 years]
Relapse-free survival rate
- OS [5 years]
Overall survival rate
Eligibility Criteria
Criteria
Inclusion Criteria:
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Histopathologically and immunohistochemically confirmed ER+ and HER2- Premenopausal BC patients
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Tumor size >0.5cm on USG
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Stage I-IIIA BC and planned curative surgery
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ECOG 0-2
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Patients with adequate bone marrow function
- Hemoglobin 10 g/dL, ANC 1,500/mm3, Plt 100,000/mm3
- Patients with adequate kidney function
- serum Cr ≤ 1.5 mg/dL
- Patients with adequate liver function
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Bilirubin: ≤ 1.5 times of upper normal limit
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AST/ALT: ≤ 1.5 times of upper normal limit
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Alkaline phosphatase: ≤ 1.5 times of upper normal limit
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Patients who decided to voluntarily participate in this trial with written informed consent
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Premenopausal women : women who has not removed both ovaries, women who had menses in recent 1 year and FSH level is less than 30mIU/ml
Exclusion Criteria:
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Previous history of ipsilateral invasive breast cancer, in situ lesion
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Previous history of chemotherapy or endocrine therapy on contralateral BC for the past 2 years
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Patients who has distant metastasis
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Patients who is pregnant or breastfeeding
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Hormon receptor negative BC
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Her-2 positive BC
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Diagnosed pituitary adenoma
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Women who has endometriosis, uterine myoma, unknown vaginal bleeding
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Inability to understand and willingness to sign a written informed consent
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Patients with endometriosis, uterine fibroids, or unexplained vaginal bleeding
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Patients with a history of bleeding constitution, coagulopathy, or thromboembolism
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Patients who have administered a CYP3A inhibitor or inducer, CYP2D6 inhibitor, etc. within 4 weeks prior to randomization
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Seoul National University Hospital | Seoul | Korea, Republic of | 03080 |
Sponsors and Collaborators
- Seoul National University Hospital
Investigators
- Principal Investigator: Hyeong-Gon Moon, Seoul National University Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MORE-T trial