A Phase 3 Comparative Study of TAP-144-SR(6M) in Postoperative and Hormone Therapy-naïve Patients With Premenopausal Breast Cancer

Study Overview
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Brief Summary
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Hormone dynamics, pharmacokinetics, safety, and efficacy of TAP-144-SR(6M) will be evaluated against TAP-144-SR(3M) in postoperative and hormone therapy-naïve patients with premenopausal breast cancer

Conditions
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Premenopausal Breast Cancer

Intervention / Treatment
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* Drug: TAP-144-SR(6M)
* Drug: TAP-144-SR(3M)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has histopathologically-confirmed primary breast cancer in Japanese. The participant is aged 20 years or older when informed consent is obtained The participant has estrogen receptor (ER)-positive tumor cells and/or progesterone receptor (PgR)-positive primary tumor. And HER-2 is negative. The participant has breast cancer in the clinical stages of T1-T3, N-any and M0 by TNM classification (the seventh edition, proposed by UICC in 2009). (No distant metastasis to lung, liver and bone should be confirmed on the image-based diagnosis at study enrollment. The image taken within 12 weeks prior to study enrollment is also available for the diagnosis.) The number of axillary lymph node metastasis is not limited. Any operative procedure for breast cancer is acceptable. In principle, after breast-conserving surgery, the participant will receive postoperative radiation to the conserving breast. Neoadjuvant chemotherapy and adjuvant chemotherapy prior to study enrollment are acceptable. (It is advisable the same kind of chemotherapy is performed at each site.) The participant has a history of regular menstrual periods within 12 weeks prior to study enrollment, or the participant has FSH of less than 40 mIU/mL and E2 of 10 pg/mL or more measured within 12 weeks prior to study enrollment. The participant has not had a chemical menopause (i.e., FSH of less than 40 mIU/mL and E2 of 10 pg/mL or more) within 12 weeks after completing adjuvant chemotherapy. The participant is in a condition to receive study drug and Tamoxifen (TAM) within 12 weeks after surgery or after adjuvant chemotherapy prior to study enrollment. Adjuvant chemotherapy prior to study is required to have been completed at the time of study enrollment. The participant has ECOG performance status of grades 0 or 1 at the time of study enrollment. The participant meets the following criteria of hepatic, renal and bone marrow functions on the laboratory test results at screening: Hepatic function: AST (GOT) ≤ 3.0 times the upper limit of normal (ULN) ALT (GPT) ≤ 3.0 times the ULN Renal function: serum creatinine level < 1.5 times the ULN Bone marrow function : white blood cell count ≥ 3,000/mm3 platelet count ≥ 100,000/μL hemoglobin ≥ 10.0g/dL The participant agrees to use a non-hormonal method of contraception through the study period. Exclusion Criteria: The participant has received neoadjuvant or adjuvant hormonal therapy for the latest breast cancer surgery. The participant has received bilateral oophorectomy and bilateral ovarian irradiation. The participant has inflammatory breast cancer or bilateral breast cancer. The participant has non-invasive ductal carcinoma. The participant has multiple primary cancers, or a history of carcinoma in other organs. The participant is pregnant or breast-feeding. The participant has a history of hypersensitivity to synthetic LH-RH, LH-RH derivative, TAM, TAM analogue (antiestrogen) or any component of the study drug. The participant has a history of, or has been diagnosed with thromboembolism including myocardial infarction, cerebral infarction, venous thrombosis, and pulmonary embolism, or cardiac failure. Patients whose QTcF interval exceeded 460 msec on the 12-lead electrocardiogram at screening.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAP-144-SR(6M)<br>TAP-144-SR(6M) 22.5 mg, injection, treatment interval 24 weeks for up to 96 weeks. | Drug: TAP-144-SR(6M)<br> <br> |
| Active Comparator: TAP-144-SR(3M)<br>TAP-144-SR(3M) 11.25 mg, injection, treatment interval 12 weeks for up to 96 weeks. | Drug: TAP-144-SR(3M)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Suppressive Effect of Serum Estradiol (E2) to Menopausal Level (=<30 pg/mL) From Week 4 Through Week 48 | Comparison of both the treatment groups was done by assessing the suppressive effect on serum E2 concentration maintained at menopausal level (=<30pg/mL). Suppression rate was calculated as proportion of participants maintained at menopausal level. | Week 4 up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Serum E2 | The measure indicates serum E2 concentration at baseline and post-baseline time points. | Baseline, Hour (hr) 1, 3, 6 on Day 1, Day 2, 3, 4, 8, 15, 22, 29, 57, 85, 113, 141, 169, 176, 183, 197, 225, 253, 281, 309, 337, 421, 505, 589 and 673 | 
| Concentration of Serum Luteinizing Hormone (LH) | This measure indicates serum LH concentration at baseline and post-baseline time points. It was measured in milli-international units per milliliter (mIU/mL). | Baseline, Hour 1, 3, 6 on Day 1, Day 2, 3, 4, 8, 15, 22, 29, 57, 85, 113, 141, 169, 176, 183, 197, 225, 253, 281, 309, 337, 421, 505, 589 and 673 | 
| Concentration of Follicle Stimulating Hormone (FSH) | This measure indicates serum FSH concentration at baseline and post-baseline time points. | Baseline, Hour 1, 3, 6 on Day 1, Day 2, 3, 4, 8, 15, 22, 29, 57, 85, 113, 141, 169, 176, 183, 197, 225, 253, 281, 309, 337, 421, 505, 589 and 673 | 
| Disease Free Survival (DFS) Rate at Week 96 | DFS is defined as time from randomization to earliest day of onset the events, recurrence [including recurrence in the ipsilateral breast], secondary cancer [including breast cancer in the contralateral breast] and death. DFS at Week 96 was defined as the percentage, calculated with Kaplan-Meier method, of participants did not experience any events at Week 96 since the randomization. | Week 96 | 
| Distant Disease Free Survival (DDFS) Rate at Week 96 | DDFS is defined as time from randomization to earliest day of onset the events, distant recurrence, secondary cancer [including breast cancer in the contralateral breast] and death. DDFS at week 96 was defined as the percentage calculated with Kaplan-Meier method, of participants did not experience any events at week 96 since the randomization. | Week 96 | 
| Serum Unchanged TAP-144 Level | This measure indicates the unchanged TAP-144 level in serum. | Baseline, Hour 1, 3, 6 on Day 1, Day 2, 3, 4, 8, 15, 22, 29, 57, 85, 113, 141, 169, 176, 183, 197, 225, 253, 281, 309 and 337 | 
| QT Interval Measured by 12-lead Electrocardiogram (ECG) | 12-lead electrocardiography measurement was performed in supine position after 5 minutes at rest. Each measurement was recorded continuously for 10 seconds at the recording speed of 25 millimeter/second (mm/second). | Baseline, Hour 1, 3, 6 on Day 1, Day 29, 85, 169 and 337 |