Efficacy and safety of leuprorelin acetate 6-month depot, TAP-144-SR (6M), in combination with tamoxifen in postoperative, premenopausal patients with hormone receptor-positive breast cancer: a phase III, randomized, open-label, parallel-group comparative study

A phase III, randomized, open-label, parallel-group comparative study of TAP-144-SR (6M) to TAP-144-SR (3M) was conducted to evaluate the efficacy, safety, and pharmacokinetics of the 2 formulations and hormone levels in postoperative, premenopausal patients with endocrine-responsive breast cancer. Following a 4-week screening period, eligible patients were randomly assigned at a 1:1 ratio to receive injection of either TAP-144-SR (6M) 22.5 mg (6M group) or TAP-144-SR (3M) 11.25 mg (3M group) for 96 weeks using dynamic allocation with the number of positive axillary lymph nodes (0, 1–3, ≥4), tumor diameter (≤2.0, >2.0 cm), estrogen receptor (ER)/progesterone receptor (PgR) status (ER+/PgR+, ER+/PgR−, ER−/PgR+), age (at the time of consent; ≤39, 40–44, ≥45 years), pre- and post-operative chemotherapy (presence, absence), and study site as factors. All patients in both groups concomitantly received oral tamoxifen citrate (20 mg daily) throughout the 96-week study period.

This study was conducted in accordance with the International Conference on Harmonisation of Good Clinical Practice Guidelines, the principles of the Declaration of Helsinki, and all applicable laws and regulations, at 20 medical centers in Japan between April 2012 and December 2014. The protocol was reviewed and approved by the Institutional Review Boards of all study participating sites. All patients provided written informed consent before enrollment. The clinical trial registration number is NCT01546649.

Japanese premenopausal patients with histologically confirmed primary breast cancer who met the following criteria were eligible: age ≥20 years; both or either ER+ or PgR+, and human epidermal growth factor receptor type 2 (HER-2)-negative primary tumor; T1–T3, any N, and M0 according to the TNM classification; any type of surgical procedure (in case of breast-conserving surgery, postoperative radiation to the breast was required); any type of preoperative and/or postoperative adjuvant chemotherapy prior to enrollment; history of regular menstruation or follicle-stimulating hormone (FSH) of <40 mIU/mL and E₂ of ≥10 pg/mL within 12 weeks prior to enrollment and not having chemical menopause (FSH of ≥40 mIU/mL and E₂ of <10 pg/mL) within 12 weeks after completion of the postoperative chemotherapy; capable of receiving the study drug and tamoxifen within 12 weeks after surgery or after postoperative chemotherapy completion prior to enrollment; Eastern Cooperative Oncology Group performance status of Grade 0 or 1.

Exclusion criteria included the following: endocrine therapy prior to surgery or postoperative endocrine therapy before enrollment; bilateral oophorectomy or ovarian irradiation; inflammatory breast cancer or bilateral breast cancer; non-invasive ductal carcinoma, multiple cancers or a history of cancer in other organs; QTcF interval exceeding 460 ms on the 12-lead electrocardiogram (ECG) at screening.

The primary endpoint was the suppression rate of serum E₂ to the menopausal level (≤30 pg/mL), which is the best index of the medicinal effect of leuprorelin, from Week 4 through Week 48. The secondary endpoints included: serum E₂, LH, and FSH concentrations; disease-free survival [DFS; defined as the time from random assignment to disease event (recurrence, second primary cancer, or death)] and distant DFS [DDFS; defined as the time from random assignment to disease event (distant recurrence, second primary cancer, or death)] throughout the study period as measures of the long-term efficacy. All the serum hormone concentrations were measured at a central laboratory (SRL Medisearch Inc., Tokyo, Japan). Electrochemiluminescence immunoassay for E₂ (ECLusys^®E2III, Roche Diagnostics K.K., Tokyo, Japan), chemiluminescence immunoassay for LH (ARCHITECT^® · LH, Abbott Japan, Chiba, Japan) and chemiluminescence immunoassay for FSH (ARCHITECT^® · FSH, Abbott Japan, Chiba, Japan) were used to measure each serum hormone concentration.

Pharmacokinetic analysis was performed by measuring the serum concentrations of unchanged TAP-144 using LC/MS/MS from the start of the study drug administration through Week 48.

Safety data were obtained from the findings of clinical signs/symptoms, body weight, vital signs, laboratory test results, 12-lead ECG, and bone mineral density (BMD) measured by dual-energy X-ray absorptiometry throughout the study period. Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

The required sample size was estimated as 74 subjects in each treatment group, a total of 148 subjects, based on which the conditions were set as a non-inferiority margin of 10 %, with a two-sided alpha level of 0.05, ensuring 80 % power. Taking a possible drop-out rate of 10 % into consideration, 82 patients in each treatment group, thus a total of 164 patients were required.

The Full Analysis Set (FAS) was defined as all patients who were randomized and received at least 1 dose of the study drug, and the Hormone Analysis Set (HAS) was defined as the patients who had no major protocol deviations, and in whom the primary endpoints were evaluable. The FAS was used for the primary and secondary endpoints and the HAS was used to examine the robustness of the results of the primary analysis. The treatment difference [TAP-144-SR (6M) − TAP-144-SR (3M)] and the two-sided 95 % confidence interval (CI) were calculated by a method based on the Wilson score method [13]. If the lower bound of the two-sided 95 % CI was greater than the prespecified non-inferiority margin of −10 %, clinical non-inferiority of TAP-144-SR (6M) to TAP-144-SR (3M) would be declared. Summary statistics were obtained for the secondary efficacy endpoints. Serum E₂ concentrations lower than or equal to the limit of quantification (10 pg/mL) were considered to be 0 pg/mL. DFS and DDFS were estimated by the Kaplan–Meier method.

For the safety analysis, AEs and their severity were analyzed by treatment group. AEs were summarized in the Safety Data Analysis Set (SAS) defined as all patients who were randomized and received at least 1 dose of the study drug and were coded by the System Organ Class Preferred Terms based on the Medical Dictionary for Regulatory Activities (MedDRA) terminology, version 16.1.

As for pharmacokinetic analysis, summary statistics were calculated for serum unchanged-TAP-144 concentrations through Week 48 in the Pharmacokinetics Analysis Set (PAS; defined as the population of patients in the FAS in whom serum unchanged-TAP-144 concentrations were appropriately measured), and for pharmacokinetic parameters in patients in whom serum unchanged-TAP-144 concentrations were measured at 3 and 6 h after the study drug administration in the PAS.

Figure 1 shows the patient disposition. Of the 180 patients who provided written informed consent, a total of 167 patients were randomized, 83 patients received TAP-144-SR (6M) and 84 patients received TAP-144-SR (3M). Overall, 150 patients (75 patients in each treatment group) completed the 96-week study treatment, and the majority of patients (92.8 and 91.7 % in the 6M and 3M groups, respectively) received the maximum doses (4 doses and 8 doses in the 6M and 3M groups, respectively).

The baseline demographic and disease characteristics of patients are summarized in Table 1. No major differences were observed in the baseline characteristics between the treatment groups.

Serum TAP-144 concentrations rapidly increased immediately after the administration of TAP-144-SR (6M), and then rapidly decreased through Day 8 (Fig. 3). Thereafter, they increased again from Week 2 through Week 3, and gradually declined through Week 24, showing a double-peak of TAP-144. The profile of serum TAP-144 concentrations after the initial administration was similar to that after the second administration. In contrast, serum TAP-144 concentration rapidly increased 1 h after the administration of TAP-144-SR (3M), and then gradually declined during the period from 3 to 12 h. The maximum drug concentration (C _max) in the 6M group was approximately one-fifth of that in the 3M group, and the area under the blood concentration–time curve in the 6M group was approximately 1.8 times that in the 3M group (data not shown). No obvious accumulation was observed either with TAP-144-SR (6M) or TAP-144-SR (3M).

Throughout the study period, 98.8 % (82/83) and 97.6 % (82/84) of patients experienced AEs in the 6M and 3M groups, respectively The most common AEs were hot flush, followed by nasopharyngitis, radiation skin injury, injection site induration, injection site pain, white blood cell count decreased, headache and arthralgia, with no significant differences between the 2 groups (Table 3). The incidence of a series of injection site reactions (induration, pain, erythema, etc.) was 57.8 % (48/83) and 60.7 % (51/84) of patients in the 6M and 3M groups, respectively.

Most AEs were Grade 1 or 2 in severity. AEs of Grade 3 were reported in 14 (16.9 %) and 18 patients (21.4 %) in the 6M and 3M groups, respectively; AEs of Grade 4 were reported in 1 patient (1.2 %) in the 6M group. Drug-related AEs of ≥Grade 3 were anal fistula, blood triglycerides increased, liver function tests abnormal, hyperlipidaemia and interstitial lung disease (1 patient each) in the 6M group, and gamma-glutamyltransferase increased (3 patients), hypertension (2 patients), weight increased, neutropenia, blood triglycerides increased and interstitial lung disease (1 patient each) in the 3M group.

Serious AEs (SAEs) were reported in 6 (7.2 %) and 7 patients (8.3 %) in the 6M and 3M groups, respectively, and included 3 drug-related SAEs: interstitial lung disease in 1 patient in each group and anal fistula in 1 patient in the 6M group.

AEs leading to discontinuation of the study drug occurred in 4 (4.8 %) and 5 patients (6.0 %) in the 6M and 3M groups, respectively. Of these, AEs for which a causal relationship could not be ruled out were found in 4 patients (palpitations in 1 patient, joint stiffness, menopausal symptoms, and dry skin in 1, liver function test abnormal in 1, and interstitial lung disease in 1) in the 6M group, and in 4 patients (radiation pneumonitis in 1 patient, gamma-glutamyltransferase increased in 1, genital hemorrhage in 1, and interstitial lung disease in 1) in the 3M group. There were no deaths throughout the study period.

For ECG data analysis, QTcF intervals declined from the baseline values through 6 h after the study drug administration in both treatment groups, and no transient prolongation of QTcF intervals was detected at around the time of the C _max. The mean changes (SD) in QTcF intervals from baseline were 9.7 (15.36) ms at Week 4, 9.2 (14.76) ms at Week 48, and 8.4 (14.73) ms at Week 96 in the 6M group, and 11.4 (13.83) ms at Week 4, 10.8 (15.13) ms at Week 48, and 13.1 (22.03) ms at Week 96 in the 3M group. Prolonged QTcF intervals of approximately 10 ms were observed from Week 4 through Week 96 in both treatment groups. Prolonged QTcF intervals of >60 ms from baseline were reported in 3 patients (2 and 1 in the 6M and 3M groups, respectively), which were transient and detected only at 1 assessment time point in each patient. At 7 institutions where it was possible to measure ECG at all assessment points, including 3 and 6 h after the study drug administration, the same ECG for all patients was used, and a total of 54 patients were interpreted at the central reading center. Prolonged QTcF intervals of approximately 15 ms were observed from Week 4 through Week 96 in both treatment groups. Similar prolonged QTcF intervals to those observed in the ECG measurements at the institutions were also observed in the measurements at the central reading center.

For BMD of the lumbar spine (L₂–L₄), the mean change from baseline tended to gradually decline over time in both treatment groups. The mean change rate in BMD from baseline at Week 48 and Week 96 were −5.1 % (95 % CI −5.8 to −4.5) and −7.6 % (95 % CI −8.5 to −6.8) in the 6M group, and −4.7 % (95 % CI −5.5 to −4.0) and −6.7 % (95 % CI −7.7 to −5.8) in the 3M group. There were no significant differences in the BMD reduction between the treatment groups (Fig. 4).