The present multicenter, collaborative, open-label, Phase II clinical study of ISMT (SBCCSG 35; University Hospital Medical Information Network identifier: 000015971) was conducted in Japanese patients with MBC. Patients were recruited centrally. All patients provided written informed consent before enrollment. The study protocol was approved by the Institutional or Central Ethics Committee, and the study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and local ethical and legal regulations.
The primary endpoint for ISMT was time to treatment failure (TTF). The secondary endpoints for ISMT were progression-free survival (PFS), the overall response rate (ORR), overall survival (OS), safety, peripheral neuropathy, and the assessment of QOL.
At the time of entry, female patients were checked for age, height, body weight, history, complications, HER2/neu expression, hormone status, hematology, and blood chemistry.
Patients were eligible if they met the following requirements: 1) a female diagnosed with histologically or cytologically confirmed breast cancer; 2) a definite diagnosis of MBC; 3) 20 to 74 years of age; 4) Eastern Cooperative Oncology Group (ECOG) performance status, 0 to 2; 5) measurable lesions according to the response evaluation criteria in solid tumors (RECIST) ; 6) major organs of well-conserved functions (bone marrow, liver, kidney, and lungs), i.e., neutrophil count: ≥ 1500/μL, platelet count: 80,000/μL, hemoglobin: ≥ 9.0 g/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and serum creatinine: ≤ 2.5-fold the upper limit at the site; 7) grade ≤ 1 peripheral neuropathy at screening; 8) HER2-negative breast cancer; 9) an expected survival period of ≥ 3 months since the day of administration onset; 10) no clinical concerns about electrocardiograms; 11) no history of treatment with paclitaxel, bevacizumab, or eribulin after metastasis; and 12) written informed consent provided by the patient herself. The key exclusion criteria were as follows: systemic infection involving fever (≥ 38.0°C), history of hypersensitivity to investigational drugs and their solvents, metastasis to the brain requiring treatment, interstitial pneumonia, pulmonary fibrosis, poorly controlled hypertension or diabetes mellitus, active double cancer, history of mental impairment, central nervous system impairment, or cerebrovascular neuropathy, pregnancy, breast-feeding, or women of childbearing age, and patients whom the investigator or subinvestigator considered ineligible.
Patients, who achieved disease control, underwent ISMT until disease progression, development of intolerable toxicities, consent withdrawal, or investigator’s discretion to discontinue study treatment. Patients, who showed progressive disease (PD), underwent post therapy.
Patients received 3 cycles of induction therapy with paclitaxel (90 mg/m2 intravenously, once daily, on days 1, 8, and 15 followed by 1-week drug holiday) and bevacizumab (10 mg/kg intravenously after the completion of paclitaxel administration on days 1 and 15) as PB therapy, followed by 1-week drug holiday on day 22. In patients whose status was rated to be stable disease (SD) or better during cycle 3 of the PB regimen, switch maintenance therapy with eribulin 1.4 mg/m2 alone was conducted for 2 consecutive weeks during which they underwent infusion, once weekly, on days 1 and 8, as well as 1-week drug holiday at week 3. This cycle was repeated to the extent possible.
The following anticancer therapies were prohibited during the study period because of their potential effects on the assessment of the present clinical study: hormone therapy, immunotherapy, chemotherapy, radiotherapy, surgery, and systemic steroid therapy.
Tumor lesions were monitored at screening, within 10 weeks (± 3 weeks) after the date of first administration, and every 6 weeks (± 3 weeks) after the date of previous monitoring of the lesions thereafter. The date of monitoring could be rescheduled as needed when a deterioration in disease status was suspected. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 . Best overall response was determined based on the following criteria: complete response (CR), partial response (PR), PD, SD, and not evaluable (NE). TTF was defined as the time from enrollment to treatment discontinuation in ISMT due to any causes including disease deterioration, treatment-related adverse events (AEs), and death. PFS was defined as the time from enrollment to an event (death or deterioration, whichever earlier) in ISMT. Overall survival (OS) was defined as the time from enrollment to any confirmed all-cause death in ISMT.
AEs were graded according to the Common Terminology Criteria for Adverse Events, Japanese version 4.0 . AEs of the worst grade were recorded. Peripheral neuropathy was assessed for its time of development and severity, and the QOL of patients in ISMT was evaluated according to the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire .
The present study was subjected to the per-protocol analysis. Continuous variables are expressed as mean ± SD or counts and percentage, while categorical variables as median and interquartile range. The Kaplan-Meier estimates (median with 95% CI) were calculated for TTF, PFS, and OS. Descriptive statistics were calculated to assess safety data. Patients were analyzed on an intent-to-treat basis, and those who received at least one investigational drug were analyzed for safety.
In our prior clinical study , median TTF for the PB regimen was 6.2 months (95% CI: 4.2–8.3). Therefore, we established an expected TTF of 9.0 months and a threshold TTF of 6.2 months in patients with MBC whose response to treatment is SD or better after 3 cycles (2.8 months) of the PB regimen. During the entry and follow-up periods of 24 months and 12 months, respectively, 51 patients will endow the study with 80% power at an α level of 0.05. The target number of patients was set to 53 in consideration of patients who might be excluded from analysis due to ineligibility. A two-tailed p-value of < 0.05 was considered statistically significant. Wilcoxon’s signed rank test was conducted to test differences between the pre- and post-treatment scores of the FACT/GOG-Ntx questionnaire. All statistical analyses were made using SPSS version 19 (IBM, Armonk, NY).