OT2-01-01: International Breast Cancer Study Group (IBCSG) Trial 22–00: Low-Dose Cytotoxics as Maintenance “Anti-Angiogenesis Treatment” Following Adjuvant Induction Chemotherapy for Patients with ER-Negative and PgR-Negative Breast Cancer.
Authors: Colleoni M 
Published: June 2012

Abstract
Background Patients with endocrine responsive disease benefit from five years of endocrine therapy after chemotherapy, but for patients with endocrine non-responsive disease there is no evidence of benefit of extending treatment beyond a standard duration (three to six months). The low-dose maintenance chemotherapy (metronomic cyclophosphamide and methotrexate (CM) given orally) regimen being tested in this trial was developed in advanced disease and resulted in tumor shrinkage even in heavily pretreated patients. The mechanism of this effect might be through anti-angiogenesis or by interference with progression of the stromal structure of metastases.
Trial Design This randomized phase III trial compares 12 months of CM Maintenance chemotherapy (CMM) (cyclophosphamide 50/mg/day orally continuously for 1 year; methotrexate 2.5 mg/twice a day orally days 1 and 2 of every week for 1 year) vs. no CMM, following breast cancer surgery and standard induction chemotherapy. Stratification factors: institution, menopausal status, induction regimen. Concurrent trastuzumab is permitted for patients with HER2−positive disease.
Major Eligibility Criteria
-Histologically proven primary breast cancer
-Both estrogen and progesterone receptor status negative (&lt;10% of tumor cells positive by IHC)
-Known HER2 status
-Approved induction chemotherapy must begin within 8 weeks after definitive surgery
-Pathological axillary staging
-Pre-randomization Quality of Life Forms completed
Specific Aim
To evaluate the efficacy of a low-dose chemotherapy regimen, hypothesized to have anti-angiogenic activity, administered following a standard chemotherapy program, in patients whose tumors are not endocrine therapy-responsive.
Statistical Methods
The primary analysis population will be intention-to-treat (all randomized patients). The primary endpoint, disease-free survival (DFS), will be compared between treatment arms using a two-sided stratified logrank test with an alpha level of 0.05.
Based on results from ER-negative populations in other IBCSG trials, we assume that the overall five-year disease-free survival for the group receiving induction chemotherapy alone will be 70%. Due to a relatively high non-adherence rate (14% of 398 early patients randomized to CMM did not start CM), the original sample size of 900 was increased to 1080 (October 2010), and the target number of events from 256 to 307. With this revision detection of a true hazard ratio of 0.70 will be achieved with a power of 72% despite a 15% non-adherence rate in the CMM group.
Present and Target Accrual
Target: 1080 patients. Present: 967 (as of June 1, 2011).
Related Research
Serum Substudy for 170 patients will evaluate differences from baseline to 18 months post baseline in serum VEGF, VCAM-1 and NRP protein values.
Patient self-reported quality-of-life assessments are collected at baseline and months 9, 12, 18, 24 for all patients.
Central pathology review of histology, grade, ER, PgR, Her2, and Ki-67 for all patients is ongoing.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-01.