Abstract OT2-6-12: A randomized pacebo-controlled phase II trial evaluating the effect of hedgehog inhibitor LDE225 on bone marrow disseminated tumor cells in women with early stage estrogen receptor negative and HER2 negative breast cancer
Authors: Aft R , Weilbaecher K , Trinkaus K , Watson M , Bernadt C , Crouch E , Dahiya N , Ellis M , Ma C 
Published: August 2014

Abstract
Background: 20% of invasive breast cancers are triple negative (TN). Chemotherapy improves the outcome for a subset of these patients. Recurrence rates of 40-50% have been reported in those patients who do not achieve a complete pathological response to neoadjuvant therapy. Currently, there are no targeted therapies to TN cancers. Data suggest that micrometastases or disseminated tumor cells (DTCs) that persist despite chemotherapy are enriched with cells that have stem cell-like features. The Hedgehog (Hh) signaling pathway, which is involved in modulating epithelial-mesenchymal transition and maintenance of breast cancer stem cells, is an attractive therapeutic target for patients with TN tumors. In preclinical models, we have shown that Hh inhibition reduced breast cancer growth and metastasis.
Trial Design: This is a placebo-controlled, double blinded, randomized phase II trial in early stage TN breast cancer patients with detectable DTCs in their bone marrow (BM) at the completion of all therapy. LDE225 is administered at 400 mg orally daily for a 28 day cycle for 20 cycles. After 6 cycles, BM will be collected for analysis.
Specific Aims: The primary endpoint is the elimination of DTCs after 6 cycles of LDE225. Additional endpoints include: 2-year disease-free survival (DFS) and overall survival (OS), effect on BM Ptch1 gene expression, toxicity profile of LDE225, DFS and OS in patients with no DTCs at screening versus DTC-positive patients in the placebo arm.
Eligibility: Patients with ER-/Her2- stage I-III invasive breast cancers who have completed all therapy and have detectable DTCs, as defined by a molecular based assay for DTCs performed in a CLIA-licensed facility are eligible.
Statistical Methods: Based on preliminary data, 60% of patients in the LDE225 arm are expected to be Ptch1 positive, and 50% of these patients are expected eliminate DTCs after 6 cycles of treatment. The expected clearance rate in the remaining 40% of the LDE225 arm is 5% with an overall clearance rate of 32%. In the placebo arm, the expected clearance rate is 5% regardless of Ptch1 status. A sample of 68 patients, 34 in each treatment arm, will have power ∼ 0.8 at a 0.05 significance level, after adjusting for one interim analysis, to detect a difference in DTC clearance rate of 32% in the LDE225 arm versus 5% in the placebo arm. Assuming that 40% of patients screened have detectable DTCs, approximately 170 patients will be screened to identify 68 with detectable DTCs.
Enrollment will be suspended for 3 months after the first 6 patients have been randomized to LDE225 therapy to allow time to document toxicity and adverse events. One interim analysis will be conducted after 50% of the patients have completed 6 months on study. The proportion of patients who are DTC-positive at 6 months will be estimated. The power of the study power to achieve its primary goal will be calculated conditional on results obtained to that point. The significance level of the final analysis will be adjusted to 0.048 in order to maintain an overall 0.05 significance level.
Accrual: Accrual is anticipated to begin August 2013. Target = 34 per arm. NCT01757327.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-12.