Abstract OT1-4-03: Phase I study of erlotinib and metformin in triple negative breast cancer
Authors: Maurer M , Kalinsky K , Forman J , Jayasena R , Crew K , Hershman D 
Published: August 2014

Abstract
Background: Triple negative breast cancers (TNBC) are enriched for increased phosphorylated EGFR expression and decreased expression of PTEN. We found that combined treatment of metformin and erlotinib induces cell death in a subset of TNBC cell lines with evidence of combined enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation. Analysis of TNBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination, which was confirmed using isogenic cell line models with and without PTEN expression. The inhibitory effects of combined erlotinib and metformin were confirmed in mouse xenografts of PTEN null TNBC breast cancer cell lines. These data provided a rationale for clinical translation and testing in advanced TNBC patients.
Trial Design: Single institution expanded Phase I design in patients with advanced TNBC. Erlotinib dosing will start and remain at 150 mg. Due to frequent GI upset in patients starting metformin, the dose of metformin will be titrated up to the assigned dose level over 2 weeks. The first metformin dose level will be 850 mg twice daily and will be escalated to its maximum FDA approved dose of 850 mg three times daily. Dose escalation will follow the standard 3 + 3 design. Dose limiting toxicities will be determined during the first 5 weeks of therapy. One metformin dose de-escalation level to 500 mg twice daily is allowed. Cycles will be defined as three weeks of treatment, and response assessments will be performed after every three cycles.
Main Eligibility Criteria:
1. Pathologic diagnosis of TNBC.
2. Measurable or non-measurable disease.
3. At least one prior treatment for metastatic disease.
4. ECOG PS = 0-2.
5. Prior metformin or EGFR targeted therapy.
6. Fasting blood glucose level &lt; 126 mg/dl.
7. Normal renal function.
8. Available archived tumor tissue.
Specific Aims: The primary endpoints are defining the maximum tolerated dose (MTD) of metformin in combination with 150 mg erlotinib, and for the extended phase, determining the potential for clinical benefit by treating 14 patients at the MTD with the goal of rejecting the null hypothesis that the regimen is futile. Clinical benefit is defined as either partial response or lack of progression after 18 weeks of therapy (stable disease). Secondary endpoints include: 1) progression free survival, and 2) pharmacodynamic assessment of the phosphorylation status of AMPK and EGFR from pre- and on-treatment skin biopsies. The exploratory endpoint will be assessment of the status of EGFR, PTEN, LKB1, and 4EBP1 from available patient tumor samples to correlate against treatment response.
Statistical Methods: If one patient meets the primary endpoint, among the 14 patients treated at the MTD, then the regimen will be considered worthy of further investigation.
Target Accrual: 17-20 patients. Four patients accrued as of June 2013. Accrual completion expected June 2015.
Contact: Matthew Maurer, Columbia University Medical Center, mm2058@columbia.edu.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-4-03.