OT3-01-13: Phase One Trial of Combined Temsirolimus, Erlotinib, and Cisplatin in Advanced Solid Tumors.
Authors: Maurer M , Kalinsky K , Crew K , Jayasena R , Forman J , Lau Y-K , Shaw J , Parsons R , Hershman D 
Published: June 2012

Abstract
Background: A large subset of triple negative breast cancers (TNBC) are driven in part by a combination of activated growth factor signaling and downstream constitutive activation of the PI3K pathway. One therapeutic strategy is to target each driver simultaneously, requiring an understanding of drug interactions and combined toxicities. There is a strong correlation between loss of PTEN and both expression of EGFR and mutation of p53 in a subset of TNBC. Single agent trials targeting EGFR in breast cancer have been a disappointment likely, in part, due to constitutive downstream activation of PI3K, AKT and mTOR signaling, mainly through loss of PTEN expression. Preclinical studies have demonstrated 1) that resistance to EGFR-targeted therapy in the setting of an activated PI3K pathway can be overcome with rapamycin (which inhibits the TORC1 mTOR complex), and 2) that a subset of TNBC cells with p53 mutations are particularly sensitive to the DNA damaging agent cisplatin due to their high expression of p63 and p73. We have hypothesized that targeting the EGFR, PTEN and DNA damage pathways simultaneously with the rapalog temsirolimus, the EGFR inhibitor erlotinib, and cisplatin will provide therapeutic benefit in a definable subset of TNBC patients.
Design: Single institution phase one dose escalation trial of combined temsirolimus, erlotinib, and cisplatin in advanced solid tumor patients. Cisplatin and temsirolimus are given on day 1 and day 8 of 21 day cycles and erlotinib is taken daily without interruption. Patients are dose escalated using a standard 3+3 design. Cisplatin is given at a fixed dose of 30 mg/m2. Erlotinib was started at 100 mg and will be escalated to 150 mg. Temsirolimus was started at 15 mg, and after erlotinib escalation, will be escalated to 25 mg. The objectives of the study are: 1) characterize toxicity of the regimen and establish combined maximal tolerated dosing, 2) measure drug target inhibition by assessing EGFR, AKT, and mTOR activation in serial assessments of peripheral blood mononuclear cells and skin biopsies, 3) measure the pharmacokinetics of all three drugs in combination, and 4) exploratory assessment of molecular measures of PTEN, EGFR, and p53 status, and markers of activated downstream pathways in patient's archived pathology specimens to assess feasibility of identifying candidate biomarkers in future trials involving patients with TNBC. Eligibility criteria include one prior treatment for advanced disease, ECOG PS=0-1, measurable or non-measurable disease, available archived tumor sample, non-smoking, normal renal function, and lack of concurrent use of strong CYP3A4 inhibitors or inducers. Because of significant rash encountered in prior combination trials of EGFR and TORC1 inhibitors, a prophylactic oral doxycycline strategy supported by randomized trials is being employed. Current accrual is 6 out of a possible 18 patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-13.