Study of Temsirolimus, Erlotinib and Cisplatin in Solid Tumors
This is a Phase I research study designed to determine the maximum tolerated doses of cisplatin, temsirolimus, and erlotinib in combination for treatment in triple negative breast cancer (TNBC) patients.
Triple Negative Breast Cancer
Drug: Temsirolimus, cisplatin, erlotinib
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Combined Temosirolimus, Erlotinib and Cisplatin in Advanced Solid Tumors|
- Maximum tolerated doses of cisplatin, temsirolimus, and erlotinib [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||September 2009|
|Estimated Study Completion Date:||September 2014|
|Estimated Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
Experimental: Temsirolimus, cisplatin, erlotinib
Cisplatin and temsirolimus will be administered weekly on days one and eight of a three week cycle.
Erlotinib will be taken by mouth daily
Drug: Temsirolimus, cisplatin, erlotinib
Cisplatin at 30mg/m2 and temosirolimus will be administered intravenously weekly on days one and eight of a three week cycle. Temosirolimus will not be given on week three (usually dosed weekly) for increased tolerability given its possible plasma accumulation during week three. Cisplatin will be given first over a 30 minute infusion with prehydration and temsirolimus will be given second over a 30 minute infusion during posthydration. Erlotinib will be taken by mouth daily starting at 100mg. On days of cisplatin and temosirolimus infusions, erlotinib should be taken at least two hours after the beginning of the temosirolimus infusion.
Dose escalation will follow the standard 3 by 3 design with three set dosing levels.
Dose Level 1: Temosirolimus 15mg, Erlotinib 100mg
Dose Level 2: Temosirolimus 15mg, Erlotinib 150mg
Dose Level 3: Temosirolimus 25mg, Erlotinib 150mg
The stratification of breast cancer patients for treatment targeting either the estrogen receptor (ER) or HER2 receptor based upon the measurement of ER/PR and HER2 in tumor tissue has revolutionized the treatment of breast cancer. However, the success of this stratification has resulted in the recognition that no effective rational treatment exists for patients that lack these receptors. The term "triple negative breast cancer" (TNBC) has been coined to define this class of unresponsive patients, which is based upon their lack of the hormone receptors for estrogen and progesterone and the HER2 oncogene. TNBC thus represents a form of breast cancer for which no targeted therapy is known.
Identifying and understanding the signaling pathways and receptors that contribute to triple negative tumor growth is therefore of high priority in order to develop rational therapies analogous to the ones that have already been developed for HER2 and ER.
TNBC is heterogeneous with regard to molecular alterations and prognosis and actually encompasses diverse forms of breast cancer; hence, no single therapeutic strategy is likely to be effective. However, subclassification of TNBC based upon the identification of distinct sets of molecular alterations has identified a basal like form of the disease with poor prognosis and enrichment for distinct molecular characteristics that we think is ripe for targeted therapeutic intervention based on clinical need and improved molecular understanding.
A phase I study of the combination of erlotinib and CCI779 (temsirolimus) in glioblastoma patients was reported at ASCO 2007. The erlotinib dose was fixed at 150 mg and the maximum tolerated dose of temsirolimus was reported to likely be 15 mg (1 of 6 patients with grade 3 rash). Rash, diarrhea, and mucositis were the encountered dose limiting toxicities. Pharmacokinetics and response data have yet to be reported. Therefore, the goal is to maintain target inhibition (both mTOR and EGFR) and minimize toxicity (in this case, rash). This toxicity may be explained in part by the interaction of erlotinib with temsirolimus metabolism. Erlotinib has been shown to reduce the clearance of the CYP450 3A4 substrate midazolam. Everolimus (RAD001) and temsirolimus are both CYP450 3A4 substrates. In a Phase I trial, erlotinib increased the systemic exposure of everolimus, which was significantly higher on day 22 (476 ± 161 ng*hr/mL) compared to day 8 (393 ± 156 ng*hr/mL; p = 0.020). A phase I of everolimus with gefitinib has also been reported, with MTDs: everolimus 5 mg, gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced doselimiting grade 5 hypotension and grade 3 stomatitis, respectively. Pharmacokinetics demonstrated no significant interaction between the agents. Thus, in Phase I trials, mTOR inhibitors and EGFR inhibitors have been safely given together at doses shown to inhibit their respective targets and Phase II studies are ongoing in advanced renal cell, pancreatic, glioma, and breast (not specifically TNBC) cancers.
The rationale for adding cisplatin to erlotinib and an mTOR inhibitor are many. Cisplatin is a known active cytotoxic against breast cancer. It has non overlapping toxicity with erlotinib and TORC1 mTOR inhibitors and patients are unlikely to have been previously treated with cisplatin. TNBC with mutant p53 are associated with an identified subset of cisplatin sensitive cell lines and p53 mutations are also associated with PTEN loss and EGFR overexpression. In, addition, synergistic interactions have been observed with the platinum agent carboplatin in breast cancer cell lines. Therefore, as a cytotoxic DNA damaging agent cisplatin could trigger apoptotic death in a cell whose PI3K survival pathways are effectively inhibited by mTOR inhibition and erlotinib.
|United States, New York|
|Columbia University Medical Center|
|New York, New York, United States, 10032|
|Principal Investigator:||Matthew Maurer, MD||Columbia University|