Phase I Study of Combined Temosirolimus, Erlotinib and Cisplatin in Advanced Solid Tumors
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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated doses of cisplatin, temsirolimus, and erlotinib
Matthew Maurer, MD
United States: Food and Drug Administration
|Columbia University Medical Center||New York, New York 10032|