A Phase I/II Trial of the Combination of Cisplatin, Cetuximab, and Temsirolimus in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
The epidermal growth factor receptor (EGFR) pathway is a key molecular pathway in the
pathogenesis of SCCHN. Cetuximab, a therapy targeting the EGFR pathway, has shown great
promise in SCCHN. The EXTREME study found that by combining cetuximab to a regimen of
cisplatin and 5-fluorouracil, PFS could be extended to 5.6 months from 3.3 months, and that
overall survival increased to 10.1 months versus 7.4 months. While this study proved a
survival benefit with the addition of cetuximab, there were high rates of Grade 3 or 4
toxicities to the chemotherapy backbone of high dose cisplatin with 5-fluorouracil.
The mammalian target of rapamycin (mTOR) pathway is activated when conditions favor cellular
growth and proliferation. The PI3K-Akt pathway is one of the key modulators in the
activation of mTOR. Phosphorylated Akt is detected in the majority of SCCHN tumors by
immunohistochemistry.
Temsirolimus is an mTOR inhibitor that has been shown to have a synergistic effect with
cisplatin and carboplatin in other tumor models. Due to the minimal toxicities associated
with temsirolimus in clinical studies to date, this is an ideal agent to use in combination
with other chemotherapies.
There is limited experience for the combination of EGFR inhibitors and mTOR inhibitors in
human subjects. These agents have been combined with a suggested synergistic effect in
preclinical models of colon cancer xenografts and cell lines from non-small cell lung,
pancreas, colon, and breast cancers. Cetuximab has been safely combined with everolimus (on
oral mTOR inhibitor) in human subjects.
There is sufficient evidence to suggest that the addition of the mTOR inhibitor,
temsirolimus, may increase both the cytotoxicity seen from platinum-based chemotherapy as
well as augment the effect of EGFR pathway inhibition from cetuximab, and possibly provide
clinical benefit of its own. It is hypothesized that the combination of cisplatin,
cetuximab, and temsirolimus will be an effective, well tolerated regimen for patients with
R/M SCCHN.
Interventional
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase one - the outcome measure for determining the optimal dose will be determined by whether the subjects experience a dose limiting toxicity (DLT)
No
Furhan Yunus, MD
Principal Investigator
University of Tennessee Cancer Institute
United States: Food and Drug Administration
HN0209
NCT01015664
February 2010
December 2012
Name | Location |
---|---|
Boston Baskin Caner Foundation | Memphis, Tennessee 38138 |