Combination of Cisplatin, Cetuximab and Temsirolimus in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
This study will accrue in two "phases". During the first "phase" of the study, the optimal dose of temsirolimus in combination with cisplatin and cetuximab will be determined. It is expected that between 9-12 patients will be needed for this dose finding phase. Once the optimal dose has been determined, an additional 41 patients will be enrolled in the second "phase" of the study. The primary purpose of second phase of the study is to learn what effects, good and/or bad, temsirolimus in combination with cisplatin and cetuximab has on recurrent or metastatic head and neck cancer.
Collection of additional blood and tissue specimens will make it possible to do special tests, which will provide us information about how tumors respond to the chemotherapy, how your body breaks down and processes the drug, how differences in the genetic makeup of each person affects how the drug may work and is processed in the body, and how the drug affects proteins and cells in the body. We hope to determine if results of the specialized tests done on blood will help to predict which patients are more likely to benefit from the use of the drugs used in this study.
Squamous Cell Carcinoma of the Head and Neck
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Phase one - the outcome measure for determining the optimal dose will be determined by whether the subjects experience a dose limiting toxicity (DLT) [ Designated as safety issue: No ]
- Phase 2 - the outcome measure of Progression-Free Survival is defined as the time from first treatment to the documented progression of disease or death, whichever comes first. [ Designated as safety issue: No ]
- Overall response rate is defined as the proportion of patients achieving any response (CR + PR) compared to the total patient population. [ Designated as safety issue: No ]
- Disease control rate is defined as the proportion of patients who achieve a CR, PR, or SD (for ≥ 12 weeks) during study treatment compared to the total patient population. [ Designated as safety issue: Yes ]
- Overall survival is defined as the time from first treatment to the time of death, regardless of cause. [ Designated as safety issue: No ]
|Study Start Date:||February 2010|
|Study Completion Date:||December 2012|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
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.
|United States, Tennessee|
|Boston Baskin Caner Foundation|
|Memphis, Tennessee, United States, 38138|
|Principal Investigator:||Furhan Yunus, MD||University of Tennessee Cancer Institute|