Rapamycin Therapy in Head and Neck Squamous Cell Carcinoma

BACKGROUND:

• The five-year survival rate for head and neck squamous cell carcinoma (HNSCC) has remained at approximately 50% for more than three decades.
• In HNSCC, the AKT-mTOR-pS6 pathway is aberrantly activated and promotes tumorigenesis and metastasis.
• Rapamycin is the most extensively studied mTOR inhibitor for which therapeutic daily oral dose and schedule, pharmacologic levels in blood, and safety have been established.
• Inhibition of mTOR by rapamycin causes the rapid apoptotic death of HNSCC tumor xenografts and decreases the tumor burden and prolongs the survival of mice harboring early and advanced oral and skin SCC lesions in a variety of experimental cancer models.
• Preliminary evidence suggests that mTOR inhibitors cause tumor shrinkage and improved tumor margins in HNSCC patients.

OBJECTIVES:

• The primary objectives are to evaluate the following for patients with HNSCC given rapamycin as neoadjuvant treatment prior to surgery or chemoradiation:
• Whether therapeutic activities of rapamycin lead to inhibition of mTOR complexes, mTORC1 and mTORC2, as assessed by the change in levels of pS6 and pAkt473 measured by immunohistochemistry (IHC) in tumor samples and by Western blotting in peripheral blood mononuclear cells (PBMCs) and reduce tumor cell proliferation, as judged by IHC for Ki-67 in tumor samples.
• Antitumor activity in terms of objective response.
• Secondary objectives include safety evaluation of rapamycin therapy, exploratory studies of possible effects of rapamycin on tumor size, dynamic CT perfusion, and FDG-PET; and evaluation of tumor proliferation, apoptosis, microvessel density, and molecular changes associated with these effects. Survival status, recurrence of disease, metastases, and adverse events/serious adverse events, including complications of wound healing, which are related to rapamycin therapy will also be assessed for 360 days after surgery or chemoradiation through medical record review.

ELIGIBILITY:

• Males and females age 18 years and older
• Previously untreated HNSCC of the oral cavity or oropharynx
• Clinical stage II, III, or IVA disease without distant metastasis
• Definitive therapy to include surgical resection or chemoradiation for curative purposes
• Life expectancy greater than six months

STUDY DESIGN:

• Pilot, single arm, open-label, interventional neoadjuvant clinical trial.
• Twenty one evaluable subjects will take rapamycin (sirolimus) orally once per day for 21 days.
• Before and after dosing, the tumor will be photographed and biopsied, peripheral blood mononuclear cells (PBMCs) will be collected, and computed tomography and positron emission tomography scans will be performed.
• Surgical or chemoradiation treatment, which is being provided outside of this protocol, will be conducted after Day 28 and when rapamycin levels are less than or equal to 3 nanograms per milliter.
• Subjects will be followed by medical record review for 360 days after surgery or chemoradiation to assess 1) survival, 2) recurrence of disease, 3) metastases, and 4) adverse events/serious adverse events that are related to rapamycin therapy, including complications of wound healing and infections due to immune compromise.
• Levels of pS6 and pAkt473 in tumor tissue and PBMCs and Ki-67 in tumor tissue before and after rapamycin therapy will be determined by immunohistochemistry and by Western blotting. Computed tomography (CT) and positron emission tomography (PET) scans of the head, neck, and chest region with and without contrast will be performed within 7 days prior to the first rapamycin administration. One day after the last administration of rapamycin the CT and PET scans (head and neck region only) with contrast will be repeated.
• A single stage design will be used based on response defined as > 25% tumor shrinkage. A Wilcoxon signed rank test will be used to compare levels of pS6, pAkt473, and Ki-67 before and after rapamycin therapy. As part of secondary analysis, the number of subjects achieving a best response of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will also be summarized.