A Pilot Trial Targeting mTOR as a Novel Mechanism-Based Neoadjuvant Therapy for Head and Neck Cancer

Trial Information

A Pilot Trial Targeting mTOR as a Novel Mechanism-Based Neoadjuvant Therapy for Head and Neck Cancer

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:

- 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 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 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 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 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.