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.

- ELIGIBILITY CRITERIA:

Males and females and members of any race or ethnic group who meet the eligibility criteria
may participate in this trial.

INCLUSION CRITERIA:

Participants must meet all of the following inclusion criteria:

1. Age 18 years and older

2. Histologically confirmed previously untreated squamous cell carcinoma o f the oral
cavity or oropharynx accessible for biopsy

3. Clinical stage II, III, or IVA disease without distant metastasis, as defined by the
American Joint Committee on Cancer Staging System, Seventh edition.

4. Definitive therapy to include surgical resection or chemoradiation for curative
purposes

5. Life expectancy o f greater than 6 months

6. Eastern Cooperative Oncology Group ( ECOG) performance status of 0 or 1

7. Willing and able to provide written informed consent

EXCLUSION CRITERIA:

Participants who meet any of the following criteria are not eligible for enrollment:

1. Surgical resection or chemoradiation of the HNSCC is contraindicated

2. Prior head or neck squamous cell carcinoma within 5 years, except for previously
treated skin cancer

3. Received chemotherapy targeted monoclonal antibody therapy or investigational therapy
within 30 days prior to enrollment

4. Previous radiation therapy to the head or neck

5. No measurable tumor remaining after prior biopsy or negative margins from prior biopsy

6. Inadequate hematologic, renal or liver function within l4 days prior to the first
rapamycin dosing visit, as defined by:

1. Absolute neutrophil count less than 1.5 times 10 (9)/L

2. CD4 count < 400 (to account for natural fluctuations in CD4 levels, participants
with at least one CD4 count (Bullet) 400 within 14 days prior to dosing will not
be excluded)

3. Platelet count less than 100 times 10(9)/L

4. Hemoglobin less than l0 g/dL (eligibility level for hemoglobin may be reached by
transfusion)

5. AST, ALT or bilirubin greater than 1.5 times the upper limit of local lab normal
values

6. Total cholesterol level greater than 350 mg/dL

7. Triglyceride level greater than 400 mg/dL

8. International Normalized Ratio (INR) greater than 1.5

9. Serum creatinine greater than 1.5mg/dL

7. Active hepatitis or HBV or HCV infection

8. Women who are pregnant or lactating (female of child-bearing age must be abstinent or
use a barrier type birth control method throughout the study)

9. Presence of any contraindications to rapamycin therapy, including HlV-protease
inhibitors and drugs or agents that are modulators of cytochrome P-450 3A4 (CYP3A4)
and p-glycoprotein(P-gp)

10. Hypersensitivity to rapamycin

11 .Has received live vaccine (such as influenza nasal vaccine measles mumps, rubella, oral
polio, B CG, yellow fever, varicella, or TY2la typhoid) in the past 30 days or has plans to
take a live vaccine in the next 3 months

12. Any cognitive impairment that limits the subject s or the subject s legally authorized
representative s ability to understand the protocol, provide informed consent or assent, or
to comply with the protocol procedures

13.Unable or unwilling to comply with the requirements of the protocol