Everolimus in Restoring Salivary Gland Function in Participants With Locally Advanced Head and Neck Cancer Treated With Radiation Therapy

PRIMARY OBJECTIVES:

I. To describe the recovery of salivary gland function after administration of a 5-day course
of everolimus, administered two weeks after completion of radiation or chemoradiation
therapy.

SECONDARY OBJECTIVES:

I. To describe the decrease of saliva flow rates during radiation or chemoradiation therapy.

II. To describe the changes in saliva protein composition during radiation or chemoradiation
therapy and following administration of a 5-day course of everolimus.

OUTLINE: This is an early phase 1 proof of principal study.

Participants receive everolimus orally (PO) once daily (QD) for 5 days beginning 2 weeks
after completion of radiation or chemoradiation treatment. Participants also undergo saliva
output testing at baseline prior to radiation or chemoradiation treatment, after 3 weeks of
RT/chemoRT, after 6 weeks of RT/chemoRT, prior to everolimus administration, at completion of
the 5 day everolimus course, and at 1, 3, and 6 months after the completion of radiation or
chemoradiation therapy.

Inclusion Criteria:

- Performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

- Platelets ≥ 100 x 10^9/L

- Hemoglobin (Hgb) > 9 g/dL

- Total serum bilirubin ≤ 2.0 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper
limits of normal (ULN) (≤ 5 x ULN in patients with liver metastases)

- International normalized ratio (INR) ≤ 2

- Serum creatinine ≤ 1.5 x ULN

- Fasting serum cholesterol ≤ 300 mg/dL or ≤ 7.75 mmol/L and fasting triglycerides ≤ 2.5
x ULN

- NOTE: in case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication

- Signed informed consent obtained prior to any screening procedures

- Patients with locally advanced squamous cell carcinoma of the head and neck, treated
with curative intent either in the post-operative or definitive setting with high dose
radiotherapy (≥ 50 Gy) with or without chemotherapy

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 2 weeks of the start of everolimus (including chemotherapy, radiation
therapy, antibody based therapy, etc.)

- Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
sirolimus, temsirolimus)

- Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus

- Uncontrolled diabetes mellitus as defined by glycated hemoglobin (HbA1c) > 8% despite
adequate therapy; patients with a known history of impaired fasting glucose or
diabetes mellitus (DM) may be included, however blood glucose and antidiabetic
treatment must be monitored closely throughout the trial and adjusted as necessary

- Patients who have any severe and/or uncontrolled medical conditions such as:

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction ≤ 6 months prior to start of everolimus, serious uncontrolled cardiac
arrhythmia, or any other clinically significant cardiac disease

- Symptomatic congestive heart failure of New York heart Association class III or
IV

- Active (acute or chronic) or uncontrolled severe infection, liver disease such as
cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.
quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive
hepatitis B virus surface antigen [HbsAg], quantifiable hepatitis C virus
[HCV]-ribonucleic acid [RNA])

- Known severely impaired lung function (spirometry and carbon monoxide diffusing
capacity [DLCO] 50% or less of normal and oxygen [O2] saturation 88% or less at
rest on room air)

- Active, bleeding diathesis

- Chronic treatment with corticosteroids or other immunosuppressive agents; topical or
inhaled corticosteroids are allowed

- Known history of human immunodeficiency virus (HIV) seropositivity

- Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study; patient should also avoid close contact with others
who have received live attenuated vaccines; examples of live attenuated vaccines
include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus
Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines

- Patients who have a history of another primary malignancy, with the exceptions of:
nonmelanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from
which the patient has been disease free for ≥ 3 years

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study

- Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing

- Pregnant or nursing (lactating) women

- Women of child-bearing potential (WOCBP) (including female pediatric patients who are
menarcheal or who become menarcheal during the treatment), defined as all women
physiologically capable of becoming pregnant, must use highly effective methods of
contraception during the study and 8 weeks after; women are considered post-menopausal
and not of child-bearing potential if they have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of
vasomotor symptoms); highly effective contraception methods include combination of any
two of the following:

- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of
hormonal contraception that have comparable efficacy (failure rate < 1%), for
example, hormone vaginal ring or transdermal hormone contraception; in case of
use of oral contraception women should have been stable on the oral agent for a
minimum of 3 months before taking everolimus

- Total abstinence

- Male partner sterilization; (the vasectomized male partner should be the sole
partner for that subject)

- Female sterilization have had surgical bilateral oophorectomy (with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks prior
torandomization; in the case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment is
she considered not of child-bearing potential

- Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment