EC-18 for Oral Mucositis in Patients With Concomitant Chemoirradiation

This is a Phase 2, randomized, double-blind, placebo-controlled, 2-stage trial in subjects
with squamous cell cancers of the mouth, oropharynx, hypopharynx and nasopharynx planned to
receive standard fractionated IMRT-delivered radiotherapy with concomitant chemotherapy
(cisplatin). Informed consent will be obtained from each subject prior to enrollment.

The trial will be performed in 2 stages:

Stage 1 will consist of a blinded parallel group safety study of 4 cohorts in which 24
subjects will be randomized (1:1:1:1) into four equally sized groups to receive one of three
doses of EC-18 (500 mg, 1000 mg, 2000 mg; unit dose of 500 mg) or placebo delivered in the
following daily schedule:

TDD AM PM Placebo 2 placebo 2 placebo 500mg 1 active + 1 placebo 2 placebo 1000mg 1 active +
1 placebo 1 active + 1 placebo 2000mg 2 active 2 active Dosing will commence on the first day
of radiation (one hour after the first fraction) and continue until the last day of
radiation. Test drug will be administered as an oral 500 mg capsule in divided daily doses as
indicated above. At the completion of 4 weeks of dosing, an independent Data Safety
Monitoring Board (DSMB) will evaluate safety endpoints in blinded fashion. If no safety
issues are identified, the DSMB will approve continuation of dosing until the last day of
radiation. If a safety issue is noted, the DSMB may unblind the treatment assignment to
ascertain if the adverse event is associated with study drug. DSMB assessment will be
repeated after completion of dosing (when each subject has been dosed through the last day of
radiation). If no safety issues are identified, the efficacy component of the study (Stage 2)
will commence using the highest dose of study drug consistent with a positive safety outcome.

Stage 2 of the study will evaluate both safety and efficacy. Sixty (60) subjects will be
randomized in a 1:1 scheme to receive either placebo or EC-18 at the dose determined in Stage
1. Twice daily dosing (assuming EC-18 dose is greater than 500 mg) will begin on the first
day of radiation (1 hour after the first fraction) and continue until the last day of
radiation (approximately 7 weeks).

The study will be performed in four phases: screening, the active dosing phase, short-term
follow-up and long-term follow-up. The screening phase will be performed within 4 weeks of
randomization and will determine subjects' eligibility. The active phase will begin on the
first day of study drug dosing (also the first day of radiation therapy) and will continue
until the last day of radiation therapy. This period typically is 7 weeks depending on the
subject's radiation plan. The short-term follow-up phase will begin on the last day of
radiation and continue for approximately 4-6 weeks until clinical and symptomatic signs of
oral mucositis have resolved. The long-term follow-up phase extends for 12 months following
the last dose of radiation and is included to assure that EC-18 does not the impact of tumor
response to treatment.

Inclusion Criteria:

- Signed informed consent

- Male or female age 18 years or older

- Pathologically confirmed diagnosis of squamous cell carcinoma of the mouth,
oropharynx, hypopharynx or nasopharynx

- Planned to receive IMRT with daily fractions of 2.0 Gy to 2.2 Gy to a cumulative dose
of at least 60 Gy and a maximum of 72 Gy

- Radiation fields to include at least two mucositis sites at risk (buccal mucosa, floor
of mouth, ventral and lateral tongue, soft palate) in which both sites receive a
minimum cumulative dose of 55 Gy

- Planned to receive concomitant single agent chemotherapy with cisplatin given either
weekly or tri-weekly

- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1

- Screening Laboratory Values Hemoglobin ≥ 9g/dL White blood cell count ≥ 3,500
cells/mm3 Absolute neutrophil count ≥ 1,500 cells/mm3 Total bilirubin ≤ 2 times upper
limit of normal Serum AST and ALT ≤ 2.5 times upper limit of normal Serum creatinine
concentration ≤ 2mg/mL Pregnancy test: negative for females of childbearing potential

- Subjects of childbearing potential must consent to utilize a medically accepted means
of contraception throughout the active dosing period with study medication and for a
minimum of 30 days following the administration of the last dose of study medication.

Exclusion Criteria:

- Unable to provide informed consent or, in the opinion of the Principal Investigator,
comply with the protocol.

- Prior radiation therapy to the head and neck

- Metastatic disease

- Presence of active infectious disease excluding oral candidiasis

- Presence of oral mucositis or any oral lesion that would confound the assessment
of oral mucositis

- Active systemic disease or condition known to impact the risk or course of oral
mucositis including chronic immunosuppression and known seropositivity for HIV

- Use of any investigational agent within 30 days of the first radiation dose

- Active alcohol abuse syndrome

- Subjects with a history of hepatitis of any etiology or hepatic insufficiency

- Pregnant or nursing at the time of signing informed consent

- Known sensitivity to any study medication

- Unwilling or unable to complete study diary

- Any other condition or prior therapy that, in the opinion of the Investigator,
would make the subject unsuitable for the study or unable to comply with the
protocol