Entolimod in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer Receiving Cisplatin and Radiation Therapy

PRIMARY OBJECTIVES:

I. To define the Phase II dose of CBLB502 (entolimod) when given as weekly injections during
irradiation with cisplatin, for patients with poor prognosis advanced squamous cell
carcinomas of the head and neck receiving chemoradiotherapy.

SECONDARY OBJECTIVES:

I. To describe the adverse event (AE) profile and the dose limiting toxicities of CBLB502
when administered weekly in combination with cisplatin and radiation therapy.

II. To determine the maximally tolerated dose (if observed) of CBLB502 in combination with
cisplatin and radiation therapy.

III. To describe the pharmacokinetics (PK) of CBLB502 when administered in combination with
cisplatin.

IV. To describe the pharmacodynamics (PD) of CBLC502 by examining plasma levels of various
cytokines, including filgrastim (granulocyte-colony stimulating factor [G-CSF]), interleukin
(IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α).

V. To describe any clinical activity of CBLB502 in the form of mitigation of mucositis.

VI. To describe the response rate to chemoradiotherapy in combination with CBLB502.

OUTLINE: This is a dose-escalation study of entolimod.

Patients undergo intensity-modulated radiation therapy (IMRT) 5 times per week for 7 weeks,
receive cisplatin intravenously (IV) once weekly for 7 weeks, and entolimod subcutaneously
(SC) on days 1, 8, 15, 22, 29, 36, and 43.

After completion of study treatment, patients are followed up for 3 months.

Inclusion Criteria:

- Histologically proven diagnosis of squamous cell carcinoma (stage III - IV) of the
nasopharynx, oropharynx, oral cavity, paranasal sinuses, larynx, hypopharynx; the
tumor must be human papillomavirus (HPV) negative or the patient should have a
greater than 10 packs year smoking history; OR need for post-operative concurrent
chemoradiotherapy (extracapsular extension, positive surgical margin, more than 1
lymph node positive, stage III - IV disease, perineural invasion, vascular tumor
embolus) for histologically proven squamous cell carcinoma of the paranasal sinuses,
nasopharynx, larynx, hypopharynx, with extension to structures of the oropharynx

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- Induction chemotherapy (up to 3 cycles of cetuximab/taxanes/platinum based regimens)
is allowed

- Patients or their legal representatives must be able to comprehend and provide
written informed consent

- Absolute neutrophil count => 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit normal (ULN)

- Calculated creatinine clearance >= 60 mL/min (Cockcroft-Gault equation)

- 12-Lead Electrocardiogram (ECG) with normal tracing or non-clinically significant
changes that do not require medical intervention

- Bazett's corrected QT (QTcB) interval < 470 msec at any timepoint prior to receiving
the first dose of study drug (mean of replicate values, correction per institutional
standard) and no history of Torsades des Pointes or other symptomatic QTcB
abnormality

- Absence of orthostatic hypotension

- Patients must be sufficiently recovered from induction chemotherapy to allow
initiation therapy

Exclusion Criteria:

- Women of childbearing potential who do not have a negative serum pregnancy test
performed within 7 days prior to the start of study drug

- Male and female patients of child-bearing potential who do not agree to use
double-barrier contraceptive measures, oral contraception, or avoidance of
intercourse during the study and for 90 days after last investigational drug dose
received

- Contraindication to full course chemoradiotherapy with cisplatin

- Previous treatment with a toll-like receptor 5 (TLR5) agonist

- Presence of neutralizing antibodies to CBLB502

- Patients with an active infection or with a fever >= 38.5ºC within 3 days of the
first scheduled day of dosing; patients who are registered but develop a fever of >=
38.5ºC may remain in the study if the fever abates prior to the expiration of the
screening procedures; if the screening procedures have expired, the patient may be
re-screened once afebrile

- Patients with a history of significant cardiovascular, neurological, endocrine,
gastrointestinal, respiratory or inflammatory illness that could preclude their
participation in the study, pose an undue medical hazard or interfere with the
interpretation of the study results, including, but not limited to, patients with
congestive heart failure (New York Heart Association [NYHA] class 3 or class 4);
unstable angina; cardiac arrhythmia; recent (within the preceding 6 months)
myocardial infarction or stroke; hypertension requiring > 2 medications for adequate
control; diabetes mellitus with > 2 episodes of ketoacidosis in the preceding 12
months; chronic obstructive pulmonary disease (COPD) requiring > 2 hospitalizations
in the preceding 12 months

- Patients with a history of, or known autoimmune disease, but not limited to systemic
lupus erythematosus, rheumatoid arthritis, systemic sclerosis, ankylosing
spondylitis, sarcoidosis, vasculitis, Wegener's granulomatosis, Hashimoto's
thyroiditis, ulcerative colitis, Crohn's disease, Goodpasture's disease, multiple
sclerosis, etc.

- Patients with any other medical, psychiatric or social condition that would preclude
their participation in the study, pose an undue medical hazard, interfere with the
conduct of the study or interfere with interpretation of the study results

- Patients taking sucralfate, palifermin or amifostine

- Patients receiving hematopoietic growth factors

- Patients currently taking, or who have taken within 30 days of the initiation of
protocol therapy, any immunomodulatory therapy, including pharmacologic doses of
glucocorticoids (topical and inhalation glucocorticoids are permitted), azathioprine,
methotrexate, interferon-alpha, interferon-beta, interluekin-2, etanercept,
infliximab, tacrolimus, cyclosporine, mycophenolic acid, etc

- Patients with a history of hypersensitivity reactions to any of the components of
CBLB502 or cisplatin

- Women who are pregnant or lactating or who are planning on becoming pregnant during
the study or for 90 days after completion of the study

- Patients who have received an investigational therapy within 4 weeks of signing the
informed consent for the current study

- Patients with a history of, patients who were treated for, or patients who are
suspected of having, hepatitis B, and hepatitis C or human immunodeficiency virus
(HIV); patients suspected of having any of these conditions should undergo
appropriate evaluations prior to being enrolled in the study

- Surgery with significant defect or flap in the oral cavity

- Poor dentition or ill-fitting dental appliances (can be enrolled if this can be
corrected by a dentist prior to start of radiation therapy)

- Presence of other medical conditions causing mucositis (e.g., rheumatologic,
gastroesophageal reflux, etc.)