TLR8 Agonist VTX-2337 and Cetuximab in Treating Patients With Locally Advanced, Recurrent, or Metastatic Squamous Cell Cancer of Head and Neck

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and to assess the dose-limiting toxicities (DLT) of
VTX-2337 (TLR8 Agonist VTX-2337) when given in conjunction with cetuximab in order to define
the maximum tolerated dose (MTD)/recommended phase II dose (RP2D).

SECONDARY OBJECTIVES:

I. To determine the pharmacodynamic immune response to VTX-2337 in combination with
cetuximab.

II. Correlative assessments of immunologic response and activity will be performed,
including: Quantitative evaluation of baseline immune status via in-vitro assessment of
cytokine and chemokine response to immunostimulatory agents; quantitative assessment of
plasma cytokines, chemokines, and other inflammatory markers via protein array; quantitative
assessment of natural killer (NK) cells via flow cytometry; quantitative assessment of
antigen-specific responses in cytokine-producing cells to common prognostic SCCHN antigens
via interferon (INF)gamma-enzyme-linked immunosorbent spot (ELISpot).

III. To assess whether subjects with functional genetic variations in the TLR8 and
FC-gamma-R IIIA genes have altered biological and/or clinical responses to VTX-2337, genetic
characterization of subjects will be performed via standard genotyping assays.

TERTIARY OBJECTIVES:

I. To assess preliminary evidence of anti-tumor activity for the combination of VTX-2337 and
cetuximab, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
criteria.

OUTLINE: This is a dose-escalation study of TLR8 Agonist VTX-2337.

Patients receive cetuximab intravenously (IV) over 60-120 minutes on days -28, -21, -14, -7
of weeks -4 to -1. Patients then receive cetuximab IV on days 1, 8, 15, and 22 and TLR8
agonist VTX-2337 subcutaneously (SC) on days 1, 8, 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Inclusion Criteria:

- Patients with a histological or cytopathological confirmed diagnosis of squamous cell
carcinoma of the head and neck region that is:

- Locally advanced/recurrent and no longer amenable to local surgical or radiation
therapy and/or

- Has evidence of metastatic disease

- Patients may have been previously treated with systemic therapy but are otherwise
deemed currently platinum-refractory, or would be deemed inappropriate or intolerant
to platinum-based chemotherapy

- Patients must have completed definitive chemotherapy and/or radiation therapy >= 3
months prior to study entry

- Prior therapy with agents targeting/blocking the epidermal growth factor receptor
(e.g. cetuximab and erlotinib) is allowable

- Performance Status: Eastern Cooperative Oncology Group (ECOG) 0 - 2

- Expected life expectancy of at least 12 weeks, as assessed by the Investigator

- Ability and willingness to comply with the study's visit and assessment schedule and
to provide voluntary written informed consent

- Absolute neutrophil count (ANC) >= 1,500 cells/μL

- Platelet count >= 75,000 cells/μL

- Hemoglobin >= 8.0 g/dL

- Creatinine =< 2.0 mg/dL

- Total bilirubin =< 2.0 x upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]),
serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
ULN

- For patients with liver metastases, AST, ALT < 5x ULN is acceptable

- Willingness to use a medically acceptable method of contraception throughout the
study period and for 4 weeks after the final administration of VTX-2337 (all
subjects)

- For female subjects with reproductive potential: a negative serum pregnancy test

Exclusion Criteria:

- Investigational therapy within 4 weeks of study entry

- Chemotherapy therapy or palliative radiation therapy within the previous 2 weeks
prior to dosing with cetuximab or VTX-2337; patients should have recovered from major
toxicities of prior therapy (If deemed reversible, toxicities should return to
baseline or =< grade 2 in severity)

- Major surgery within the past 4 weeks prior to dosing with cetuximab or VTX-2337

- Concurrent symptomatic central nervous system (CNS) involvement, brain or
leptomeningeal metastases; treated CNS involvement which has been stable > 28 days
off systemic steroids may be included

- Major active psychiatric disorders which would limit compliance

- Treatment with oral or parenteral corticosteroids within 2 weeks prior to dosing with
VTX-2337 or a requirement for systemic immunosuppressive therapy for any reason

- Active autoimmune disease

- Clinically significant cardiac disease (e.g., congestive heart failure, unstable or
uncontrolled angina, myocardial infarction) within 6 months of dosing with VTX-2337

- Clinically significant ophthalmologic disease, defined as:

- Current retinal vascular disorder, including active untreated diabetic
retinopathy and/or

- Previous or current uveitis

- Infection requiring parenteral antibiotic therapy or causing fever (temp > 100.5
degrees Fahrenheit [F] or 38.1 degrees Celsius [C]) within 1 week prior to dosing
with VTX-2337

- Pregnant or breast-feeding females

- Uncontrolled inter-current illness, pre-planned surgery or procedure requiring
hospitalization during the study period, or any other condition or circumstance that
could interfere with adherence to the study's procedures or requirements, or
otherwise compromise the study's objectives

- Second primary malignancy that is clinically detectable (not including in situ
carcinoma of the cervix, non-melanoma skin cancer or low-grade [Gleason score =< 6]
localized prostate cancer) and demonstrating active progression at the time of
consideration for study enrollment

- Known prior severe allergic/hypersensitivity to cetuximab or any of the components of
the study treatment

- Known prior severe (>= Grade 3) rash and / or diarrhea toxicities to cetuximab