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Phase I Clinical Trial of VTX-2337, a Small Molecule Toll-Like Receptor 8 (TLR8) Agonist in Combination With Cetuximab in Patients With Recurrent or Metastatic Squamous Cell Carcinomas of the Head and Neck (SCCHN)


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma, Recurrent Metastatic Squamous Neck Cancer With Occult Primary, Recurrent Salivary Gland Cancer, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Oropharynx, Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Recurrent Verrucous Carcinoma of the Larynx, Recurrent Verrucous Carcinoma of the Oral Cavity, Salivary Gland Squamous Cell Carcinoma, Stage III Salivary Gland Cancer, Stage III Squamous Cell Carcinoma of the Hypopharynx, Stage III Squamous Cell Carcinoma of the Larynx, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage III Squamous Cell Carcinoma of the Nasopharynx, Stage III Squamous Cell Carcinoma of the Oropharynx, Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage III Verrucous Carcinoma of the Larynx, Stage III Verrucous Carcinoma of the Oral Cavity, Stage IV Salivary Gland Cancer, Stage IVA Squamous Cell Carcinoma of the Larynx, Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVA Squamous Cell Carcinoma of the Oropharynx, Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVA Verrucous Carcinoma of the Larynx, Stage IVA Verrucous Carcinoma of the Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Larynx, Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVB Squamous Cell Carcinoma of the Oropharynx, Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVB Verrucous Carcinoma of the Larynx, Stage IVB Verrucous Carcinoma of the Oral Cavity, Stage IVC Squamous Cell Carcinoma of the Larynx, Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IVC Squamous Cell Carcinoma of the Oropharynx, Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IVC Verrucous Carcinoma of the Larynx, Stage IVC Verrucous Carcinoma of the Oral Cavity, Tongue Cancer

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Trial Information

Phase I Clinical Trial of VTX-2337, a Small Molecule Toll-Like Receptor 8 (TLR8) Agonist in Combination With Cetuximab in Patients With Recurrent or Metastatic Squamous Cell Carcinomas of the Head and Neck (SCCHN)


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and the toxicities of TLR8 agonist VTX-2337 in combination with cetuximab

Outcome Description:

Frequency and severity of hematologic and non-hematologic adverse events will be compiled for each dose cohort. Assessment of adverse events will include type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0), duration, seriousness, and relatedness; and clinically significant laboratory abnormalities.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Laura Chow

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

7406

NCT ID:

NCT01334177

Start Date:

June 2011

Completion Date:

Related Keywords:

  • Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma
  • Recurrent Metastatic Squamous Neck Cancer With Occult Primary
  • Recurrent Salivary Gland Cancer
  • Recurrent Squamous Cell Carcinoma of the Hypopharynx
  • Recurrent Squamous Cell Carcinoma of the Larynx
  • Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Recurrent Squamous Cell Carcinoma of the Nasopharynx
  • Recurrent Squamous Cell Carcinoma of the Oropharynx
  • Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Recurrent Verrucous Carcinoma of the Larynx
  • Recurrent Verrucous Carcinoma of the Oral Cavity
  • Salivary Gland Squamous Cell Carcinoma
  • Stage III Salivary Gland Cancer
  • Stage III Squamous Cell Carcinoma of the Hypopharynx
  • Stage III Squamous Cell Carcinoma of the Larynx
  • Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage III Squamous Cell Carcinoma of the Nasopharynx
  • Stage III Squamous Cell Carcinoma of the Oropharynx
  • Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage III Verrucous Carcinoma of the Larynx
  • Stage III Verrucous Carcinoma of the Oral Cavity
  • Stage IV Salivary Gland Cancer
  • Stage IVA Squamous Cell Carcinoma of the Larynx
  • Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IVA Squamous Cell Carcinoma of the Oropharynx
  • Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVA Verrucous Carcinoma of the Larynx
  • Stage IVA Verrucous Carcinoma of the Oral Cavity
  • Stage IVB Squamous Cell Carcinoma of the Larynx
  • Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IVB Squamous Cell Carcinoma of the Oropharynx
  • Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVB Verrucous Carcinoma of the Larynx
  • Stage IVB Verrucous Carcinoma of the Oral Cavity
  • Stage IVC Squamous Cell Carcinoma of the Larynx
  • Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity
  • Stage IVC Squamous Cell Carcinoma of the Oropharynx
  • Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
  • Stage IVC Verrucous Carcinoma of the Larynx
  • Stage IVC Verrucous Carcinoma of the Oral Cavity
  • Tongue Cancer
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Neoplasms, Squamous Cell
  • Head and Neck Neoplasms
  • Laryngeal Diseases
  • Tongue Neoplasms
  • Carcinoma, Verrucous
  • Neoplasms, Unknown Primary
  • Salivary Gland Neoplasms
  • Hypopharyngeal Neoplasms
  • Laryngeal Neoplasms
  • Paranasal Sinus Neoplasms
  • Oropharyngeal Neoplasms
  • Nasopharyngeal Neoplasms

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109