A Phase I Trial of Pazopanib Suspension Plus Cetuximab in Patients With Incurable Head and Neck Squamous Cell Carcinoma

Inclusion Criteria:

- Patient must have histologically confirmed diagnosis of incurable metastatic or
recurrent head and neck squamous cell carcinoma

- Patient must have measurable disease defined as lesions that can be accurately
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm with
CT scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam (Expanded
Cohort only; patients without measurable disease by RECIST 1.1 criteria but with
evaluable disease will be eligible for the dose-finding phase).

- Patient must be ≥ 18 years of age.

- Patient must have an ECOG performance status 0-1

- Patient must have normal bone marrow and organ function as defined below:

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 9.0 g/dL

- INR ≤ 1.2 x IULN; patients receiving anticoagulant therapy are eligible if their
INR is stable and within the recommended range for the desired level of
anticoagulation

- aPTT ≤ 1.2 x IULN

- Corrected QT interval (QTc) < 480 msecs

- Total bilirubin ≤ 1.5 x IULN

- AST(SGOT) ≤ 2.5 x IULN and ALT(SGPT) ≤ 2.5 x IULN

- Creatinine ≤ 1.5 mg/dL OR Creatinine clearance ≥ 50 mL/min/1.73 m2 for patients
with creatinine levels > 1.5 mg/dL

- Urine protein to creatinine ratio (UPC) < 1; if UPC ≥ 1, then a 24-hour urine
protein must be assessed; patients must have a 24-hour urine protein value < 1 g
to be eligible

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) beginning 14 days prior to
first dose of pazopanib, through the dosing period, and for at least 28 days after
the last dose of pazopanib.

- Patient must be able to understand and willing to sign an IRB approved written
informed consent document.

Exclusion Criteria:

- For the expanded cohort only, patient must not have had prior therapy with an
EGFR-specific monoclonal antibody or EGFR-specific TKI for treatment of incurable
HNSCC. Prior therapy with an EGFR-specific monoclonal antibody as part of the
definitive treatment of curable HNSCC is acceptable if this occurred more than 3
months prior to study enrollment. For the dose-finding cohorts, prior EGFR-specific
therapy in the incurable setting is allowed.

- Patient must not have had radiation therapy, minor surgery, or tumor embolization
with 14 days prior to the first dose of pazopanib.

- Patient must not have had chemotherapy, immunotherapy, biologic therapy, hormonal
therapy, or investigational therapy within 14 days or 5 half-lives of the drug prior
to the first dose of pazopanib.

- Patient must not have prior major surgery, trauma, presence of any non-healing wound,
fracture, or ulcer within 28 days prior to first dose of study drug.

- Patient must not have a history of other malignancy ≤ 2 years previous with the
exception of completely resected non-melanomatous skin carcinoma or successfully
treated in situ carcinoma.

- Patient must not be receiving any medication that is a strong CYP3A4 inhibitor
beginning 14 days prior to first dose of study drug. Strong CYP3A4 inhibitors
include (but are not limited to): antibiotics such as clarithromycin, telithromycin,
troleandromycin; protease inhibitors such as ritonavir, indinavir, saquinavir,
nelfinavir, lopinavir; antifungals such as itraconazole, ketoconazole, voriconazole;
and antidepressants such as nefazodone.

- Patient must not be receiving any other investigational agents.

- Patient must not be experiencing any ongoing toxicity from prior anti-cancer therapy
that is > grade 1 or that is progressing in severity, except alopecia.

- Patient must not have a history of or clinical evidence of central nervous system
metastases or leptomeningeal carcinomatosis, except for individuals who have had
previously-treated CNS metastases, are asymptomatic, and have had no requirement for
steroids or anti-seizure medications for 6 months prior to first dose of pazopanib.

- Patient must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to pazopanib, cetuximab, or other agents
used in the study.

- Patient must not have any clinically significant gastrointestinal abnormality that
may increase the risk of GI bleeding including, but not limited to, active peptic
ulcer disease, known intraluminal metastatic lesions with risk of bleeding,
inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease), other GI
conditions with increased risk of perforation, history of abdominal fistula or GI
perforation or intra-abdominal abscess within 28 days prior to beginning study
treatment.

- Patient must not have any clinically significant abnormality that may affect
absorption of investigational product including, but not limited to, malabsorption
syndrome or major resection of the stomach or small bowel.

- Patient must not have an uncontrolled intercurrent illness within the 6 months prior
to study entry including, but not limited to, ongoing or active infection, Class III
or IV congestive heart failure (as defined by the New York Heart Association (NYHA)),
unstable angina pectoris, cardiac arrhythmia, myocardial infarction, cardiac
angioplasty or stenting, coronary artery bypass graft surgery, symptomatic peripheral
vascular disease, or psychiatric illness/social situations that would limit
compliance with study requirements.

- Patient must not have poorly controlled hypertension (defined as systolic blood
pressure of ≥ 140 mmHg or diastolic blood pressure of ≥ 90 mmHg). Initiation or
adjustment of antihypertensive medications is permitted prior to study entry. Blood
pressure must be re-assessed on two occasions that are separated by a minimum of one
hour; on each of these occasions, the mean (of 3 readings) from each assessment must
be < 140/90 mmHg for a patient to be eligible for this study.

- Patient must not have a history of cerebrovascular accident including transient
ischemic attack within the past 6 months. Patients with recent deep venous
thrombosis or pulmonary embolism who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible as long as INR is stable.

- Patient must not have evidence of active bleeding or bleeding diathesis.

- Patient must not have any known endobronchial lesions and/or lesions infiltrating
major pulmonary vessels.

- Patient must not experience hemoptysis in excess of 2.5 mL within 8 weeks prior to
the first dose of pazopanib.

- Patient must not be pregnant and/or breastfeeding. Patient must have a negative
serum pregnancy test within 14 days of study entry.

- Patient must not be known to be HIV-positive on combination antiretroviral because of
the potential for pharmacokinetic interactions with pazopanib. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.