Testing Lenvatinib and Cetuximab in Patients With Advanced Head and Neck Squamous Cell Carcinoma and Cutaneous Squamous Cell Carcinoma

Inclusion Criteria:

- Histological or cytologic diagnosis of squamous cell cancer

- Clinical diagnosis of squamous cell cancer of the head and neck (non-nasopharynx
primary tumors: oral cavity, oropharynx, hypopharynx, larynx and sinonasal) or skin

- HNSCC and cSCC cannot be curable by surgery and/or radiation therapy

- Measureable disease as per RECIST v1.1, which includes locoregional lesions (not
amenable to curative surgery and/or radiation) and distant metastatic lesions

- Blood pressure < 150/90 at screening with or without antihypertensive medications and
no change in antihypertensive medications within 1 week prior to initiation of
treatment

- ECOG Performance Status of 0-1

- Adequate renal function as evidenced by calculated creatinine clearance > 30 ml/min
according to the Cockcroft and Gault Formula or by 24 hour urine creatinine clearance

- Adequate liver function as determined by (1) Bilirubin < 1.5 x upper limit of normal
(ULN) except for unconjugated hyperbilirubinemia or Gilbert‟s syndrome; (2) ALT and
AST < 3 x ULN (<5 x ULN if subject has liver mets)

- Adequate hematologic function as determined by (1) platelets > 100,000; (2) Hemoglobin
> 9 gm/dl; (3) absolute neutrophil count > 1200

- Adequate archival tissue to perform molecular analysis through MSK-IMPACT if
MSK-IMPACT has not been performed previously on the patient‟s tumor; if MSK-IMACT has
not been previously performed and adequate archival tissue is not available, a patient
should be agreeable to a pre-treatment biopsy

Exclusion Criteria:

- Prior grade 3 hypersensitivity to cetuximab requiring discontinuation

- Prior lenvatinib

- Major surgery within 2 weeks of first dose of lenvatinib

- Metastatic brain or leptomeningeal tumors (treated metastatic brain or leptomeningeal
tumors are allowed).

- Anticancer treatment (e.g., radiation therapy, chemotherapy) within 21 days of first
dose

°An exception is cetuximab treatment, which can be received within 21 days of the
first treatment on study

- No prior palliative radiation to a target lesion is allowed. Note, prior radiations to
a non-target lesion is allowed. Please see section 9.3.Subjects having a spot Urine
Protein:Creatinine ratio of >1 will undergo 24-hour collection for quantitative
assessment of proteinuria. If urine protein > 1 gram/24 hours, the subject will be
ineligible

- Significant cardiovascular impairment within 6 months as defined as (1) congestive
heart failure greater than New York Heart Association Class II, (2) unstable angina,
(3) myocardial infarction; (4) stroke, (5) symptomatic cardiac arrhythmia

- On electrocardiogram, QTc interval > 500 msec

- Active infection requiring systemic therapy

- Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to first dose
of lenvatinib

- Other active malignancy except for basal cell or squamous cell carcinoma of the skin,
or carcinoma in situ of the cervix or bladder

- Women who are breast feeding or pregnant ° Men or women of reproductive potential who
are not willing to employ effective birth control from screening to 30 days after the
last dose of study drugs; the definition of adequate contraception will be based on
the judgment of the principal investigator or a designated associate.

For a female patient to be considered as not of child bearing potential, she should fulfill
one of the following:

° Post-menopausal women, defined as either women aged more than 50 years and amenorrhoeic
for at least 12 months following cessation of all exogenous hormonal treatments, or, women
under 50 years old who have been amenorrhoeic for at least 12 months following the
cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution.

Or

° Have documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy (but not tubal ligation)

- Evidence of clinically significant disease (e.g., cardiovascular, respiratory,
gastrointestinal, renal disease) that in the opinion of the investigator could affect
the subject safety or interfere with the study assessments