Cabozantinib in Combination With Cetuximab in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Cancer

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the
head and neck.

- Disease must be considered incurable. Incurable is defined as metastatic disease or a
local or regional recurrence in a previously irradiated site that is unresectable (or
patient declines resection).

- 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.

- Patients in the expansion phase (only) must be cetuximab refractory. Cetuximab
refractory patients are those who have received either single agent cetuximab or
cetuximab in combination with chemotherapy and have progressed after treatment.

- Cetuximab refractory patients are those who have received either single agent
cetuximab or cetuximab in combination with chemotherapy and have progressed after
treatment.

- Measurable disease per RECIST v1.1 as determined by the investigator;

- The subject has had an assessment of all known disease sites e.g., by computerized
tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate,
within 28 days before the first dose of cabozantinib.

- The subject is ≥ 18 years old on the day of consent.

- The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1.

- Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.

- The subject has organ and marrow function and laboratory values as follows within 14
days before the first dose of cabozantinib.

1. The ANC ≥ 1500/mm3 without colony stimulating factor support.

2. White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).

3. Platelets ≥ 100,000/mm3;

4. Hemoglobin ≥ 9 g/dL;

5. Bilirubin ≤ 1.5 x the ULN. For subjects with known Gilbert's disease, bilirubin ≤
3.0 mg/dL;

6. Albumin ≥ 2.8 g/dl;

7. Creatinine ≤ 2.0 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For creatinine
clearance estimation, the Cockcroft and Gault equation should be used:

i. Male: CrCl (mL/min) = (140 - age) × wt (kg) / (creatinine × 72); h. Female:
Multiply above result by 0.85; Alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal
(ULN). ALP ≤ 5 x ULN with documented bone metastases.

i. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of
pancreatitis.

j. UPCR ≤ 1. k. Phosphorus, calcium, magnesium and potassium ≥ LLN.

- The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document;

- Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (e.g., male or female condom) during the course of the study
and for 4 months after the last dose of study drug(s), even if oral contraceptives are
also used. All subjects of reproductive potential must agree to use both a barrier
method and a second method of birth control during the course of the study and for 4
months after the last dose of study drug(s).

- Female subjects of childbearing potential must not be pregnant at screening. Females
of childbearing potential are defined as premenopausal females capable of becoming
pregnant (i.e., females who have had any evidence of menses in the past 12 months,
with the exception of those who had prior hysterectomy). However, women who have been
amenorrheic for 12 or more months are still considered to be of childbearing potential
if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body
weight, ovarian suppression or other reasons.

- No Grade 3-4 hypersensitivity reaction to cetuximab.

Exclusion Criteria:

- Any patient with incurable disease who has not received cetuximab (for expansion phase
portion of study only).

- Any patient who has received >70 Gy of XRT to the neck in the same radiation field. No
head and neck radiation within 2 months prior to initiation. Treatment areas should be
healed with no sequelae from RT that would predispose to fistula formation.

- A history of other malignancy ≤ 5 years previous with the exception of basal cell or
squamous cell carcinoma of the skin which were treated with local resection only,
carcinoma in situ of the cervix, synchronous H&N primaries or low grade tumors deemed
cured and not treated with systemic therapy. Other cancers that will not affect the
study outcome may be included with the consent of the PI (Dr. Michel) as long as it
would not affect the study outcome (e.g., low grade prostate cancer on surveillance
alone).

- Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment with
the exception of cetuximab and small molecule kinase inhibitors (kinase inhibitors
must be stopped within 2 weeks of first dose of study treatment.

- Prior treatment with cabozantinib.

- Radiation therapy for bone metastasis within 2 weeks, any other external radiation
therapy within 4 weeks before the first dose of study treatment. Systemic treatment
with radionuclides within 6 weeks before the first dose of study treatment. Subjects
with clinically relevant ongoing complications from prior radiation therapy are not
eligible.;

- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 14 days before the first dose of study treatment. Note:
Subjects with prostate cancer currently receiving LHRH or GnRH agonists may be
maintained on these agents.

- The subject has received any other type of investigational agent within 28 days before
the first dose of study treatment.

- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
before the first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of the start of study
treatment.

- The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
1.3 x the laboratory ULN within 7 days before the first dose of study treatment.

- Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel).

Allowed anticoagulants are the following:

1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted.

2. Low-dose low molecular weight heparins (LMWH) are permitted.

3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known
brain metastases who are on a stable dose of LMWH for at least 6 weeks before first
dose of study treatment, and who have had no clinically significant hemorrhagic
complications from the anticoagulation regimen or the tumor.

- The subject has experienced any of the following:

a. clinically-significant GI bleeding within 6 months before the first dose of study
treatment; b. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the
first dose of study treatment;

- Any other signs indicative of pulmonary hemorrhage within 3 months before the first
dose of study treatment. Clinically significant hematuria, hematemesis, or hemoptysis
of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding
(e.g., pulmonary hemorrhage) within 12 weeks before first dose.

- The subject has radiographic evidence of cavitating pulmonary lesion(s);

- The subject has tumor invading or encasing any major blood vessels.

- The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
within 28 days before the first dose of cabozantinib.

- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
before the first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of the start of study
treatment.

- The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
1.3 x the laboratory ULN within 7 days before the first dose of study treatment.

- Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed
anticoagulants are the following:

1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is
permitted.

2. Low-dose low molecular weight heparins (LMWH) are permitted.

3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
known brain metastases who are on a stable dose of LMWH for at least 6 weeks
before first dose of study treatment, and who have had no clinically significant
hemorrhagic complications from the anticoagulation regimen or the tumor.

- The subject has experienced any of the following:

1. clinically-significant GI bleeding within 6 months before the first dose of study
treatment;

2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the
first dose of study treatment;

- any other signs indicative of pulmonary hemorrhage within 3 months before the first
dose of study treatment. Clinically significant hematuria, hematemesis, or hemoptysis
of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding
(e.g., pulmonary hemorrhage) within 12 weeks before first dose.

- The subject has radiographic evidence of cavitating pulmonary lesion(s).

- The subject has tumor invading or encasing any major blood vessels.

- The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor
within 28 days before the first dose of cabozantinib.

- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York
Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of
screening; ii. Concurrent uncontrolled hypertension defined as sustained blood
pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study treatment; iii.
Any history of congenital long QT syndrome; iv. Any of the following within 6 months
before the first dose of study

- treatment: unstable angina pectoris;

- clinically-significant cardiac arrhythmias;

- stroke (including transient ischemic attack (TIA), or other ischemic event);

- myocardial infarction;

- thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a
venous filter (e.g., vena cava filter) are not eligible for this study).

- GI disorders particularly those associated with a high risk of perforation or fistula
formation including: i. Tumors invading the GI tract, active peptic ulcer disease,
inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis,
symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of
the pancreatic duct or common bile duct, or gastric outlet obstruction. Abdominal
fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months
before randomization

- Note: Complete healing of an intra-abdominal abscess must be confirmed prior to
randomization ii.

ii. No pre-existing fistula of the head and neck. No pre-existing osteonecrosis of the jaw.

- Other clinically significant disorders that would preclude safe study participation;

- Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (e.g., simple excision,
tooth extraction) at least 10 days before first dose. Subjects with clinically
relevant ongoing complications from prior surgery are not eligible.

- QTcF > 500 msec within 1 month before the first dose of study treatment:

a. Three ECGs must be performed for eligibility determination. If the average of these
three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in
this regard.

- Pregnant or lactating females;

- Inability to swallow intact tablets;

- Previously identified allergy or hypersensitivity to components of the study treatment
formulations;

- The subject requires chronic concomitant treatment with strong CYP3A4 inducers (e.g.,
phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St.

John's Wort).

- Other clinically significant disorders that would preclude safe study participation.

1. Serious non-healing wound/ulcer/bone fracture.

2. Symptomatic hypothyroidism.

3. Moderate to severe hepatic impairment (Child-Pugh B or C).