Pembrolizumab & Cabozantinib in Patients With Head and Neck Squamous Cell Cancer Who Have Failed Platinum Based Therapy

PRIMARY OBJECTIVE:

To estimate the overall response rate (ORR) of patients with recurrent/metastatic (RM)
squamous cell carcinoma of the head and neck (SCCHN) who receive the combination of
pembrolizumab and cabozantinib.

SECONDARY OBJECTIVES:

- To estimate the progression-free survival (PFS) of patients treated with the combination
of pembrolizumab and cabozantinib.

- To identify potential biomarkers related to response to the combination of pembrolizumab
and cabozantinib in patients with RM SCCHN.

- To evaluate whether markers of angiogenesis, Met or pMet expression, or inflammatory
activation can predict response to the combination or PFS.

- To gather exploratory clinical data on a potentially predictive set of biomarkers
(potential biomarkers include MET expression by fluorescence in situ hybridization
[FISH], next generation sequencing [NGS] and immunohistochemistry
[IHC]/immunofluorescence [IHF] of MET proto-oncogene (cMET), phosphorylated cMET (pMET),
hepatocyte growth factor (HGF), human epidermal growth factor receptor 2 (HER2), human
epidermal growth factor receptor 3 (HER3) and heregulin messenger ribonucleic acid
[mRNA] level).

- To further define the toxicities associated with these regimens in patients with SCCHN.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and cabozantinib
orally (PO) once daily (QD) on days 1-21. Courses repeat every 3 weeks in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 2 years.

Inclusion Criteria:

- The subject has a histologic or cytologic diagnosis of squamous cell carcinoma of the
oral cavity, oropharynx, paranasal sinuses, hypopharynx, or larynx; squamous cell
carcinoma of unknown primary in cervical lymph node can be included only if human
papillomavirus (HPV) status is positive

- Patients must have refractory, recurrent or metastatic disease, which is deemed to be
inoperable

- Patients must have failed platinum based therapy; if patients were found to be
intolerant of standard first line systemic chemotherapy, patients are eligible to
enroll to this study provided platinum based therapy was administered prior to
enrollment

- Disease progression must be documented following platinum based chemotherapy; this can
be in the recurrent or metastatic setting following platinum or in the concurrent
setting

- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as
determined by the investigator

- A maximum of one prior radiotherapy regimen, curative or palliative, to the head and
neck is allowed; if the radiation is combined with chemotherapy, a minimum of 4 months
must elapse between the end of radiotherapy and registration; if the radiation is
given alone, a minimum of 8 weeks must elapse between the end of radiotherapy and
registration; a minimum of 3 weeks must elapse between prior radiation to other areas
and registration; treatment areas should be healed with no sequelae from radiation
therapy (RT) that would predispose to fistula formation

- The subject has had an assessment of all known disease sites eg, by computerized
tomography (CT) scan, magnetic resonance imaging (MRI), bone scan or positron emission
tomography (PET)/CT scan as appropriate, within 28 days before the first dose of
cabozantinib

- Life expectancy of greater than 3 months

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

- Recovery to baseline or ≤ grade 1 Common Terminology Criteria for Adverse Events
(CTCAE) version (v.)4.0 from toxicities related to any prior treatments, unless AE(s)
are clinically nonsignificant and/or stable on supportive therapy

- Within 7 days before the first dose of cabozantinib: The absolute neutrophil count
(ANC) ≥ 1000/mm³ without colony stimulating factor support

- Within 7 days before the first dose of cabozantinib: Platelets ≥ 100,000/mm³

- Within 7 days before the first dose of cabozantinib: Hemoglobin ≥ 9 g/dL

- Within 7 days before the first dose of cabozantinib: Bilirubin ≤ 1.5 x the upper limit
of normal (ULN); for subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL

- Within 7 days before the first dose of cabozantinib: Serum albumin ≥ 2.8 g/dl

- Within 7 days before the first dose of cabozantinib: Serum creatinine ≤ 1.5 x ULN or
creatinine clearance (CrCl) ≥ 40 mL/min; for creatinine clearance estimation, the
Cockcroft and Gault equation should be used

- Within 7 days before the first dose of cabozantinib: Alanine aminotransferase (ALT)
and aspartate aminotransferase (AST) ≤ 2.0 x ULN

- Within 7 days before the first dose of cabozantinib: Lipase < 2.0 x the upper limit of
normal and no radiologic or clinical evidence of pancreatitis

- Within 7 days before the first dose of cabozantinib: Urine protein/creatinine ratio
(UPCR) ≤ 1

- Within 7 days before the first dose of cabozantinib: Serum phosphorus, calcium,
magnesium and potassium ≥ lower limit of normal (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 (eg, 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 (ie, 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

Exclusion Criteria:

- Patients who have HPV negative squamous cell carcinoma of unknown primary in cervical
lymph node

- The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 4 weeks, or
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment

- Prior treatment with cabozantinib or pembrolizumab

- 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

- The subject has received any other type of investigational agent within 28 days or 5
half-lives, whichever is shorter, 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)/institutional normalized ratio (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 at therapeutic doses with oral anticoagulants (eg,
warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg,
clopidogrel)

- Note: Low-dose aspirin for cardioprotection (per local applicable guidelines),
low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins
(LMWH) are permitted; anticoagulation with therapeutic doses of LMWH is allowed
in subjects 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:

- Clinically-significant GI bleeding within 6 months before the first dose of study
treatment

- Hemoptysis of ≥ 0.5 teaspoon (2.5 ml) 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

- 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 gastrointestinal (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:

- Cardiovascular disorders including:

- Congestive heart failure (CHF): New York Heart Association (NYHA) class III
(moderate) or class IV (severe) at the time of screening;

- 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;

- Any history of congenital long QT syndrome;

- 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;

- GI disorders particularly those associated with a high risk of perforation or
fistula formation including:

- Tumors invading the GI tract, active peptic ulcer disease, inflammatory
bowel disease (eg, 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. Also no pre-existing fistula of head and neck
area; no pre-existing osteonecrosis of jaw (ONJ)

- Other clinically significant disorders that would preclude safe study
participation

- Major surgery within 12 weeks before the first dose of study treatment; complete wound
healing from major surgery must have occurred 1 month before the first dose of study
treatment; minor surgery (including uncomplicated tooth extractions) within 28 days
before the first dose of study treatment with complete wound healing at least 10 days
before the first dose of study treatment; subjects with clinically relevant ongoing
complications from prior surgery are not eligible

- Corrected QT interval by Fridericia's formula (QTcF) > 500 msec within 1 month before
the first dose of study treatment

- Three electrocardiography (ECG)s 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 or inability to take pembrolizumab or cabozantinib

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

- Patients with a history of other prior malignancy must have been treated with curative
intent and must have remained disease-free for 1 year post diagnosis; patients with a
prior history of squamous cell or basal carcinoma of the skin or in situ cervical
cancer must have been curatively treated