Cabozantinib-S-Malate in Treating Patients With Refractory Thyroid Cancer

PRIMARY OBJECTIVES:

I. The objective response rate, defined as the proportion of patients who have had a partial
response (PR) or complete response (CR) within the first 6 months after initiation of therapy
with cabozantinib (cabozantinib-s-malate).

SECONDARY OBJECTIVES:

I. To assess duration of objective response, progression-free survival and overall survival.

II. To assess tolerability and adverse events of cabozantinib as a 2nd line therapy in
patients with differentiated thyroid cancer (DTC).

TERTIARY OBJECTIVES:

I. To assess effect of cabozantinib on serum tumor marker thyroglobulin and its correlation
with overall response rate.

II. To assess response of cabozantinib in bone metastasis (bone metastasis-specific
progression free survival) as evaluated by pre- and on-study functional imaging such as bone
scan, fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET) scan and/or 18F
sodium fluoride (NaF) PET scan.

III. To assess effect of cabozantinib on serum and urinary markers of bone turnover and its
correlation with response to bone metastasis.

IV. To assess predictors of response by performing tumor genotype studies (e.g. v-raf murine
sarcoma viral oncogene homolog B [BRAF], rat sarcoma [RAS],
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha [PIK3CA],
mitogen-activated protein kinase 1 [MAP2K1], v-akt murine thymoma viral oncogene homolog 1
[AKT1], mesenchymal-epithelial transition [MET], rearranged in transformation [RET]/papillary
thyroid carcinoma [PTC] rearrangement) in archived tumor tissue.

V. To assess predictors of response by assessing baseline expression levels of vascular
endothelial growth factor (VEGF), phosphorylated vascular endothelial growth factor receptor
(pVEGFR), phosphorylated mitogen-activated protein kinase 1 (pERK), phosphorylated AKT1
(pAKT) and/or total met proto-oncogene (MET) by immunohistochemistry in archived tumor
tissue.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) daily on days 1-28. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 3
months for 1 year.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed papillary thyroid cancer,
follicular thyroid cancer or hurthle cell thyroid cancer (cancer, follicular variant
of papillary thyroid cancers or any of the above mixed histology will be allowed;
these patients will be enrolled on Arm A of the trial); patients with the following
aggressive histologies will be enrolled on Arm B of the trial; tall cell, insular or
poorly differentiated thyroid cancer

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 2.0 cm with conventional
techniques or as >= 1.0 cm (or >= 1.5 cm in short axis for lymph node) with spiral
computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by
clinical exam

- Patients must have radioactive iodine (RAI)-refractory/resistant disease as defined by
one or more of the following criteria:

- One or more measurable lesions that do not demonstrate RAI uptake

- One or more measurable lesions progressive by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 within 12 months of prior RAI therapy

- One or more measurable lesion present after cumulative RAI dose of >= 600 mCi

- Patients must have "progressed on" up to 2 lines of prior vascular endothelial growth
factor receptor (VEGFR)-targeted therapy (including but not limited to sorafenib,
sunitinib, vandetanib, pazopanib, or lenvatinib) as defined by progressive disease per
RECIST while receiving VEGFR-targeted therapy; Note: patients who progressed on kinase
inhibitor that target VEGFR and MET will not be eligible

- Prior external beam radiation, systemic cytotoxic chemotherapy or BRAF- or
non-VEGFR-targeted therapies will be allowed, provided that >= 4 weeks has elapsed
since receiving prior treatment and they have recovered to =< grade 1
treatment-related toxicities

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Absolute neutrophil count >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Thyroid stimulating hormone (TSH) < lower limit of normal (LLN) (patients not able to
tolerate TSH suppression can be granted an exception)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients [Pts] with Gilbert's
syndrome are excluded from this requirement)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x
institutional upper limit of normal

- Creatinine =< 1.5 x ULN

- Serum albumin >= 2.8 g/dL

- Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

- Urine protein/creatinine ratio (UPCR) =< 1

- Serum phosphorus, calcium, magnesium and potassium >= LLN

- Prothrombin time (PT) < 1.3 x ULN

- International normalized ratio (INR) < 1.3 x ULN

- Partial thromboplastin time (PTT) test < 1.3 x ULN

- Women of childbearing potential must have a negative pregnancy test at screening;
women of childbearing potential include women who have experienced menarche and who
have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is
defined as amenorrhea >= 12 consecutive months; Note: 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, ovarian suppression
or any other reversible reason

- Women of child-bearing potential and men must agree to use adequate contraception;
women of child-bearing potential and men must agree to use adequate contraception
prior to study entry and for the duration of study participation; should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately; men treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of study participation, and 4 months after completion of
cabozantinib administration; 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)

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior treatment with cabozantinib or any tyrosine kinase inhibitor that targets MET or
monoclonal antibody (mAb) targeting MET (such as onartuzumab [MetMAb])

- The subject has received radionuclide treatment =< 6 weeks of the first dose of study
treatment

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

- The subject has not recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and
other non-clinically significant adverse events (AEs)

- The subject has active brain metastases or epidural disease; subjects with brain
metastases previously treated with whole brain radiation or radiosurgery or subjects
with epidural disease previously treated with radiation or surgery who are
asymptomatic and do not require steroid treatment for at least 2 weeks before starting
study treatment are eligible; baseline brain imaging with contrast-enhanced CT or MRI
scans for subjects with known brain metastases is required to confirm eligibility;
eligible patients with brain metastases can be taking anti-convulsant medications but
only non-enzyme inducing anti-epileptic agents (NEIAED) will be allowed

- The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or factor xabans (Xa)
inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81
mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight
heparin (LMWH) are permitted

- The subject requires chronic concomitant treatment of strong cytochrome P450, family
3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin,
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort) or
strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir,
nefazodone, nelfinavir, ritonavir, voriconazole, and posaconazole); Note: because the
lists of these agents are constantly changing, it is important to regularly consult a
frequently-updated lists; medical reference texts such as the Physicians' Desk
Reference may also provide this information; as part of the enrollment/informed
consent procedures, the patient will be counseled on the risk of interactions with
other agents, and what to do if new medications need to be prescribed or if the
patient is considering a new over-the-counter medicine or herbal product

- The subject has experienced any of the following:

- Clinically-significant gastrointestinal bleeding =< 6 months before the first
dose of study treatment

- Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood =< 3 months before the first
dose of study treatment

- Any other signs indicative of pulmonary hemorrhage =< 3 months before the first
dose of study treatment

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

- The subject has tumor that is 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 =< 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) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal
antihypertensive treatment =< 7 days of the first dose of study treatment

- Any history of congenital long QT syndrome

- Any of the following =< 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)

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

- Any of the following =< 28 days before the first dose of study treatment

- Intra-abdominal tumor/metastases invading GI mucosa

- Active peptic ulcer disease as evidenced by esophagogastroduodenoscopy
(EGD)

- Inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis

- Malabsorption syndrome

- Any of the following =< 6 months before the first dose of study treatment:

- Abdominal fistula

- Gastrointestinal perforation

- Bowel obstruction or gastric outlet obstruction

- Intra-abdominal abscess; Note: complete resolution of an
intra-abdominal abscess must be confirmed prior to initiating treatment
with cabozantinib even if the abscess occurred more than 6 months
before the first dose of study treatment

- Other disorders associated with a high risk of fistula formation including
percutaneous endoscopic gastrostomy (PEG) tube placement =< 3 months before the
first dose of study therapy

- Other clinically significant disorders such as:

- Active infection requiring systemic treatment =< 28 days before the first
dose of study treatment

- Serious non-healing wound/ulcer/bone fracture =< 28 days before the first
dose of study treatment

- History of organ transplant

- History of major surgery as follows:

- Major surgery =< 3 months of the first dose of cabozantinib if there
were no wound healing complications or =< 6 months of the first dose of
cabozantinib if there were wound complications

- Minor surgery =< 1 months of the first dose of cabozantinib if there
were no wound healing complications or =< 3 months of the first dose of
cabozantinib if there were wound complications

- In addition, complete wound healing from prior surgery must be
confirmed at least 28 days before the first dose of cabozantinib
irrespective of the time from surgery

- The subject is unable to swallow tablets

- The subject has a corrected QT interval calculated by the Fridericia or Bazett's
formula (QTcF) > 480 ms within 28 days before registration; Note: if initial QTcF or
QTcB is found to be > 480 ms, two additional electrocardiograms (EKGs) separated by at
least 3 minutes should be performed; if the average of these three consecutive results
for QTcF or QTcB is =< 480 ms, the subject meets eligibility in this regard

- The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee

- The subject has had evidence within 2 years of the start of study treatment of another
malignancy which required systemic treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cabozantinib

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy; Note: patients known to be
HIV positive, but without clinical evidence of an immunocompromised state, are
eligible for this trial

- The subject has received prior treatment with a small molecule kinase inhibitor or a
hormonal therapy (including investigation kinase inhibitors or hormones) within 14
days or five half-lives of the compound or active metabolites, whichever is longer,
before the first dose of the treatment