Cabozantinib for Advanced Urothelial Cancer

Background:

- In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common

malignancy in men and the ninth most common in women with an estimated 69,250 new

cases and 14,990 deaths in the year 2011

- There is no FDA-approved second line drug for patients with metastatic UC

- Multiple lines of evidence support targeting angiogenesis in UC

- In human bladder cancer, overexpression of c-Met/Axl/PDGFR-alpha or c-Met alone showed

significant correlation with poor survival

- Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with

growth-promoting and angiogenic properties.

- The primary targets of cabozantinib are MET, VEGFR2, and RET

Objectives:

- To determine the response rate of cabozantinib in patients with progressive urothelial
cancer who have received prior cytotoxic chemotherapy

Eligibility:

-Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic,
progressive

urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis .

- Patients in cohort 2 must have a histologically confirmed diagnosis of bone only
metastatic,

urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

- Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional
cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine,

adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal
pelvis.

- Patients must have been previously treated, as defined by treatment with at least one prior

cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior

cytotoxic agents.

- 18 years of age or older.

Design:

- A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II
trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1
(metastatic, progressive urothelial cancer. The remainder will be enrolled on
exploratory cohorts 2 & 3, bone only metastatic urothelial disease and non TCC bladder
cancer respectively, during the time the study is accruing patients for cohort 1. Note:
Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first
restaging time period) without (Bullet) grade 2 toxicity may undergo dose escalation to
80 mg daily at the discretion of the Principal Investigator.

- A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error
probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2
or more of cohort 1 subjects experiences a response, enrollment will continue until a
total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3
patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the
accrual period.

- Each patient will undergo response evaluation assessments with CAP CT (or MRI) with or
without Na18F PET CT every 8 weeks while on active protocol therapy starting at
baseline. Patients will undergo investigational FDG PET/CT and PET/MRI (optional) at
baseline, week 4 and week 8.

- INCLUSION CRITERIA:

Cohort 1 only (urothelial progressive disease)

- Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the
bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA
certified lab.

- Patients must have progressive metastatic disease. Progressive disease will be defined
as new or progressive lesions on cross-sectional imaging.

- Patients must have at least one measurable site of disease

Cohort 2 only (Bone-only)

- Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the
bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA
certified lab.

- Patients must not have measurable progressive disease

- Patient must have appearance of at least one new bone lesion.

Cohort 3 (Rare histologies)

- Patient must have a histologically confirmed diagnosis of non-transitional cell
carcinoma of the bladder, urethra, ureter, or renal pelvis including but not limited
to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid.
Confirmation may be obtained from any CLIA certified lab.

- Patients must have progressive metastatic disease. Progressive disease will be defined
as new or progressive lesions on cross-sectional imaging.

- Patients must have at least one measurable site of disease

All cohorts

- Patients must have been previously treated, as defined by treatment with at least one
prior cytotoxic regimen or agent.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of cabozantinib in patients <18 years of age, children
are excluded from this study, but may be eligible for future pediatric trials.

- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
60%

- Adequate organ function as defined by the following criteria:

- Hemoglobin greater than or equal to 9 g/dL

- Absolute neutrophil count (ANC) greater than or equal to 1500/microL

- Platelets greater than or equal to 75,000/ L

- Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and
serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) less than
or equal to 3.0 times upper limit of normal (ULN); less than or equal to 5.0 times ULN
in cases of liver metastases

- Total serum bilirubin less than or equal to 1.5 times the upper limit of normal (ULN).
For subjects with known Gilbert s disease or similar syndrome with slow conjugation of
bilirubin, total bilirubin less than or equal to 3.0 mg/dL

- Serum creatinine less than or equal to 1.5 X institutional upper limits of normal or
for patients with creatinine levels above 1.5 x institutional normal: creatinine
clearance greater than or equal to 50 mL/min/1.73 m2 by 24 hour urine collection or
estimated creatinine clearance of greater than or equal to 50 mL/min. For creatinine
clearance estimation , the Cockcroft and Gault equation should be used:

- Male: CrCl (mL/min) = (140 - age) times wt (kg) / (serum creatinine times 72)

- Female: Multiply above result by 0.85

- Urine protein/creatinine ratio (UPCR) less than or equal to 2

- Patient must be able to provide either archival tumor samples (H&E slides and one
paraffin block or 10 unstained slides) or undergo tumor biopsy.

- Patient must be capable of understanding and complying with protocol requirements and
is willing to give informed consent

- The effects of XL184 on the developing human fetus are unknown. For this reason and
because tyrosine kinase inhibitors agents are known to be teratogenic, women of
childbearing 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 XL184 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).

- 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
greater than or equal to 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.

EXCLUSION CRITERIA:

- The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or
nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.

- Prior treatment with cabozantinib

- Prior treatment with other small molecule inhibitors of VEGFR within less than or
equal to 2 years of study enrollment.

- The subject has received radiation therapy:

- to the thoracic cavity or gastrointestinal tract within 3 months before the first dose
of study treatment

- to bone or brain metastasis within 14 days before the first dose of study treatment

- to any other site(s) within 28 days before the first dose of study treatment

- The subject has received radionuclide treatment within 6 weeks before the first dose
of study treatment

- The subject has received prior treatment with a small molecule kinase inhibitor or a
hormonal therapy (including investigational 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 study treatment.

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

- The subject has not recovered to baseline or CTCAE . Grade 1 from toxicity due to all
prior therapies except alopecia and other non-clinically significant AEs.

- The subject has a primary brain tumor

- The subject has active brain metastases, leptomeningeal or epidural disease (Note:
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. Neurosurgical resection of brain
metastases or brain biopsy is permitted if completed at least 3 months before starting
study treatment. Baseline brain scans are not required to confirm eligibility.)

- The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial
thromboplastin time (PTT) test greater than or equal to 1.3 times the laboratory ULN
within 7 days before the first

dose of study treatment.

- The subject requires treatment, in therapeutic doses, with oral anticoagulants such as
warfarin prior to initiation of protocol therapy. Low dose aspirin (less than or equal
to 81 mg/day), lowdose warfarin (less than or equal to 1 mg/day), and low molecular
weight heparin (LMWH) are permitted. Subjects will be permitted to use anticoagulation
as described if treatment is required while they are enrolled on the protocol.

- The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g.,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,
phenobarbital, and St. John's Wort).

Because the lists of these agents are constantly changing, it is important to regularly
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/;
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-thecounter medicine or
herbal product.

- The subject has experienced any of the following within 3 months before the first dose
of study treatment:

- clinically-significant hematemesis or gastrointestinal bleeding

- hemoptysis of greater than or equal to 0.5 teaspoon (greater than or equal to 2.5 mL)
of red blood

- any other signs indicative of pulmonary hemorrhage

- The subject has tumor invading (or concern for invasion) major blood vessels

- Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the Investigator would make the patient inappropriate for entry into
this

study.

- The subject has evidence of tumor invading the GI trac (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 is unable to swallow tablets

- The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)
>500 ms within 28 days before treatment initiation.

- The subject has a previously identified allergy or hypersensitivity to components of
the study treatment formulation.

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

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

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with the study agents. 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.