Study of Regorafenib for Urothelial Cancer Following Chemotherapy (UAB 1477)

Advanced urothelial carcinoma (UC) has a poor long-term prognosis. The disease has not seen
improved outcomes despite research efforts in over two decades. Novel therapeutic options are
needed. Regorafenib is a novel oral multikinase inhibitor but is more potent than a similar
multikinase inhibitor drug that treats advanced renal cell carcinoma and hepatocellular
carcinoma. Regorafenib has been shown to have a broader capacity to inhibit blood supply to
tumor sources.

This trial evaluates a proof-of-concept using Regorafenib in patients with metastatic
progressive urothelial carcinoma following chemotherapy but still have a high level of
activity performance in their daily living. The initial dose of Regorafenib will be 120 mg
daily and then be escalated to 160 mg daily before gradually tapering.

Inclusion Criteria:

- Patients must have pathologically or cytologically proven transitional cell carcinoma
of the urothelium.

- Progressive disease after 1-3 prior chemotherapy regimens (perioperative chemotherapy
within 12 months will be considered one regimen).

- Prior regimen must be within 6 months of registration

- Measurable disease by RECIST 1.1

- Eastern Cooperative Oncology Group (ECOG) Performance status 0-1

- Patients with metastatic (lymph node or distant metastasis, i.e. N+ or M1) or locally
advanced unresectable (T4b) transitional cell carcinoma.

- Age ≥19 years

- Life expectancy of at least 12 weeks (3 months)

- Subjects must be able to understand and be willing to sign the written informed
consent form.

- Adequate bone marrow, liver and renal function as assessed by the following laboratory
requirements:

- Total bilirubin ≤ 1.5 x the upper limits of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or
equal to 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their
cancer)

- Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver
involvement of their cancer)

- Serum creatinine ≤ 1.5 x the ULN

- International normalized ratio (INR) less than or equal to 1.5 x ULN. (Subjects
who are prophylactically treated with an agent such as warfarin or heparin will
be allowed to participate provided that no prior evidence of underlying
abnormality in coagulation parameters exists.Close monitoring of at least weekly
evaluations will be performed until INR/PTT is stable based on a measurement that
is pre-dose as defined by the local standard of care.

- Platelet count >100,000/mm3, hemoglobin (Hb) >8 g/dL, absolute neutrophil count
(ANC) 1500/mm3. The patient cannot be transfused in order to meet study entry
criteria.

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of study drug. Post- menopausal women (defined as no
menses for at least 1 year) and surgically sterilized women are not required to
undergo a pregnancy test. The definition of adequate contraception will be based on
the judgment of the investigator.

- Subjects (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the informed consent form until at least 3
months after the last dose of study drug. The definition of adequate contraception
will be based on the judgment of the principal investigator or a designated associate.

- Subject must be able to swallow and retain oral medication.

Exclusion Criteria:

- Component of small-cell cancer or sarcomatoid cancer

- Prior therapy with any systemic therapy (chemotherapy or biologic therapy) within
twenty-eight days prior to study entry

- Patients must have recovered from toxicities from prior systemic anticancer treatment
or local therapies.

- Patients who have undergone major surgery <4 weeks or minor surgery <2 weeks prior to
registration. Wounds must be completely healed prior to study entry and patients
recovered from all toxicities from surgery. Placement of a vascular access device is
not considered major or minor surgery in this regard.

- Prior radiation therapy is allowed as long as the irradiated area was not the sole
source of measurable disease and radiotherapy was completed with recovery from
toxicity, at least three weeks prior to enrollment. If the irradiated area is the only
site of disease, there must be evidence of progressive disease.

- Uncontrolled central nervous system (CNS) metastases (previously treated with
radiation and off steroids is acceptable).

- Patient with active or uncontrolled infection.

- Recent or active bleeding diathesis or arterial vascular event within 4 weeks.

- Pregnant or nursing (Fertile patients must use effective contraception during and for
up to 3 months after completion of study treatment.)

- Patients may not be receiving any other investigational agents.

- Previous assignment to treatment during this study. Subjects permanently withdrawn
from study participation will not be allowed to re-enter study.

- Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure >90 mm
Hg on repeated measurement) despite optimal medical management.

- Active or clinically significant cardiac disease including:

- Congestive heart failure - New York Heart Association (NYHA) Class II.

- Active coronary artery disease.

- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin.

- Unstable angina (angina symptoms at rest), new-onset angina within 3 months
before randomization, or myocardial infarction within 6 months before
randomization.

- Evidence or history of bleeding diathesis or coagulopathy.

- Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of
study medication.

- Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular
accident (including transient ischemic attacks) deep vein thrombosis or pulmonary
embolism within 6 months of start of study treatment within 6 months of informed
consent.

- Subjects with any previously untreated or concurrent cancer that is distinct in
primary site or histology from breast cancer except cervical cancer in-situ, treated
localized basal cell carcinoma, Gleason score 6 prostate cancer or superficial bladder
tumor. Subjects surviving a cancer that was curatively treated and without evidence of
disease for more than 3 years before randomization are allowed. All cancer treatments
for another malignancy must be completed at least 3 years prior to study entry (i.e.,
signature date of the informed consent form).

- Patients with pheochromocytoma.

- Known history of human immunodeficiency virus (HIV) infection or current chronic or
active hepatitis B or C infection requiring treatment with antiviral therapy.

- Ongoing infection >Grade 2 NCI-CTCAE v4.0.

- Symptomatic metastatic brain or meningeal tumors.

- Presence of a non-healing wound, non-healing ulcer, or bone fracture.

- Renal failure requiring hemo-or peritoneal dialysis.

- Dehydration Grade >1 NCI-CTCAE v4.0.

- Patients with seizure disorder requiring medication.

- Persistent proteinuria greater than or equal to Grade 3 NCI-CTCAE v4.0 (> 3.5 g/24
hrs, measured by urine protein:creatinine ratio on a random urine sample).

- Interstitial lung disease with ongoing signs and symptoms at the time of informed
consent.

- Pleural effusion or ascites that causes respiratory compromise (≥ NCI- CTCAE version
4.0 Grade 2 dyspnea).

- History of organ allograft (including corneal transplant).

- Known or suspected allergy or hypersensitivity to any of the study drugs, study drug
classes, or excipients of the formulations given during the course of this trial.

- Any malabsorption condition.

- Women who are pregnant or breast-feeding.

- Any condition which, in the investigator's opinion, makes the subject unsuitable for
trial participation.

- Substance abuse, medical, psychological or social conditions that may interfere with
the subject's participation in the study or evaluation of the study results.