Regorafenib Plus Gemcitabine in Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To assess the efficacy (progression-free survival) of regorafenib and gemcitabine
(gemcitabine hydrochloride) in previously treated patients with metastatic pancreatic cancer.

SECONDARY OBJECTIVES:

I. To assess the safety of regorafenib in combination with gemcitabine. II. To assess
response rate (RR). III. To assess overall survival (OS).

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21 and gemcitabine
hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 30 days and then every 3
months thereafter.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic pancreatic
adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant)

- 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) as >
20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT)
scan

- Prior Therapies: Patients must have received at least one prior systemic chemotherapy
regimen for metastatic pancreatic cancer. They should have experienced disease
progression or intolerable toxicity from that regimen.

- Patients who have received prior non-gemcitabine-based systemic chemotherapy for
metastatic disease at any time 4 weeks prior to enrollment, or those who are beyond 12
months of exposure to gemcitabine-based chemotherapy regimen are allowed.

- Prior chemotherapy, radiation therapy, concurrent chemoradiation are allowed if used
for treatment of non-metastatic disease.

- Any chemotherapy must have been completed 4 weeks prior to enrollment

- Any radiotherapy must have been completed 2 weeks prior to enrollment

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

- 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; a signed informed consent form must be appropriately obtained prior to
the conduct of any trial-specific procedure

- All acute toxic effects of any prior treatment have resolved to National Cancer
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)4.0
grade 1 or less at the time of signing the informed consent form (ICF)

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

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 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)

- Lipase =< 1.5 x the ULN

- Serum creatinine =< 1.5 x the ULN

- International normalized ratio (INR)/partial thromboplastin time (PTT) 1.5 x ULN;
(subjects who are therapeutically 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 >= 100000/mm^3, hemoglobin (Hb) ≥ 9 g/dL, absolute neutrophil count
(ANC) ≥ 1500/mm^3; blood transfusion to meet the inclusion criteria will not be
allowed

- 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

- Subjects (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the ICF 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:

- Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks
prior to entering the study or failure to recover from adverse events to grade 1 or
less due to agents administered more than 4 weeks earlier

- Use of 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 [NCI-CTCAE v4.0] 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 (anginal 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 informed consent

- Subjects with any previously untreated or concurrent cancer that is distinct in
primary site or histology from pancreatic cancer except cervical cancer in-situ,
treated basal cell carcinoma, 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 must be completed at
least 3 years prior to study entry (i.e., signature date of the informed consent form)

- Patients with phaeochromocytoma

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

- Any infection requiring ongoing intravenous antibiotics for management

- Symptomatic metastatic brain or meningeal tumors; treated and stable, asymptomatic
brain metastases, as long as treatment was greater than 4 weeks prior to informed
consent, are allowed

- 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 >= 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