Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

PRIMARY OBJECTIVES:

I. To assess progression-free survival (PFS) in advanced/metastatic in patients with
carcinoid or pancreatic islet cell tumors.

SECONDARY OBJECTIVES:

I. To assess overall survival and response rate in advanced/metastatic poor prognosis in
patients with carcinoid or pancreatic islet cell tumors.

II. To assess the toxicity of patients treated with regorafenib. III. To explore markers of
angiogenesis as they relate to outcome in carcinoid and pancreatic islet cell tumors.

OUTLINE:

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Courses repeat every
28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Advanced metastatic, progressing carcinoid or pancreatic islet cell cancers

- No prior targeted treatment (tx) or anti-angiogenic therapy; patients may have
received one line of prior therapy with octreotide, locoregional therapy; continuation
of concurrent octreotide is allowed; patients will be maintained on octreotide
(sandostatin) for the duration of their treatment

- 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 (ICF); a signed ICF 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); exceptions to
this include alopecia

- 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 phosphastase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver
involvement of their cancer)

- Lipase =< 1.5 x the ULN

- Amylase =< 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 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 [day 5 of cycle 1 and day 1 of each cycle] is
mandatory) 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 /mm^3

- Hemoglobin (Hb) >= 9 g/dL

- Absolute neutrophil count (ANC) >= 1,500/mm^3; blood transfusion to meet the inclusion
criteria will not be allowed

- Glomerular filtration rate (GFR) >= 30 ml/min/1.73 m^2 according to the Modified Diet
in Renal Disease (MDRD) abbreviated formula

- 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 judgement of the investigator

- 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

- Southwest Oncology Group (SWOG) performance status 0-1

- Patients must have measurable disease

Exclusion Criteria:

- 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 start of study treatment

- Subjects with any previously untreated or concurrent cancer that is distinct in
primary site or histology from carcinoid or pancreatic islet 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 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

- 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

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to regorafenib or other agents used in study

- Uncontrolled, intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Excluded therapies and medications, previous and concomitant

- Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
immunotherapy, biologic therapy, or tumor embolization) other than study
treatment (regorafenib)

- Prior use of regorafenib

- Concurrent use of chemotherapy, radiotherapy or another investigational drug or
device therapy (i.e., outside of study treatment) during, or within 4 weeks of
trial entry (signing of the ICF)

- Major surgical procedure, open biopsy, or significant traumatic injury within 28
days before start of study medication

- Use of any herbal remedy (e.g. St. John's wort [Hypericum perforatum])