Regorafenib in Treating Patients with Advanced or Metastatic Neuroendocrine Tumors

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 somatostatin analogue, locoregional therapy; continuation of concurrent somatostatin analogue is allowed; patients will be maintained on somatostatin analogue 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; 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); 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 phosphatase 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 informed consent form) * 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])