Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors
Condition: Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma
MeSH terms: Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Malignant Carcinoid Syndrome; Gastrointestinal Neoplasms; Insulinoma; Carcinoma, Islet Cell; Gastrinoma; Glucagonoma; Somatostatinoma; Recurrence
Intervention: regorafenib; laboratory biomarker analysis
Intervention description: Given PO; Correlative studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies regorafenib in treating patients with neuroendocrine tumors that
      have spread from the primary site (place where it started) to other places in the body.
      Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for
      cell growth.
    

Eligibility criteria:

        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])