Regorafenib in Treating Patients with Metastatic Medullary and Differentiated Radioiodine Refractory Thyroid Cancer

Inclusion Criteria

• 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
• Age >= 18 years
• Eastern Cooperative Oncology Group performance status of =< 1
• Histologically or cytologically confirmed diagnosis of metastatic medullary thyroid cancer or histologically or cytologically confirmed diagnosis of RAI refractory differentiated thyroid cancer for which no curative treatment option exists
• Documented disease progression as defined by RECIST within 6 to 12 months prior to study registration for patients with MTC and within 12 months prior to study registration for patients with RAI refractory DTC
• Must have at least 1 site of measurable disease by RECIST criteria, by version 1.1
• Archival tissue block or unstained slides (from primary or metastatic site) must be available, otherwise fresh tissue biopsy sample will be collected for patients with accessible tumors
• Any number of prior chemotherapies and targeted therapies are allowed
• Total bilirubin =< 1.5 x the upper limits of normal (ULN) within 3 weeks prior to study registration
• Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) within 3 weeks prior to study registration
• Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) within 3 weeks prior to study registration
• Serum creatinine =< 1.5 x the ULN within 3 weeks prior to study registration
• International normalized ratio (INR)/ partial thromboplastin time (PTT) =< 1.5 x ULN within 3 weeks prior to study registration; 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 >= 100000 /mm^3 within 3 weeks prior to study registration; blood transfusion to meet the inclusion criteria will not be allowed
• Hemoglobin (Hb) >= 9 g/dL within 3 weeks prior to study registration; blood transfusion to meet the inclusion criteria will not be allowed
• Absolute neutrophil count (ANC) > 1500/mm^3 within 3 weeks prior to study registration; 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 study registration; 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 (ICF) until at least 2 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

• Prior treatment with regorafenib
• 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 [National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0]) 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 v4.0 grade 3 within 4 weeks prior to study registration
• 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 registration
• Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology 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 registration are allowed; all cancer treatments must be completed at least 3 years prior to study registration
• 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, or non-healing ulcer, (that is not tumor related) or bone fracture
• Major surgical procedure or significant traumatic injury within 28 days prior to study registration
• Other investigational treatment during or within 4 weeks prior to study registration
• Use of any approved tyrosine kinase inhibitors within 2 weeks or 6 half-lives of the agent, whichever is shorter, prior to study registration
• Prior radiation within 14 days before start of study registration
• 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
• 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
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment (regorafenib, other agents being investigated in combination with regorafenib)
• Prior use of regorafenib
• Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks prior to study registration. Subjects are allowed to participate in trials involving investigational agents used for the treatment of palmar-plantar erythrodysesthesia (PPE) symptoms
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
• Therapeutic anticoagulation with vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids * However, prophylactic anticoagulation as described below is allowed: ** Low dose warfarin (1 mg orally, once daily) with prothrombin time (PT)-INR =< 1.5 x ULN is permitted; infrequent bleeding or elevations in PT-INR have been reported in some subjects taking warfarin while on regorafenib therapy; therefore, subjects taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes ** Low dose aspirin (=< 100 mg daily) ** Prophylactic doses of heparin
• Use of any herbal remedy (e.g. St. John’s wort [hypericum perforatum])