A Study Using Regorafenib as Second or Third Line Therapy in Metastatic Medullary Thyroid Cancer
A Study Using Regorafenib as Second or Third Line Therapy in Metastatic Medullary Thyroid Cancer
This research study is studying a targeted therapy as a possible treatment for thyroid
 cancer. A targeted therapy is a type of treatment that uses drugs or other substances to
 identify and attack specific types of cancer cells with less harm to normal cells.

 - The name of the study intervention involved in this study is regorafenib.
This is a phase II clinical trial. Phase II clinical trials test the safety and effectiveness
 of an investigational intervention to learn whether the intervention works in treating a
 specific disease. "Investigational" means that the intervention is being studied.

 The FDA (the U.S. Food and Drug Administration) has approved regorafenib as a treatment for
 metastatic colorectal cancer and locally advanced, unresectable or metastatic
 gastrointestinal stromal tumor. Regorafenib has not been approved for treatment against
 thyroid cancer.

 Regorafenib is an oral anti-tumor agent that blocks activity of a specific kind of protein
 involved in normal cellular functions and in pathologic processes such as tumor formation and
 maintenance.
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.

 -  Life expectancy of at least 12 weeks (3 months).

 -  Eastern Cooperative Oncology Group performance status of ≤1.

 -  Histologically or cytologically confirmed diagnosis of metastatic medullary thyroid
 cancer.

 -  Documented disease progression within 6 months prior to study registration, as defined
 by RECIST criteria.

 -  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.

 -  Any number of prior chemotherapies and targeted therapies are allowed.

 -  Patients must have received at least one prior line of targeted therapy.

 -  Adequate bone marrow, liver and renal function as assessed by the following laboratory
 requirements within 3 weeks prior to study registration:

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

 -  Alanine aminotransferase (ALT) and aspartate amino-transferease (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)

 -  Serum creatinine ≤ 1.5 x the ULN

 -  International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x
 ULN. (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. (See
 Section 3.3)

 -  Platelet count > 100000 /mm3, hemoglobin (Hb) > 9 g/dL, absolute neutrophil count
 (ANC) 1500/mm3. 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 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 [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 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 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.

 -  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 before start
 of study medication.

 -  Other investigational treatment during or within 30 days before starting study
 treatment.

 -  Use of any approved tyrosine kinase inhibitors within 2 weeks or 6 half-lives of the
 agen, whichever is shorter, prior to receiving study drug.

 -  Prior radiation within 14 days before start of study medication.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.

 -  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, 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 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.

 -  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 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])