Biomarkers in Predicting Response to Regorafenib in Patients with Metastatic Colorectal Cancer

Inclusion Criteria

• Patients with metastatic colorectal cancer who have progressed on, or are ineligible for standard therapy such as fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab and anti-epidermal growth factor receptor (EGFR) antibodies where appropriate, but are suitable candidates for regorafenib 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; ideally, a signed informed consent form will be appropriately obtained prior to the conduct of any trial-specific procedure; however, if patients have had standard of care assessments performed within the screening period, but before the consent was signed, these will be admissible
• Total bilirubin =< 1.5 x the upper limits of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate amino-transferase (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)
• Serum creatinine =< 1.5 x the ULN
• International normalized ratio (INR)/partial thromboplastin time (PTT) has to be =< 1.5 x ULN
• Platelet count > 100000 /mm^3
• Hemoglobin (Hb) value > 9 g/dL
• Absolute neutrophil count (ANC) >= 1500/mm^3 is necessary; blood transfusion to meet the inclusion criteria will not be allowed
• Glomerular filtration rate (GFR) >= 60 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; 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 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 but is generally defined as a hormonal or barrier method of birth control, or abstinence
• Subject must be able to swallow and retain oral medication

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• Previous assignment to treatment during this study; subjects permanently withdrawn from study participation will not be allowed to re-enter study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 [National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (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 within 6 months of informed consent
• Subjects with any previously untreated or concurrent cancer that is distinct in primary site or histology from breast 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 version (v) 4.0
• Symptomatic metastatic brain or meningeal tumors, neuroblastoma (NB); if a patient does not have known or symptomatic central nervous system (CNS) metastases at screening, then brain imaging is not required for the purpose of this trial
• 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
• 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; the washout period between radiation therapy or tumor embolization is two weeks; given the refractory nature of the study population, the washout period between study treatment and prior chemotherapy or biological therapy, will be three weeks prior to 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])