Capecitabine, Lenvatinib Mesylate, and External Beam Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer before Surgery

Inclusion Criteria

• Histologically (archival tissue) confirmed adenocarcinoma of the rectum that begins within 12 cm of the anal verge as determined by sigmoidoscopy and/or colonoscopy with no evidence of distant metastasis
• Locally advanced rectal cancer determined by any of the following features * Fixed or immobile tumor on physical exam and/or * T3 disease with invasion through the muscularis propria as defined by transrectal ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) * T4 disease with invasion of adjacent structures such as pelvic sidewall, sacrum, pelvis, bladder and/or prostate as determined appropriate imaging modalities such as ultrasound, CT or MRI * Any T with + N on CT scan/MRI or transrectal ultrasound
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Hemoglobin >= 9.0 g/dl
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Total bilirubin =< 1.5 times upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the ULN
• Creatinine =< 1.5 times ULN
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment
• Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation; men should use adequate birth control for at least three months after the last administration of lenvatinib
• Ability to understand and the willingness to sign a written informed consent; a signed informed consent must be obtained prior to any study specific procedures

Exclusion Criteria

• Cardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months
• Previous pelvic irradiation therapy
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management
• Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
• Active clinically serious infection > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
• Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic, attacks, deep vein thrombosis (DVT) within the past 6 months
• Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar agents requiring therapeutic international normalized ration (INR) monitoring; (treatment with low molecular weight heparin [LMWH] is allowed)
• No active malignancy except for nonmelanoma skin cancer or in situ cervical cancer or treated non-pelvic cancer from which the patient has been continuously disease free more than three years
• Marked baseline prolongation of QT/corrected QT (QTc) interval (QTc interval >= 500 msec) using the Fridericia method (QTc = QT/RR0.33) for QTc analysis
• > 30 mg/dL on urine analysis; patients with > 30 mg/dL on urine analysis on urine analysis will undergo 24-hour urine collection for quantitative assessment of proteinuria; subjects with 24-hour protein >= 1 g/24 hours will be ineligible
• Needing medical attention for serious bleeding in past 4 weeks
• Previous chemotherapy except for antiangiogenic agent or tyrosine kinase inhibitor (TKI) will be allowed as long as it is more than 5 years
• No major surgeries within 3 weeks of starting chemotherapy
• Evidence or history of bleeding diathesis
• Use of St. John’s wort or rifampin
• Known or suspected allergy to lenvatinib or any agent given in the course of this trial
• Any condition that impairs patient‘s ability to swallow whole pills
• Any malabsorption problem
• Medical need for the continued use of potent inhibitors/inducers of CYP3A4
• Creatinine clearance < 30 mL/min