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

Status: Active


This phase I trial studies the side effects and best dose of capecitabine when given together with lenvatinib mesylate and external beam radiation therapy in treating patients with rectal cancer that has spread from where it started to nearby tissue or lymph nodes before surgery. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenvatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x rays to kill tumor cells. Giving capecitabine, lenvatinib mesylate, and external beam radiation therapy may kill more tumor cells.

Eligibility Criteria

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

Locations & Contacts


Moffitt Cancer Center
Status: Active
Contact: Richard D. Kim
Phone: 813-745-1277

Trial Objectives and Outline


I. To determine the maximally tolerated dose of lenvatinib mesylate (lenvatinib) when delivered concurrently with capecitabine and external beam radiation in patients with locally advanced rectal adenocarcinoma.


I. To determine the pathologic response rate after pre-operative therapy and surgery.

II. To further define safety profile of the combination.


I. To explore potential correlations between blood biomarkers and pathologic response.

II. To determine if low radiosensitivity index (RSI) will correlate with pathologic complete response (pCR).

OUTLINE: This is a dose escalation study of lenvatinib mesylate.

Patients receive lenvatinib mesylate orally (PO) once daily (QD) on days 1-5, capecitabine PO twice daily (BID) on days 1-5, and undergo external beam radiation therapy on days 1-5. Courses repeat every week for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Moffitt Cancer Center

Principal Investigator
Richard D. Kim

Trial IDs

Primary ID MCC-18646
Secondary IDs NCI-2016-01553 ID NCT02935309