Pre-operative 5-Fluorouracil (5-FU) and Sorafenib With External Radiation in Locally Advanced Rectal Cancer

NCT01376453 | Completed Phase 1 DMC

• 2 other identifiers: MCC-16475IST 000575
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The main purpose of this study is to find the maximum tolerable dose of sorafenib when administered along with another drug called 5-Fluorouracil (5-FU) and to find out more about whether these drugs, along with radiation, can help people with rectal cancer when given before surgery. 5-FU and radiation are both approved by the US Food and Drug Administration (FDA) for use in people with rectal cancer. The investigators will utilize a standard 3 + 3 phase I study design. In the phase I part of the study, the investigators will attempt dose escalation of sorafenib in combination with standard infusional 5-FU and external beam at standard doses. Clinical staging should be done by endorectal ultrasound (ERUS) and/or pelvic magnetic resonance imaging (MRI) for T and N stage; chest and abdomen computed tomography (CT) for staging of metastatic disease; undergo sigmoidoscopy and/or colonoscopy done by crude odds ratios (CORS); biopsy is taken for diagnosis and extra is sent for tissue bank. At the maximum tolerated dose (MTD) of sorafenib we will expand the cohort to 6 more patients to further evaluate toxicity profile and efficacy.

Conditions

Rectal Cancer

Keywords

External Radiation Therapy; Locally Advanced Rectal; Adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  To determine maximally tolerated dose of sorafenib when delivered concurrently with 5-FU and external beam radiation in patients with locally advanced rectal adenocarcinoma

  Start of treatment through end of follow up - average of 21 weeks

Secondary Outcomes (2)

• Number of Participants With Pathologic Response

  Start of treatment through end of follow up - average of 21 weeks

• Number of Participants With Serious Adverse Events (SAEs)

  Start of treatment through end of follow up - average of 21 weeks

Study Arms (1)

Sorafenib Dose Escalation

EXPERIMENTAL

Pre-operative Continuous 5-FU, and Sorafenib with External Radiation Therapy. Dose level -1 will only be evaluated if dose level 1 exceeds MTD. The sorafenib and infusional 5-FU will only be given Day 1-5(Monday-Friday) with radiation only.

Drug: Sorafenib; Drug: 5-Fluorouracil (5-FU); Radiation: Radiation

Interventions

Sorafenib DRUG

In addition to radiation and 5-FU, sorafenib will be taken by mouth daily every day until the last day of radiation. The dose of sorafenib will be one of the following: 200 mg every other day, 200 mg daily, 400 mg daily, or 800 mg daily

Also known as: BAY 43-9006, NSC 724772, Nexavar®

Sorafenib Dose Escalation

5-Fluorouracil (5-FU) DRUG

5-FU will be delivered at a dose of 225 mg/m\^2 daily through a catheter in a large vein continuously until the last day of radiation.

Also known as: Adrucil®, Carac™, Efudex®, Fluoroplex®

Sorafenib Dose Escalation

Radiation RADIATION

Radiation sessions will be daily, Monday through Friday, except for holidays.

Sorafenib Dose Escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically 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, CT or 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
• Adequate bone marrow, liver and renal function as assessed by the following: 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 ( \< 5 x ULN for patients with liver involvement), 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 sorafenib.
• 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.
• Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin will be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until international normalized ratio (INR) is stable.

You may not qualify if:

• 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.
• 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.
• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic, attacks, deep vein thrombosis (DVT) within the past 6 months.
• 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 five years.
• 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.
• Evidence or history of bleeding diathesis
• Use of St. John's Wort or rifampin
• Known or suspected allergy to sorafenib or any agent given in the course of this trial.
• Any condition that impairs patient's ability to swallow whole pills.
• Any malabsorption problem.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Bayer: collaborator

Study Sites (1)

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Related Publications (1)

• Kim R, Prithviraj GK, Shridhar R, Hoffe SE, Jiang K, Zhao X, Chen DT, Almhanna K, Strosberg J, Campos T, Shibata D. Phase I study of pre-operative continuous 5-FU and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma. Radiother Oncol. 2016 Feb;118(2):382-6. doi: 10.1016/j.radonc.2016.01.018. Epub 2016 Feb 6.

  PMID: 26861740 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms; Adenocarcinoma

Interventions

Sorafenib; Fluorouracil; Radiation

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Uracil; Pyrimidinones; Pyrimidines; Physical Phenomena

Study Officials

• Richard Kim, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2011
• First Posted: June 20, 2011
• Study Start: June 1, 2011
• Primary Completion: November 1, 2014
• Study Completion: March 1, 2016
• Last Updated: September 12, 2016

Record last verified: 2016-04

Locations

US (1)