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Preoperative Chemoradiotherapy Utilizing Intensity Modulated Radiation Therapy in Combination With Bevacizumab-FOLFOX

Primary Purpose

Rectal Cancer

Status
Completed
Phase
Phase 1
Locations
Taiwan
Study Type
Interventional
Intervention
CCRT
Sponsored by
National Taiwan University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rectal Cancer

Eligibility Criteria

20 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Biopsy proven adenocarcinoma of the rectum located up to 15 cm from the anal verge on flexible endoscopy
  • Patient evaluated by surgeon and found to be a potential surgical candidate. Since the objectives are response to chemoradiation and acute toxicity, lesions which are initially unresectable are eligible-provided the surgeon feels that, if there is sufficient response, surgery could become feasible
  • Clinical evidence of T3 or T4, N0-N2 and M0 disease. This can be by imaging studies (transrectal ultrasound or MRI) or by physical findings (tethering on palpation for T3 lesions or invasion of a neighboring organ for T4 lesions)
  • Karnofsky Performance Status >70
  • Laboratory criteria: Absolute neutrophil count > 1.5 K; Platelets > 100 K; Total Bilirubin < 2.0; aspartate aminotransferase (AST) and Alkaline Phosphatase < 2 x upper limit of normal; Creatinine < 1.5; Hemoglobin > 8.0; international normalized ratio (INR): < 1.5
  • Hepatitis B (HBsAg+) or hepatitis C virus (anti-HCV Ab+) carrier status (anti-viral agents allowed if clinically needed)
  • Informed consent signed

Exclusion Criteria:

  • Pregnant women, patient's age < 20 years or > 70 years, or patients unable to give informed consent
  • Patients with a past history of pelvic radiotherapy
  • Patients with any other malignancy within the past 5 years except: skin cancer or in-situ cervical cancer
  • Patients with known allergy/intolerance to 5-FU, Leucovorin, Oxaliplatin, Bevacizumab
  • Patients with prior chemotherapy for colorectal cancer
  • Patients with grade > 2 peripheral neuropathy
  • Patients with any condition which, in the opinion of the treating medical oncologist, renders the patient unfit for 5FU, Leucovorin, Oxaliplatin chemotherapy and bevacizumab
  • Patients with evidence of bleeding diathesis or coagulopathy, INR>1.5
  • Patients who require the use of warfarin sodium > 1 mg
  • Patients with active GI ulcers, GI bleeding, or active inflammatory bowel disease
  • Patients with clinically significant cardiac disease (e.g., uncontrolled hypertension [blood pressure of >160/90 mmHg on medication], history of myocardial infarction or unstable angina within 12 months of registration), New York Heart Association (NYHA) Class II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) are not eligible
  • Patients with a history of aneurysms, cerebrovascular accident (CVA) and arteriovenous malformations
  • Patients with arterial thromboembolic events, including transient ischemic attack (TIA), or clinically significant peripheral artery disease within 6 months of registration
  • Patients with serious, non-healing wound, ulcer, or current healing fracture
  • Patients with a history of any type of fistula (vesicovaginal, gastrointestinal, etc) or gastrointestinal perforation
  • Patients with intra-abdominal abscess within 6 months of study entry
  • Patients who have had an organ transplant
  • Patients with the placement of endorectal stent

Sites / Locations

  • National Taiwan University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bevacizumab + CCRT followed by surgery

Arm Description

Bevacizumab 5 mg/kg every 2 weeks + radiotherapy 45~55 Gy/25 fractions, followed by total mesorectal excision

Outcomes

Primary Outcome Measures

Maximally tolerated dose
To define the maximally tolerated dose of radiotherapy and the treatment related acute toxicity and to demonstrate that preoperative highly conformal radiotherapy and concurrent bevacizumab-chemotherapy will lead to acceptable acute gastrointestinal morbidity

Secondary Outcome Measures

Improved rate
To demonstrate that preoperative highly conformal radiotherapy and concurrent bevacizumab-5-fluorouracil/leucovorin/oxaliplatin chemotherapy will elicit a comparable or improved rate of T stage downstaging and complete response pathologically (pCR).

Full Information

First Posted
July 14, 2011
Last Updated
November 8, 2016
Sponsor
National Taiwan University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01395667
Brief Title
Preoperative Chemoradiotherapy Utilizing Intensity Modulated Radiation Therapy in Combination With Bevacizumab-FOLFOX
Official Title
A Phase I Dose Escalation Trial of Preoperative Chemoradiotherapy Utilizing Intensity Modulated Radiation Therapy(IMRT)in Combination With Bevacizumab-FOLFOX for Patients With Locally Advanced Rectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
November 2016
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Taiwan University Hospital

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
In this phase I trial neoadjuvant CCRT combining IMRT with three escalated dose levels (45 Gy, 50 Gy, and 55 Gy in 25 fractions) and BV-fluorouracil/ leucovorin/oxaliplatin (FOLFOX) regimens is planned for 15 locally advanced rectal cancer patients. The primary goal is to define the maximally tolerated dose of radiotherapy and the treatment related acute toxicity, and to demonstrate that preoperative highly conformal IMRT and concurrent BV-chemotherapy will lead to acceptable acute gastrointestinal morbidity. The secondary goal is to demonstrate that this treatment modality will elicit a comparable or improved rate of T stage downstaging and complete response pathologically.
Detailed Description
Rectal cancer has been one of the leading cancers in Taiwan and other countries in the world. Preoperative neoadjuvant concurrent chemoradiotherapy (CCRT) is the well accepted and widely used modality for locally advanced rectal cancer, to improve the local control, reduce the treatment related toxicity, and to increase the anal preservation rate. Intensity modulated radiation therapy (IMRT), the most common advanced technique in recent 10 years, has been proven effective in dose escalation, treatment target conformity, and normal tissue sparing. The ongoing trials on rectal cancer increasingly adopt IMRT as the treatment technique. Bevacizumab (BV), the developed drug targeting on vascular endothelial growth factor, has been proven for its effective use in metastatic colorectal cancer. Besides, BV has showed its good radiosensitizing effects in the evolving neoadjuvant CCRT trials using traditional big-field pelvis radiotherapy on rectal cancer, the ongoing brain tumor trials, and the basic researches. Neoadjuvant CCRT using the combination of IMRT and BV may have the dual advantages of reduced treatment toxicity by technique and increased pathological response by radiosensitization for the possible improved outcomes. In this phase I trial neoadjuvant CCRT with combined IMRT with three escalated dose levels (45 Gy, 50 Gy, and 55 Gy in 25 fractions) and BV-fluorouracil/ leucovorin/oxaliplatin (FOLFOX) regimens is planned for 15 locally advanced rectal cancer patients. The primary goal is to define the maximally tolerated dose of radiotherapy and the treatment related acute toxicity, and demonstrate that preoperative highly conformal IMRT and concurrent BV-chemotherapy will lead to acceptable acute gastrointestinal morbidity. The secondary goal is to demonstrate that this treatment modality will elicit a comparable or improved rate of T stage downstaging and complete response pathologically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bevacizumab + CCRT followed by surgery
Arm Type
Experimental
Arm Description
Bevacizumab 5 mg/kg every 2 weeks + radiotherapy 45~55 Gy/25 fractions, followed by total mesorectal excision
Intervention Type
Other
Intervention Name(s)
CCRT
Other Intervention Name(s)
IMRT, Bevacizumab, Fluorouracil, Leucovorin, Oxaliplatin
Intervention Description
Combined IMRT with three escalated dose levels (45 Gy, 50 Gy, and 55 Gy in 25 fractions) and Bevacizumab-fluorouracil/ leucovorin/oxaliplatin (FOLFOX) regimens
Primary Outcome Measure Information:
Title
Maximally tolerated dose
Description
To define the maximally tolerated dose of radiotherapy and the treatment related acute toxicity and to demonstrate that preoperative highly conformal radiotherapy and concurrent bevacizumab-chemotherapy will lead to acceptable acute gastrointestinal morbidity
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Improved rate
Description
To demonstrate that preoperative highly conformal radiotherapy and concurrent bevacizumab-5-fluorouracil/leucovorin/oxaliplatin chemotherapy will elicit a comparable or improved rate of T stage downstaging and complete response pathologically (pCR).
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Biopsy proven adenocarcinoma of the rectum located up to 15 cm from the anal verge on flexible endoscopy Patient evaluated by surgeon and found to be a potential surgical candidate. Since the objectives are response to chemoradiation and acute toxicity, lesions which are initially unresectable are eligible-provided the surgeon feels that, if there is sufficient response, surgery could become feasible Clinical evidence of T3 or T4, N0-N2 and M0 disease. This can be by imaging studies (transrectal ultrasound or MRI) or by physical findings (tethering on palpation for T3 lesions or invasion of a neighboring organ for T4 lesions) Karnofsky Performance Status >70 Laboratory criteria: Absolute neutrophil count > 1.5 K; Platelets > 100 K; Total Bilirubin < 2.0; aspartate aminotransferase (AST) and Alkaline Phosphatase < 2 x upper limit of normal; Creatinine < 1.5; Hemoglobin > 8.0; international normalized ratio (INR): < 1.5 Hepatitis B (HBsAg+) or hepatitis C virus (anti-HCV Ab+) carrier status (anti-viral agents allowed if clinically needed) Informed consent signed Exclusion Criteria: Pregnant women, patient's age < 20 years or > 70 years, or patients unable to give informed consent Patients with a past history of pelvic radiotherapy Patients with any other malignancy within the past 5 years except: skin cancer or in-situ cervical cancer Patients with known allergy/intolerance to 5-FU, Leucovorin, Oxaliplatin, Bevacizumab Patients with prior chemotherapy for colorectal cancer Patients with grade > 2 peripheral neuropathy Patients with any condition which, in the opinion of the treating medical oncologist, renders the patient unfit for 5FU, Leucovorin, Oxaliplatin chemotherapy and bevacizumab Patients with evidence of bleeding diathesis or coagulopathy, INR>1.5 Patients who require the use of warfarin sodium > 1 mg Patients with active GI ulcers, GI bleeding, or active inflammatory bowel disease Patients with clinically significant cardiac disease (e.g., uncontrolled hypertension [blood pressure of >160/90 mmHg on medication], history of myocardial infarction or unstable angina within 12 months of registration), New York Heart Association (NYHA) Class II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia) are not eligible Patients with a history of aneurysms, cerebrovascular accident (CVA) and arteriovenous malformations Patients with arterial thromboembolic events, including transient ischemic attack (TIA), or clinically significant peripheral artery disease within 6 months of registration Patients with serious, non-healing wound, ulcer, or current healing fracture Patients with a history of any type of fistula (vesicovaginal, gastrointestinal, etc) or gastrointestinal perforation Patients with intra-abdominal abscess within 6 months of study entry Patients who have had an organ transplant Patients with the placement of endorectal stent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jason CH Cheng, M.D. Ph.D.
Organizational Affiliation
National Taiwan University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Taiwan University Hospital
City
Taipei
Country
Taiwan

12. IPD Sharing Statement

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Preoperative Chemoradiotherapy Utilizing Intensity Modulated Radiation Therapy in Combination With Bevacizumab-FOLFOX

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