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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

Phase 1
20 Years
70 Years
Open (Enrolling)
Rectal Cancer

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Trial Information

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

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.

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; AST and Alkaline Phosphatase < 2 x upper limit of normal; Creatinine
< 1.5; Hemoglobin > 8.0; INR: < 1.5

- Hepatitis B (HBsAg+) or C (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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximally tolerated dose

Outcome 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

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Jason CH Cheng, M.D. Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Taiwan University Hospital


Taiwan: Department of Health

Study ID:




Start Date:

June 2011

Completion Date:

May 2013

Related Keywords:

  • Rectal Cancer
  • Rectal Neoplasms