Clinical trial NCT01395667: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Rectal Cancer
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2011-07-15
Enrollment: 15
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Maximally tolerated dose
timeFrame: 5 years
Secondary outcomes:
measure: Improved rate
timeFrame: 5 years
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: National Taiwan University Hospital
name: Jason CH Cheng, M.D. Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: