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A Phase II, Multicentre, Open-Label, Randomised Study of Neoadjuvant Chemotherapy and Bevacizumab in Patients With MRI Defined High-Risk Cancer of the Rectum

Phase 2
18 Years
70 Years
Open (Enrolling)
Rectal Cancer

Thank you

Trial Information

A Phase II, Multicentre, Open-Label, Randomised Study of Neoadjuvant Chemotherapy and Bevacizumab in Patients With MRI Defined High-Risk Cancer of the Rectum

The purpose of this study is to look at two different combinations of anticancer drugs to
see how effective they are at shrinking your cancer and preventing it from coming back after
surgery. Patients with locally advanced rectal cancer are sometimes treated with
radiotherapy, with or without chemotherapy, before having surgery. Radiotherapy treats only
the main tumour in the rectum. This means that if tiny deposits of cancer have spread to
other parts of the body (metastases), these could continue to grow. Giving chemotherapy and
radiotherapy together (chemoradiotherapy) can treat both the main tumour and any spread.
However, due to the side-effects we can't give as much chemotherapy in combination with
radiotherapy than if chemotherapy were given on its own and treatment of possible metastases
may not be as good as it could be. If the risk of the main tumour coming back is quite
small, then giving treatment that targets metastases should be the best option.

This study looks at two well known combinations of chemotherapy drugs: FOLFOX (folinic acid,
5-fluorouracil, oxaliplatin) and FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin,
irinotecan). Chemotherapy works by killing cancer cells. In addition, the anticancer drug
bevacizumab will be given with both the FOLFOX and FOLFOXIRI. Bevacizumab is an
"anti-angiogenesis" drug. It works by stopping tumours from making new blood vessels.
Without new blood vessels, the cancer cells do not get the food and oxygen they need to
survive and grow. Attacking the cancer in these ways may be more effective than chemotherapy

Inclusion Criteria


- Histologically confirmed diagnosis of adenocarcinoma of the rectum

- Distal part of the tumour within 4-12 cm of the anal verge

- No unequivocal evidence of established metastatic disease (on chest/abdominal/pelvis
CT).Patients with equivocal lesions (as determined at MDT) are eligible

- MRI-evaluated locally advanced tumour:

- T3b T3c or T3d, N0-N2

- OR presence of macroscopic extramural venous invasion (V2 disease)

- AND T3 tumour must be >2mm from the mesorectal fascia.

- Measurable disease (using RECIST criteria v1.1)

- WHO performance status 0 - 1

- In the opinion of the investigator:

- General condition considered suitable for radical pelvic surgery

- Candidate for systemic therapy with FOLFOX/FOLFOXIRI plus bevacizumab

- Adequate bone marrow, hepatic and renal function:

- Haemoglobin ≥8.0 g/dL

- ANC ≥2 x 109/L

- Platelet count ≥100 x 109/L

- ALT or AST ≤1.5 x ULN (upper limit of normal)

- ALP ≤1.5 x ULN

- Total bilirubin ≤1.5 x ULN

- Serum creatinine ≤1.5 x ULN

- Creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula

- INR ≤ 1.1

- Urine protein ≤1+ with dipstick or urine analysis

- For proteinuria >1+ or urine protein/creatinine ratio ≥ 1.0, 24-h urine protein
should be obtained and the level must be <2 g for eligibility

- No evidence of established or acute ischaemic heart disease on ECG and normal
clinical cardiovascular assessment

- No known significant impairment of intestinal absorption

- At least 18 years of age, but not more than 70 years

- Willing and able to give informed consent, comply with treatment and follow up


- Primary tumour or lymph node on MRI extending <1mm from, or breaching the
circumferential resection margin

- Disease outside of the mesorectal envelope (internal iliac/lateral pelvic lymph node)

- Clinically significant cardiovascular or coronary disease <2 years before

- History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or
evidence of interstitial lung disease on baseline chest CT scan

- History of an arterial thromboembolic event during the previous 2 years

- Evidence of bleeding problems or coagulopathy

- Significant and continuing rectal bleeding leading to a haemoglobin <8 g/dL

- Patients receiving warfarin/coumarin derived anticoagulants at full therapeutic doses
are excluded, but prophylactic doses of 1mg to prevent Hickman line clotting are

- Chronic use of aspirin (>325 mg/day) or clopidogrel (>75 mg/day) within 10 days of
first planned study treatment

- Require regular use of anti-diarrhoeal (e.g. daily use of loperamide)

- Serious uncontrolled intercurrent illness including poorly controlled diabetes

- Known hypersensitivity to any of the study drugs

- Serious wound, ulcer or bone fracture

- Current or impending rectal obstruction

- Metallic colonic or rectal stent in situ

- Previous pelvic radiotherapy

- Previous intolerance to fluoropyrimidine chemotherapy

- Previous treatment with bisphosphonates

- Infectious illness requiring antibiotics within 1 week of randomisation

- Previous treatment with another investigational agent within 30 days prior to

- Patients with a history of previous malignancy in the past 5 years, excepting
basocellular or squamous cell skin cancer, or properly treated cervicouterine cancer
in situ

- Known HIV, HBV or HCV infection

- Current smoker, or clinically relevant history of drug or alcohol abuse

- Pregnant or lactating women or pre menopausal women not using adequate contraception.
Men and women of child-bearing potential must use adequate contraception

- Patients with any other condition or concurrent medical or psychiatric disease who,
in the opinion of the investigator, is not eligible to enter the study

- Inability or unwillingness to comply with the protocol

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathological Complete Response (PCR)

Outcome Description:

The proportion of patients in each arm who achieve a pCR will be presented, along with a 95% CI. Within each group the achieved pCR rate will be compared to the rate achieved by radiotherapy alone (5%).

Outcome Time Frame:

The pCR rate will be assessed after surgery, therefore approximately 24 weeks after randomisation.

Safety Issue:


Principal Investigator

Rob Glynne-Jones, BA MB FRCP FRCR

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mount Vernon Hospital


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

April 2013

Completion Date:

December 2017

Related Keywords:

  • Rectal Cancer
  • Rectal Cancer
  • Bevacizumab
  • Neoadjuvant
  • Chemotherapy
  • Randomised
  • Rectal Neoplasms