Bevacizumab And Combination Chemotherapy in Rectal Cancer Until Surgery

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 evaluate the efficacy, toxicity and feasibility of FOLFOX/ bevacizumab and FOLFOXIRI/ bevacizumab neoadjuvant therapy in poor prognosis rectal cancer as defined by MRI.

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 alone.

Inclusion

• 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 with the following:

• T3 tumours extending (≥ 4 mm), beyond the muscularis propria N0-N2

• Or tumours (involving or threatening the peritoneal surface)

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

• AND for tumours below the peritoneal reflection, the primary tumour or involved lymph node (on MRI) must be >1 mm 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 ≥80 g/L
  • 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 ≥2+ 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 75 years

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

Exclusion

• Disease outside of the mesorectal envelope (internal iliac/lateral pelvic lymph node)
• Clinically significant cardiovascular or coronary disease <2 years before randomisation
• 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 eligible
• 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 mellitus
• 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 randomisation
• 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