Clinical trial NCT01650428: Bevacizumab And Combination Chemotherapy in Rectal Cancer Until Surgery
Official title: A Phase II, Multicentre, Open-Label, Randomised Study of Neoadjuvant Chemotherapy and Bevacizumab in Patients With MRI Defined High-Risk Cancer of the Rectum
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rectal Cancer
Keywords: Rectal Cancer
Bevacizumab
Neoadjuvant
Chemotherapy
Randomised
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
name: Hoffmann-La Roche
First posted: 2012-07-26
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Pathological Complete Response (PCR)
timeFrame: The pCR rate will be assessed after surgery, therefore approximately 24 weeks after randomisation.
Secondary outcomes:
measure: RECIST Response Rate
timeFrame: This will be assessed after chemotherapy has ended. Chemotherapy will be given for up to 12 weeks.
measure: CRM Negative Resection Rate
timeFrame: This will be assessed after surgery, therefore approximately 24 weeks after randomisation.
measure: T and N stage downstaging
timeFrame: This will be assessed at the completion of treatment. Treatment will be given for up to 12 weeks.
measure: Progression Free Survival
timeFrame: This will be assessed pre-cycle 4 and post-treatment, therefore at 6 weeks and 12 weeks after randomisation.
measure: Disease Free Survival
timeFrame: This will be length of time from date of surgery till relapse, second colorectal primary or death from any cause, whichever occurs first. These occurrences will be reported on CRFs every six months for up to three years.
measure: Overall Survival
timeFrame: From study entry until death, until 3 years after randomisation.
measure: Local Control
timeFrame: From date of surgery until local failure, until 3 years after randomisation.
measure: 1 year Colostomy Rate
timeFrame: Post surgery (approximately 24 weeks after randomisation) and 1 year after randomisation.
measure: Frequency and severity of Adverse Events
timeFrame: This will be from date of randomisation until 30 days after completion of treatment. Treatment is given for up to 12 weeks.
measure: Compliance of Chemotherapy
timeFrame: This will be at the end of treatment (up to 12 weeks)
measure: Tumour Regression Grade (TRG)
timeFrame: Assessed after surgery, approximately 24 weeks after randomisation.
measure: Tumour Cell Density
timeFrame: This will be assessed after surgery, approximately 24 weeks after randomisation.
Other outcomes:
Locations:
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas' Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: North MiddlesexHospital
city: London
country: United Kingdom
facility: Royal Marsden Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: UCLH
city: Middlesex
country: United Kingdom
facility: Mount Vernon Hospital
city: Slough
country: United Kingdom
facility: Wexham Park Hospital
city: Stevenage
country: United Kingdom
facility: Lister Hospital
Study officials:
affiliation: Mount Vernon Hospital
name: Rob Glynne-Jones, BA MB FRCP FRCR
role: PRINCIPAL_INVESTIGATOR
References:
citation: Glynne-Jones R, Hava N, Goh V, Bosompem S, Bridgewater J, Chau I, Gaya A, Wasan H, Moran B, Melcher L, MacDonald A, Osborne M, Beare S, Jitlal M, Lopes A, Hall M, West N, Quirke P, Wong WL, Harrison M; Bacchus investigators. Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum. BMC Cancer. 2015 Oct 23;15:764. doi: 10.1186/s12885-015-1764-1.