Bevacizumab And Combination Chemotherapy in Rectal Cancer Until Surgery (BACCHUS)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by University College, London
Sponsor:
Collaborators:
Cancer Research UK
Hoffmann-La Roche
Information provided by (Responsible Party):
University College, London
ClinicalTrials.gov Identifier:
NCT01650428
First received: July 16, 2012
Last updated: April 22, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Rectal Cancer
Biological: Bevacizumab
Drug: Irinotecan
Drug: Oxaliplatin
Drug: 5-Fluorouracil
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University College, London:

Primary Outcome Measures:
  • Pathological Complete Response (PCR) [ Time Frame: The pCR rate will be assessed after surgery, therefore approximately 24 weeks after randomisation. ] [ Designated as safety issue: No ]
    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%).


Secondary Outcome Measures:
  • RECIST Response Rate [ Time Frame: This will be assessed after chemotherapy has ended. Chemotherapy will be given for up to 12 weeks. ] [ Designated as safety issue: No ]
    Complete response and Partial response will be considered as responses.

  • CRM Negative Resection Rate [ Time Frame: This will be assessed after surgery, therefore approximately 24 weeks after randomisation. ] [ Designated as safety issue: No ]
    Those with a resection distance >1mm amongst those having surgery.

  • T and N stage downstaging [ Time Frame: This will be assessed at the completion of treatment. Treatment will be given for up to 12 weeks. ] [ Designated as safety issue: No ]
    This will examine T and N stage to assess whether stage has worsened from baseline to post-treatment. A patient will be considered to have downstaged if i) both T and N stage decrease; ii) either T or N stage decreases and the other remains stable.

  • Progression Free Survival [ Time Frame: This will be assessed pre-cycle 4 and post-treatment, therefore at 6 weeks and 12 weeks after randomisation. ] [ Designated as safety issue: No ]
    This is defined as time from randomisation to disease progression or death, whichever occurs first. Disease progression will be assessed by the RECIST criteria at pre-cycle 4 and post-treatment.

  • Disease Free Survival [ Time Frame: 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. ] [ Designated as safety issue: No ]
    This is defined as the time from surgery with complete resections (R0) to the occurrence of relapse, second colorectal primary or death from any cause, whichever occurs first. Only subjects who have a complete resection (R0) will be included in this analysis. Patients who are alive, without recurrence and with no secondary colorectal cancer at the time of cut-off will be right-censored at the most recent date of assessment.

  • Overall Survival [ Time Frame: From study entry until death, until 3 years after randomisation. ] [ Designated as safety issue: No ]
    This is defined as the time from study entry until death. The OS of all subjects and of the subgroup who had complete resection (R0) will be calculated.

  • Local Control [ Time Frame: From date of surgery until local failure, until 3 years after randomisation. ] [ Designated as safety issue: No ]
    This will be assessed just for those patients who attain a CRM negative resection.

  • 1 year Colostomy Rate [ Time Frame: Post surgery (approximately 24 weeks after randomisation) and 1 year after randomisation. ] [ Designated as safety issue: No ]
    This will be assessed post-surgery. The Kaplan-Meier estimate will be used to estimate the colostomy rate at 1 year.

  • Frequency and severity of Adverse Events [ Time Frame: This will be from date of randomisation until 30 days after completion of treatment. Treatment is given for up to 12 weeks. ] [ Designated as safety issue: Yes ]
    This will be tabulated for both treatment arms, including all grade 1-5 toxicities.

  • Compliance of Chemotherapy [ Time Frame: This will be at the end of treatment (up to 12 weeks) ] [ Designated as safety issue: No ]
    Dose reductions and dose delays to all chemotherapy agents will be recorded.

  • Tumour Regression Grade (TRG) [ Time Frame: Assessed after surgery, approximately 24 weeks after randomisation. ] [ Designated as safety issue: No ]
    This results from post-resection tumour sample will be used to categorise TRG into five groups using Dworak method.

  • Tumour Cell Density [ Time Frame: This will be assessed after surgery, approximately 24 weeks after randomisation. ] [ Designated as safety issue: No ]
    This results from post-resection tumour sample will be used to provide an estimate of the average TCD and its 95% CI. This may be expressed as a mean, or if the date is skewed, the median.


Estimated Enrollment: 60
Study Start Date: April 2013
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: FOLFOX & Bevacizumab

Bevacizumab - 5 mg/kg IV over 30-90 minutes (cycles 1-5 only), Oxaliplatin - 85 mg/m2 IV over 2 hours, Folinic acid - 350 mg IV over 2 hours, 5-Fluorouracil - 3200 mg/m2 IV continuous infusion over 48 hour.

Treatment given every 2 weeks for 12 weeks (for 6 cycles)

Biological: Bevacizumab
5 mg/kg, IV (in the vein) over 30-90 minutes, on day 1 of each 2 weekly cycles. Number of cycles: 1-5 (bevacizumab should not be administered during cycle 6).
Other Name: Avastin
Drug: Oxaliplatin
165 mg/m2 IV (intravenous) over 1 hour on day 1 of two weekly cycle. Number of cycles: 1-6
Other Name: Eloxatin
Drug: 5-Fluorouracil
3200 mg/m2 IV (intravenous), continuous infusion over 48 hours starting on day 1 of two weekly cycle. Number of cycles: 1-6
Other Name: 5-FU
Experimental: FOLFOXIRI & Bevacizumab

Bevacizumab - 5 mg/kg IV over 30-90 minutes (cycles 1-5 only), Irinotecan - 165 mg/m2 IV over 1 hour, Oxaliplatin - 85 mg/m2 IV over 2 hours, Folinic acid - 350 mg IV over 2 hours, 5-Fluorouracil - 3200 mg/m2 IV continuous infusion over 48 hour.

Treatment given every 2 weeks for 12 weeks (for 6 cycles)

Biological: Bevacizumab
5 mg/kg, IV (in the vein) over 30-90 minutes, on day 1 of each 2 weekly cycles. Number of cycles: 1-5 (bevacizumab should not be administered during cycle 6).
Other Name: Avastin
Drug: Irinotecan
165 mg/m2 IV (intravenous) over 1 hour on day 1 of two weekly cycle. Number of cycles: 1-6
Other Name: Campto
Drug: Oxaliplatin
165 mg/m2 IV (intravenous) over 1 hour on day 1 of two weekly cycle. Number of cycles: 1-6
Other Name: Eloxatin
Drug: 5-Fluorouracil
3200 mg/m2 IV (intravenous), continuous infusion over 48 hours starting on day 1 of two weekly cycle. Number of cycles: 1-6
Other Name: 5-FU

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

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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:

    • 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 schedule

Exclusion

  • 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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01650428

Contacts
Contact: Natasha Hava 02076799287 ctc.bacchus@ucl.ac.uk
Contact: Marian Duggan 02076799883 marian.duggan@ucl.ac.uk

Locations
United Kingdom
Royal Marsden Hospitals NHS Foundation Trust Recruiting
London and Surrey, United Kingdom
Principal Investigator: Ian Chau, MBBS MRCP MD CCT GMC FRCP         
Sponsors and Collaborators
University College, London
Cancer Research UK
Hoffmann-La Roche
Investigators
Principal Investigator: Rob Glynne-Jones, BA MB FRCP FRCR Mount Vernon Hospital
  More Information

No publications provided

Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT01650428     History of Changes
Other Study ID Numbers: UCL/09/0176
Study First Received: July 16, 2012
Last Updated: April 22, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: National Health Service
United Kingdom: National Institute for Health Research
United Kingdom: Research Ethics Committee

Keywords provided by University College, London:
Rectal Cancer
Bevacizumab
Neoadjuvant
Chemotherapy
Randomised

Additional relevant MeSH terms:
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Oxaliplatin
Irinotecan
Bevacizumab
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Radiation-Sensitizing Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Angiogenesis Inhibitors

ClinicalTrials.gov processed this record on August 19, 2014