A Phase II, Double-blind, Randomized Study to Compare the Efficacy of AZD2171 in Combination with 5-fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) and the Efficacy of Bevacizumab in Combination with FOLFOX in the Second-line Treatment of Patients with Metastatic Colorectal Cancer

• Register: EUCTR
• Last refreshed on: 18 April 2012
• Main ID: EUCTR2005-003443-31-CZ
• Date of registration: 25/11/2005
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: A Phase II, Double-blind, Randomized Study to Compare the Efficacy of AZD2171 in Combination with 5-fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) and the Efficacy of Bevacizumab in Combination with FOLFOX in the Second-line Treatment of Patients with Metastatic Colorectal Cancer
• Scientific title: A Phase II, Double-blind, Randomized Study to Compare the Efficacy of AZD2171 in Combination with 5-fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) and the Efficacy of Bevacizumab in Combination with FOLFOX in the Second-line Treatment of Patients with Metastatic Colorectal Cancer
• Date of first enrolment: 19/01/2006
• Target sample size: 210
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-003443-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Belgium, Czech Republic, Germany, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
- Provision of written informed consent.
- Males or females aged 18 years and older.
- Histological or cytological confirmation of adenocarcinoma of the colon or rectum.
- Stage IV (metastatic) disease with one or more measurable lesions at least 10 mm in the longest diameter by spiral computed tomography scan or 20 mm with conventional techniques (RECIST).
- Patients must have received one prior systemic therapy for metastatic disease.
- Patients must have documented progression during or following first line therapy.
- Patients must be suitable for subsequent treatment with FOLFOX.
- World Health Organisation (WHO) Performance score =2.
- Life expectancy of =12 weeks.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
- Any unresolved toxicity >CTC grade 2 from previous treatments.
- Prior therapy with FOLFOX or other oxaliplatin containing regimens including adjuvant therapy <12 months before entry into the study.
- Prior therapy with a VEGF inhibitor.
- Untreated unstable brain or meningeal metastases. Patients with radiological evidence of stable brain metastases are eligible providing that they are asymptomatic and either do not require corticosteroids or have been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids.
- Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count £1.5 x 109/L or platelet count £100 x 109/L or requiring regular blood transfusions to maintain haemoglobin >9 g/dl.
- Serum bilirubin ³1.5 x upper limit of reference range (ULRR).
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ³2.5 x ULRR. If liver metastases are present, ALT or AST >5 x ULRR.
- Serum creatinine >1.5 x ULRR or a creatinine clearance of £50 mL/min calculated by Cockroft-Gault formula (see Section 4.7.2.2).
- Greater than +1 proteinuria on 2 consecutive dipsticks taken no less than 1 week apart or if urinary protein =1.5 g in a 24 hour urine collection.
- Patients with a history of poorly controlled hypertension with resting BP >150/100 mmHg in the presence or absence of a stable regimen of anti hypertensive therapy. Measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2 minute intervals and averaged. If the first 2 diastolic readings differ by more than 5 mmHg then an additional reading should be obtained, and averaged.
- Any evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated respiratory disease, cardiac disease including arrhythmias, hepatic or renal disease).
- Mean QTc with Bazett’s correction >470 msec in screening electrocardiogram (ECG) or history of familial long QT syndrome (as per ICH guideline E14).
- Recent (<14 days) major surgery prior to entry into the study, or a surgical incision that is not fully healed.
- Significant haemorrhage (>30 mL/episode in previous 3 months) or haemoptysis (>5 mL fresh blood in previous 4 weeks).
- Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication.
- Known severe hypersensitivity to AZD2171, bevacizumab, oxaliplatin, 5 FU or leucovorin, or any of the excipients of these products.
- Other concomitant anti-cancer therapy.
- History of other malignancies within 5 years except for adequately treated basal or squamous cell skin cancer or carcinoma in situ.
- History of central nervous disorders or uncontrolled seizures.
- History of significant gastrointestinal impairment, as judged by the investigator that would significantly affect the absorption of AZD2171.
- Peripheral neuropathy.
- Known dihydropyrimidine dehydrogenase deficiency.
- Hypersensitivity to Chinese hamster ovary cell products or other recombinant or humanised antibodies.
- Previous enrolment or randomisation of treatment in the present study.
- Participation in a clinical study during the last 30 days.
- Known infection with hepatitis B or C or HIV



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Metastatic colorectal cancer

Intervention(s)

Product Code: AZD2171
Pharmaceutical Form: Film-coated tablet
Current Sponsor code: AZD2171
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Current Sponsor code: AZD2171
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Current Sponsor code: AZD2171
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Avastin
Product Name: Avastin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Bevacizumab
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: Eloxatin
Product Name: Eloxatin
Pharmaceutical Form: Solution for injection
INN or Proposed INN: oxaliplatin
Concentration unit: mg/m2 milligram(s)/square meter
Concentration type: equal

Trade Name: Fluorouracil
Product Name: Fluorouracil
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Fluorouracil
Other descriptive name: 5-FU

Trade Name: Leucovorin
Product Name: Leucovorin
Pharmaceutical Form: Solution for injection
INN or Proposed INN: leucovorin

Primary Outcome(s)

Main Objective: Determine the efficacy of AZD2171 in combination with FOLFOX compared to efficacy of bevacizumab in combination with FOLFOX by assessment of PFS

Secondary Objective: - The efficacy of AZD2171 in combination with FOLFOX compared to the efficacy of bevacizumab in combination with FOLFOX by assessment of overall survival (OS) and overall response rate (ORR; complete response [CR] + partial response [PR]).

- The effects on quality of life (QoL) and disease-related symptoms, as assessed by FACT C, of AZD2171 in combination with FOLFOX, compared with the effects of bevacizumab in combination with FOLFOX.

- The safety and tolerability of randomised study therapies in combination with FOLFOX.

Primary end point(s): The primary variable for the study is PFS. All patients will be followed until evidence of one of the following:
- progression of disease (patients will be followed for subsequent therapy and death)
- death without evidence of progression

Secondary ID(s)

2005-003443-31-GB

D8480C00041