| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This is a Phase II / III trial in Patients with Previously Untreated Metastatic Colorectal Cancer. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is to determine:
The efficacy of AZD2171 in combination with FOLFOX compared to the efficacy of bevacizumab in combination with FOLFOX by assessment of progression free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to determine:
The efficacy of AZD2171 in combination with FOLFOX compared to the efficacy of bevacizumab in combination with FOLFOX by assessment of OS, overall response rate (ORR; complete response [CR] + partial response [PR]) and duration of response.
The safety and tolerability of randomised study therapies in combination with FOLFOX.
The effects on quality of life (QoL) and disease-related symptoms of AZD2171 in combination with FOLFOX, compared with the effects of bevacizumab in combination with FOLFOX.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study, patients must fulfil all of the following criteria:
Provision of written informed consent.
Males or females aged 18 years and older.
Histological or cytological confirmation of carcinoma 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 criteria). Patients who have previously been disease free following a neoadjuvant chemotherapy regimen and resection of all primary tumours and metastatic disease are eligible provided they have measurable disease as above
Patients must have received no prior systemic therapy for metastatic disease. Any adjuvant/neo-adjuvant oxaliplatin therapy must have been received more than 6 months prior to study entry
Life expectancy of ≥12 weeks.
|
|
| E.4 | Principal exclusion criteria |
Any of the following is regarded as a criterion for exclusion from the study:
Termination of adjuvant oxaliplatin therapy within 12 months of study entry or termination of adjuvant 5FU therapy within 6 months of study entry.
Any unresolved toxicity >CTC grade 1 from previous anticancer therapy (including radiotherapy) except haematological toxicity and alopecia.
Prior therapy with monoclonal antibodies or small molecule inhibitors against VEGF or VEGF receptors, including bevacizumab and cedaranib.
Prior therapy with oxaliplatin within 12 months of study entry.
Untreated brain or meningeal metastases. Patients with radiological evidence of stable brain metastases are eligible providing 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 less than or equal to 1.5 x 10 to the power 9/L or platelet count less than or equal to 100 x 10 to the power 9/L or requiring regular blood transfusions to maintain haemoglobin >9 g/dL.
Serum bilirubin greater than or equal to 1.5 x upper limit of reference range (ULRR) except in the case of Gilberts syndrome.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 2.5 x ULRR. If liver metastases are present, ALT or AST >5 x ULRR.
Serum creatinine >1.5 x ULRR or a creatinine clearance of less than or equal to 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 unless urinary protein, <1.5 g in a 24 hour urine collection.
Patients with a history of poorly controlled hypertension or 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 5mmHg, then an additional reading should be obtained, and averaged.
Any evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated respiratory, cardiac including arrhythmias, hepatic or renal disease).
Mean QTc with Bazett’s correction >470 msec in screening ECG or history of familial long QT syndrome (as per ICH guideline E14).
Recent (<28days) major abdominal or thoracic surgery prior to entry into the study, or a procedure considered to have a significant risk of internal bleeding. Presence of a surgical wound incision that is not fully healed.
Significant haemorrhage (>30mL/bleeding episode in previous 3 months) or haemoptysis (>5mL fresh blood) in previous 4weeks) or thrombotic event (including transient ischaemic attack) in the previous 12 months.
Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication.
Known severe hypersensitivity to cedaranib, bevacizumab, oxaliplatin, 5 FU, or leucovorin, or any of the excipients of these products.
Other concomitant anti-cancer therapy.
History of other malignancies (except for adequately treatedbasal or squamous cell carcinoma in situ) within 5 years unless the patient has been disease free for 2 years and there is a tissue diagnosis of the primary cancer of interest from a target leison.
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 cedaranib.
Peripheral neuropathy ≥CTC grade 2.
Known dihydropyrimidine dehydrogenase (DPD) deficiency.
Hypersensitivity to Chinese hamster ovary cell products or other recombinant or humanised antibodies.
Previous enrolment or randomisation in the present study.
Treatment with an investigational (non-registered) drug during the last 30 days.
Known risk of the patient transmitting HIV or hepatitis B or C via infected blood |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary outcome variable:
PFS
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The date of the last visit of the last subject for any protocol related activity. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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