| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 this study is to assess the efficacy of ZD6474 (100 mg and 300 mg) in combination with the modified FOLFOX 6 regimen (mFOLFOX6) versus mFOLFOX6 alone for the treatment of patients with colorectal cancer that have failed prior treatment with irinotecan and a fluoropyrimidine by assessment of disease progression. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to assess the safety and tolerability of ZD6474 (100 mg and 300 mg) in combination with mFOLFOX6 in the treatment of colorectal cancer by review of AEs and laboratory parameters. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have histologically confirmed colorectal cancer.
2. Have failed therapy with an irinotecan and fluoropyrimidine containing regimen defined as:
- Progression on or following treatment for metastatic colorectal cancer
- Progression within 12 months of adjuvant chemotherapy for colorectal cancer.
3. Have World Health Organisation (WHO) performance status 0-2 and life expectancy > 12 weeks.
4. Are suitable for treatment with oxaliplatin, 5-FU and leucovorin (FOLFOX) (see Appendix E of protocol).
5. Be aged at least 18 years.
6. Provide written informed consent to participate in the study.
|
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with small molecule tyrosine kinase inhibitors of VEGFR or EGFR eg, erlotinib, gefitinib. Prior monoclonal antibodies are permitted eg, cetuximab, bevacizumab.
2. Previous adjuvant therapy with oxaliplatin within 12 months of randomisation.
3. More than one prior course of chemotherapy for treatment of metastatic colorectal cancer.
4. Any recent surgery, unhealed surgical incision or severe concomitant condition which, in the Investigator’s opinion, makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the study protocol.
5. Current or prior malignancy within previous 3 years (other than colorectal cancer or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix).
6. Brain metastases or spinal cord compression unless treated and stable off steroids for one month.
7. With the exception of alopecia, any unresolved toxicity ≥ CTCAE grade 2 from previous anticancer therapy. (unless specified else where within these selection criteria)
8. Persistent neuropathy following prior oxaliplatin therapy.
9. At time of randomisation less than 4 weeks since completion of prior radiotherapy to the primary tumour or persistence of any acute radiotherapy toxicity.
10. Chronic inflammatory bowel disease, bowel obstruction or other current active gastrointestinal disease.
11. Significant cardiovascular event (eg, myocardial infarction, New York Heart Association classification of heart disease (NYHA) ≥ 2) within 3 months of randomisation, or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
12. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, symptomatic or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication, is not excluded.
13. Left bundle branch block.
14. Hypertension not controlled by medical therapy (systolic blood pressure > 160 mmHg or diastolic blood pressure > 110 mmHg).
15. Baseline mean QTc measurement ≥ 480ms using Bazett’s formula.
16. Patients with factors that increase risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of unexplained sudden death under 40 years of age or any concomitant medication known to prolong QTc.
17. Any of the following laboratory values:
- Potassium <4.0 mmol/l despite supplementation
- Calcium (or calcium adjusted for albumen) or magnesium out of normal range despite supplementation.
18. Any of the following laboratory values:
- Total bilirubin > 1.5 x ULN (upper limit of normal)
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN if no demonstrable liver metastases or > 5 x ULN in presence of liver metastases.
19. Any of the following laboratory values:
- Platelets < 100 x10e9/l.
- Haemoglobin < 9 g/dl despite transfusion
- Absolute neutrophil count < 2.0 x10e9/l.
20. Creatinine clearance < 50 ml/min and/or an elevated serum creatinine > 1.5 ULN.
21. Presence of clinically significant blood or protein on repeat urine labstix test.
22. Concomitant use of the inducers of CYP3A4 (eg, phenytoin, rifampicin, carbamazepine, barbiturates and St John’s Wort) are not allowed for 2 weeks prior to randomisation or while on any study treatment.
23. History of hypersensitivity to active or inactive excipients of any study medication (ZD6474/placebo, oxaliplatin, fluorouracil, leucovorin).
24. Pregnancy, breast feeding or women of child bearing potential not using an effective method of birth control.
25. Previous enrolment and randomisation of treatment in the present study.
26. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site).
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Assess efficacy of ZD6474 (100mg and 300mg) in combination with mFOLFOX6 versus mFOLFOX6 alone in the treatment of colorectal cancer. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | No |
| 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 end of the study will be data cut-off, following which no further data are expected on the clinical database. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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