| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Colorectal Cancer |
|
| MedDRA Classification |
| 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 main objective of this trial is to assess whether the addition of ZD4054 to the widely used FOLFIRI chemotherapy regimen improves the clinical outcome for participants with metastatic colorectal cancer who have failed to respond to treatment with oxaliplatin-containing chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this trial are to determine if the combination of FOLFIRI chemotherapy plus ZD4054 is safe and tolerable in participant with metastatic colorectal cancer and to collect blood and tissue samples from this patient population to facilitate future translational research. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Participants will be asked to participate in an optional sub-study of the main FOLFERA trial (see full title provided in Section A.3 of this form) and detailed in Section 13.0 FOLFERA Translational Sub-study research of the trial protocol supplied with this application (Version Number 1.1, 22nd October 2009). All FOLFERA participants will be asked to consider the provision of additional blood samples for translational research. A separate research proposal will be submitted to fund analysis of collected samples. These samples will be collected pre- and post-treatment at baseline and at week 16. Permission will also be sought to analyse paraffin tissue blocks of diagnostic tumour tissue specimens. The objective of the sub-study is to analyse these samples to gain a better understanding of the FOLFIRI and ZD4054 treatment combination in colorectal cancer. |
|
| E.3 | Principal inclusion criteria |
Patients meeting all of the following criteria may be included in the trial:
1)Histological or cytological diagnosis of metastatic colorectal cancer.
2)Patients must be resistant to oxaliplatin. If metastatic patients progress at any time after oxaliplatin containing chemotherapy, or if adjuvant patients progress within 6 months of oxaliplatin containing chemotherapy they will be included in this study providing that they have no significant ongoing toxicity (excluding grade 1 neurotoxicity)
3)Measurable disease by RECIST criteria.
4)Adequate bone marrow, hepatic and renal function including the following:
a)Haemoglobin ≥ 9.0 g/L (no prior transfusion) or ≥ 10.0 g/L (transfusion within last 4 weeks), absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L;
b)Total bilirubin < 1.5 x upper normal limit;
c)AST and ALT ≤ 2.5 x upper normal limit (or ≤ 5x UNL in the presence of liver metastases);
d)Creatinine clearance (as measured by Cockcroft and Gault equation, appendix 2) ≥50mls/min.
5)Age ≥ 18 years.
6)ECOG Performance status 0 or 1.
7)Patients must have recovered from effects of major surgery.
8)In view of concerns of possible teratogenicity, female patients must have no child bearing potential. A negative urine or serum pregnancy test within 3 days prior to start of trial treatment is required. A pregnancy test is not necessary for women who are post-menopausal.
9)Males with reproductive potential should be prepared to use adequate contraception
10)Life expectancy of at least 12 weeks.
11)The patient has provided written informed consent.
|
|
| E.4 | Principal exclusion criteria |
If any of the following criteria apply, patients cannot be included in the trial:
1)Any chemotherapy, radiotherapy (except for palliative reasons), endocrine therapy or immunotherapy within four weeks prior to commencing treatment. Patients may continue the use of corticosteroids provided the dose is stable for 4 weeks and not altered during the first 15 days of the study.
2)Have received more than one course of chemotherapy for metastatic disease, and any previous treatment with ZD4054 or Irinotecan. Where oxaliplatin has been used in an intermittent schedule allowing patient holidays, it will be considered equivalent to one prior line of therapy providing that patients have had at least stable disease whilst on active treatment.
3)Extensive prior irradiation (likely to deplete bone marrow reserve).
4)Major surgery within 4 weeks of starting the study.
5)Co-existing active infection or serious concurrent medical condition.
6)Significant cardiovascular disease as defined by:
a)history of congestive heart failure requiring therapy (NYHA grade 2 or higher);
b)history of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry;
c)presence of severe valvular heart disease;
d)presence of a ventricular arrhythmia requiring treatment.
e)Prolonged QTc interval, >470msec.
7)Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study or potentially hamper compliance with the study protocol and follow-up schedule.
8)Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or compliance with the study protocol.
9)Bone metastases.
10)Known brain or leptomeningeal metastases unless patients have stable disease following surgical resection or radiosurgery of oligometastases.
11)Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel obstruction or malabsorption).
12)Patients known to be serologically positive for Hepatitis B or Hepatitis C (mandatory testing not required).
13)Immunocompromised patients e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV) (mandatory testing not required).
14)Women of childbearing potential who are pregnant or breast-feeding. Women of childbearing potential are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who have had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test ≤ 3 days prior to starting study treatment.
15)Other previous or current malignant disease likely to interfere with protocol treatment or comparisons.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival(PFS). Progression is defined according to RECIST 1.1. |
|
| 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 | Yes |
| 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 | Yes |
| 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 | 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) | 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
| For the purposes of complying with UK Medicines for Human Use (Clinical Trial) Regulations introduced in May 2004, the trial will be considered closed when the last participant has completed protocol treatment. However, further observational follow up will continue for a minimum of one year. For the purposes of Research Ethics Committee approval, the study date is deemed to be the date of last data capture. |
|
| 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 | |
| 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 |
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