E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer after 1 previous line of treatment |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic colorectal cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
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E.2.2 | Secondary objectives of the trial |
Tumor assessment
- Overall Progression Free Survival (PFS)
- PFS rate every 8 weeks
- Overall Time To Progression (TTP)
- TTP rate every 8 weeks
- Best response rate, Objective response rate (CR + PR) and Disease control rate (CR + PR + SD) every 8 weeks
• Quality of life assessment at week every 8 weeks
- ECOG Performance Status
- Quality of Life according to the EORTC QLQ-C30
- Analgesic intake
- Pain improvement (VAS)
• Pharmacogenomic assessment (Relationship between genomic data and overall survival)
• Safety profile using the NCI CTCAE v4.02 classification
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1/ Patient with non-resectable metastatic colorectal cancer with histological or cytological documentation of adenocarcinoma of the colon or rectum
2/ Metastatic disease not amenable to surgical resection with curative intent
3/ Patient in second line treatment after progression according to RECIST criteria following administration of a standard chemotherapy regimen for treatment of metastatic disease
4/ Patient with measurable lesions according to RECIST criteria (version 1.1) with spiral CT scan and defined as 10 mm in longest diameter and 2X the slice thickness for extra nodal lesions and/or >15 mm in short axis diameter for nodal lesions
5/ Patient eligible for a standard second line therapy with FOLFIRI
•Patient with ECOG ≤ 2
•Patient with adequate organ function
•Absolute neutrophils count (ANC) ≥ 1.5 x 109/L
•Haemoglobin ≥ 10 g/dl
•Platelets (PLT) ≥ 75 x 109/L
•AST and/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases)
•GammaGT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases)
•Bilirubin ≤ 1.5 x ULN (≤ 3 x ULN in case of liver metastasis)
•Normal cCreatinine or if abnormal creatinine, creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)
•Albuminaemia> 1 x LLN
•Proteinuria < 30 mg/dL (1+) on the dipstick. If proteinuria is ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours
8/ Patient with life expectancy > 3 months
9/ Female or male patient ≥ 18
10/ Patient weight >40 kg and BMI > 18 kg/m2
11/ Contraception
•Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception include:
-A documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository)
-Documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used
-Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
-Any other contraceptive method with a documented failure rate of <1% per year
-Abstinence when this is in line with the preferred and usual lifestyle of the patient.
•Male patients must use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. The acceptable methods of contraception are as follows:
-Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
-Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository)
-If his female partner uses oral contraceptives (combination oestrogen/progesterone pills), injectable progesterone or subdermal implants, in addition a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used.
-Medically prescribed topically-applied transdermal contraceptive patch and a barrier method ()
-If his female partner has undergone documented tubal ligation , in addition a barrier method should also be used.
-If his female partner has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS), in addition a barrier method
-Abstinence when this is in line with the preferred and usual lifestyle of the patient.
Male patients must use medically acceptable methods of contraception Acceptable methods include:
-Condom
-If the patient has undergone surgical sterilization, a condom should also be used.
12/ Female patient of childbearing potential must have a negative pregnancy test at screening and baseline
13/ Patient able and willing to comply with study visits and procedures as per protocol
14/ Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures are performed. If the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable, the designated legal guardian must sign the informed consent.
15/ Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe skin toxicity
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E.4 | Principal exclusion criteria |
1./ Patient intolerant to one of these treatments: irinotecan, 5-fluorouracil (5-FU), folinic acid
2/ More than 1 prior chemotherapy regimens for metastatic colorectal cancer.
3/ Pregnant, intent to be pregnant, or nursing female patient
4/ Patient with any chronic inflammatory bowel disease
5/ Patient treated for a cancer other than colorectal cancer within five years before enrollment, with the exception of basal cell carcinoma or cervical cancer in situ
6/ Patient required to receive other therapy than FOLFIRI for second line metastatic colorectal cancer
7/ Patient with an hepatic involvement > 50%
8/ Patient with active central nervous system (CNS) metastasis or history of CNS metastases
9/ Patient with an active infection (Human immunodeficiency virus infection and/or hepatitis B or C infection …)
10/ Patient presenting with cardiac disorders defined by at least one of the following conditions:
•Patient with recent cardiac history (within 6 months) of:
-Acute coronary syndrome
-Acute heart failure (class III or IV of the NYHA classification)
-Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
•Patient with cardiac failure class III or IV of the NYHA classification
•Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
•Syncope without known aetiology within 3 months
•Uncontrolled severe hypertension, according to the judgement of the investigator, or symptomatic hypertension
11/ Patient with a history of poor compliance or of drug/alcohol abuse, or excessive alcohol beverage consumption, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
WASH OUT
12/Any previous treatment with an investigational agent or chemotherapy or biological agent will require a wash-out period of four weeks prior to baseline.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Overall Survival (OS) is defined as the time from the randomization to the date of documented death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Survival rate is defined as the rate of patients alive at each time point
• Overall Progression Free Survival (PFS) is defined as the delay between the date of randomization to the date of documented progression or any cause of death during the study. Progression will be assessed by CT scan according to RECIST criteria version 1.1 as defined in table 5.
• PFS rate is defined as the rate of patients without progression or death at each time point
• Overall Time To Progression (TTP) is defined as the time from the date of randomization to the date of documented progression defined according to RECIST criteria version 1.1
• TTP rate is defined as the rate of patients without documented progression at each time point
• Best Response is defined as the best response (CR or PR or SD or PD) defined according to to RECIST criteria version 1.1 recorded from the start of the treatment until end of study.
• Best Response rate is defined as the number of patients achieving the Best Response divided by the total number of patients in the population of analysis.
• Objective response rate (CR + PR) is defined as the number of patients with documented partial response or complete response defined according to RECIST, divided by the number of randomized patients
• Disease control rate (CR + PR + SD) is defined as the number of patients with documented partial response, complete response or stable disease defined according to RECIST criteria version 1.1, divided by the number of patients randomized at each time point.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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 | Information not present in EudraCT |
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 | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 | No |
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 |
Argentina |
Austria |
Canada |
China |
Cyprus |
Czech Republic |
Egypt |
France |
Germany |
Greece |
Hong Kong |
Hungary |
India |
Israel |
Italy |
Korea, Democratic People's Republic of |
Korea, Republic of |
Lebanon |
Malaysia |
Mexico |
Morocco |
Myanmar |
Peru |
Philippines |
Romania |
Russian Federation |
Serbia |
Singapore |
Slovakia |
South Africa |
Spain |
Taiwan |
Tunisia |
Ukraine |
United Kingdom |
United States |
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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
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patient treated until disease progression limitoing toxicity or consnet withdrawal. Follow-up performed until patient's death |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |