E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer refractory to irinotecan treatment |
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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 |
To compare in skin biopsies the effects of an cetuximab dose escalation regimen on EGFR and downstream signaling pathway markers with those of the standard cetuximab regimen |
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E.2.2 | Secondary objectives of the trial |
To compare the percentages of patients experiencing Grade 2 or higher skin toxicity in patients randomized to receive cetuximab at the standard dosing regimen (dose group A) and in patients randomized to receive an escalating dosing regimen (dose group B) using NCI-CTC criteria, version 2.0. To compare the two treatment regimens (groups A and B) with respect to efficacy.·To compare the two treatment regimens (groups A and B) with respect to toxicity (safety and tolerability).·To investigate effects of higher cetuximab doses on EGFR and downstream signaling pathway markers in tumor.·To investigate the relationship between efficacy, skin toxicity and alterations in molecular profiles to identify pharmacogenomic markers that correlate with response or resistance.·To investigate differences in molecular markers between baseline and on-treatment samples·To perform evaluations of pharmacokinetics |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Histologically confirmed diagnosis of adenocarcinoma of the colon or rectum. Metastatic colorectal adenocarcinoma not suitable for curative-intent treatment. Presence of at least one bidimensionally measurable lesion, not in a previously irradiated area. Immunohistochemical evidence of EGFR expression prior to study entry in primary tumor and/or at least one metastasis. Irinotecan 180 mg/m2 (210mg/m² is accepted), either as monotherapy or in combination with other agents, every 2 weeks for at least six weeks as most recent chemotherapy treatment. Up to two prior licensed dosage attenuations below 180mg/m² for irinotecan-associated toxicity are permitted. Time between last treatment and progression on the irinotecan-based therapy should not be longer than 90 days. Documented progression according to modified WHO criteria by comparison of CT or MRI scans on/after the irinotecan based therapy (new lung lesions may be documented by chest x-ray) whereby the time between documentation of progression and start of study treatment should not be longer than 90 days. At least one tumor site suitable for biopsy sampling. Still being able to tolerate therapy with irinotecan. Karnofsky performance status of ³ 80 at study entry. Effective contraception for both male and female patients if risk of conception exists. Neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL. Bilirubin level either normal or < 1.5 x ULN, ASAT and ALAT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastasis) and serum creatinine < 1.5 x ULN. Recovered from relevant toxicities of previous chemotherapy. |
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E.4 | Principal exclusion criteria |
Brain metastasis (known or suspected). Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry. Having participated in another study within the preceding 30 days. Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or hormone therapy not indicated in the study protocol. Any investigational agent within 4 weeks prior to entry. Having received mitomycin C within 6 weeks prior to study entry. Any active dermatological condition > Grade 1. Previous exposure to EGFR pathway targeting therapy. Having previously participated in a study which included a possibility of being allocated to cetuximab therapy (whether or not the patient actually received cetuximab). Clinically relevant coronary artery disease or a history of a myocardial infarction within the last 12 months or left ventricular ejection fraction (LVEF) below the institutional range of normal. Acute or subacute intestinal occlusion or history of inflammatory bowel disease. Known allergic/hypersensitivity reaction to any of the components of the treatment. Pregnancy (absence confirmed by serum/urine b-HCG) or breast-feeding. Other previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix. Known drug abuse/ alcohol abuse. Legal incapacity or limited legal capacity medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Expression of EGFR and markers for the downstream signalling pathways in normal skin expressed by means of percentage of stained cells and staining intensity. IHC staining will allow a semi quantitative analysis of protein markers of the EGFR related signalling pathway. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
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.8.5 | 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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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Last subject out about 9 months (April 2006) after enrolment of the last patient (July 2005). |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |