E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
resectable liver metastases of colorectal carcinoma with proven K-RAS wildtype |
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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 |
The first primary objective of the study is to compare the postoperative complication rate according to Clavien score (> grade 1) of a perioperative chemotherapy with a postoperative regimen. A second primary objective of the study is to compare for the patient subgroup with >3 liver metastases or at least one metastasis ≥ 5 cm in diameter the median disease free survival.
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E.2.2 | Secondary objectives of the trial |
• To compare the overall disease-free survival. • To compare the overall survival. • To compare operation, resection and R0 rates. • To compare the safety and chemotherapy-associated toxicity (NCI-CTC V4.0) • To compare the effect of a perioperative therapy on health-related quality of life (EORTC QLQ-C30 + QLQ-LMC21). • To compare the number of cycles, dose intensity and dose modifications applied. • To evaluate the response rate (RECIST V1.1 no confirmation of response needed) after preoperative chemotherapy. • Resected liver mass
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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 |
1st Sub-study: Biomarker Program in colorectal liver metastases: • Improve management and selection of patients with colorectal liver metastases through identification of biomarkers (or pathways) that predict response to neoadjuvant chemotherapy in combination with Cetuximab • To identify biomarkers (or pathways) that predict general clinical outcome of patients with colorectal liver metastases +/- neoadjuvant chemotherapy + Cetuximab and/or R0-resection • To identify biomarkers (or pathways) associated with adverse effects of neoadjuvant chemotherapy + Cetuximab and resection of liver metastases (liver toxicity (CASH, SOS), wound healing problems, infections, post-OP liver failure, etc.) • To compare biomarkers (or pathways) profile of the primary tumor before neoadjuvant therapy with the colorectal liver metastases (+/-) neoadjuvant therapy
2nd Sub-study: Evaluation der Prognosegüte und Detektionskraft der Kontrastmittelsonographie bei primär resektablen Lebermetastasen eines kolorektalen Karzinoms: Primäre Studienziele: Erhoben in Therapiearm B und an der Targetmetastase: 1. Wie gut kann mittels der KMUS-Ergebnisse nach dem 2. Zyklus das Therapieansprechen prognostiziert werden? 2. Wie gut kann mittels der KMUS-Ergebnisse nach dem 6. bzw. 2. Zyklus das progressionsfreie Überleben prognostiziert werden? Dabei werden hierarchisch erst die Ergebnisse nach dem 6. Zyklus und dann die Ergebnisse nach dem 2. Zyklus untersucht.
Wichtigste sekundäre Studienziele: Erhoben in Therapiearm B und an der Targetmetastase: • Wie gut kann mittels der KMUS-Ergebnisse nach dem 6. Zyklus das Therapieansprechen prognostiziert werden? Erhoben in Therapiearm A und an allen Metastasen pro Patient: • Sensitivität, Spezifität und Gesamtgenauigkeit der KMUS in der Detektion von Lebermetastasen bei Patienten mit kolorektalem Karzinom mit der Histologie des Resektats als Goldstandard. • Vergleich der Diagnosegüte von CT und KMUS. (Aufgrund der unterschiedlichen Standards in der CT-Beurteilung in den einzelnen Zentren ist die Aussagekraft hierbei beschränkt)
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E.3 | Principal inclusion criteria |
1. Signed written informed consent obtained prior to any study-specific procedure 2. Age ≥ 18 years, full contractual capability 3. Proven K-RAS wildtype in primary tumour or metastasis tissue 4. Diagnosis of metachronous metastases after complete resection (R0) of primary tumour without gross or microscopic evidence of residual disease. or Diagnosis of synchronous metastases after complete resection (R0) of primary tumour more than 1 month before study. or Diagnosis of synchronous metastases with sufficient evidence (i.e., CT scan or diagnostic laparoscopy) that both the primary tumour and liver metastases can be completely resected during the same procedure and resection of primary tumour may be delayed 3-4 months 5. Negative pregnancy test 6. Highly effective contraception during treatment and for at least 3 months thereafter in women (defined as pearl index < 1), if necessary also for partners of test persons, complete abstinence of intercourse (during study participation and follow-up time) 7. Planned start of study medication between 0 and 3 weeks post randomization 8. ECOG performance status 0 or 1 (Appendix 1) 9. Adequate hematology: neutrophils > 1.5 /nl, platelets > 100/nl, INR < 1.5, aPTT < 1.5 x UNL 10. Adequate biochemistry: total bilirubin < 1.5 x UNL, ASAT and ALAT < 5 x UNL, alkaline phosphatase < 5 x UNL, serum creatinine < 1.5 x UNL
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E.4 | Principal exclusion criteria |
1. Patients with any relationship of dependence to the sponsor or the investigator 2. Patients committed to an institution (court-ordered or by official orders) 3. Extrahepatic metastatic disease 4. Proven K-RAS mutation or unknown K-RAS mutational status in tumour tissue. 5. Oxaliplatin-based adjuvant chemotherapy within 1 year before randomization. 6. Neuropathy ≥ grade 3 (NCI-CTC V4.0) during prior oxaliplatin-based chemotherapy. 7. Any prior chemotherapy for metastatic disease. 8. Previous treatment with EGFR antibodies. 9. Prior non-colorectal malignancies, except adequately treated basalioma of the skin or carcinoma in situ of the cervix. 10. Bleeding diathesis or coagulation disorders 11. Females with a positive pregnancy test (within 14 days before treatment start) or breast feeding. 12. Fertile women (< 2 years after last menstruation) and women of childbearing potential not willing to use effective means of contraception 13. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for drug intake. 14. Clinically significant (i.e. active) cardiovascular disease, e.g. cerebrovascular accidents (<6 months prior to randomization), myocardial infarction (<1 year prior to randomization), Congestive heart failure (NYHA Grades III or IV), uncontrolled hypertension while receiving chronic medication, unstable angina pectoris, significant arrhythmia. 15. Known peripheral neuropathy, including oxaliplatin-induced neuropathy ≥ grade 1 (NCI-CTC V4.0). Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible. 16. Known DPD-deficiency (Dihydropyrimidine dehydrogenase). 17. Organ allografts requiring immunosuppressive therapy. 18. Serious non-healing wound, ulcer or bone fracture. 19. Serious intercurrent infections (uncontrolled or requiring treatment). 20. Current or recent (within 28 days prior to randomisation) treatment with another investigational drug or participation in another investigational study. 21. Any contraindications against study medication (including auxiliary substances). 22. Patients unwilling to consent to saving and propagation of pseudonymized medical data for study reasons.
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E.5 End points |
E.5.1 | Primary end point(s) |
The first primary objective of the study is to compare the postoperative complication rate according to the Clavien score (> grade 1) (Appendix 2) of a perioperative chemotherapy with a postoperative regimen. A second primary objective of the study is to compare for the patient subgroup with > 3 liver metastases or at least one metastasis ≥ 5 cm in diameter the median disease free survival between the two treatment arms
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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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
perioperative chemotherapy compared to adjuvant chemotherapy |
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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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 | 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
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The end of study is defined as the last visit of the last patient, either at the end of study treatment or in the follow-up-period (individual follow up: 5 years). |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |