E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histologically confirmed and inoperable or irresectable metastatic colorectal cancer (stage IV) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10010035 |
E.1.2 | Term | Colorectal cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Investigating the efficacy of maintenance and reinduction treatment or no treatment and watchful waiting in subjects with inoperable or irresectable and non-progressive metastatic colorectal cancer after first line induction treatment for 24 weeks with a fluoropyrimidine-, oxaliplatin- and bevacizumab-based chemotherapy. The maintenance treatment with capecitabine or 5-FU/folinic acid and bevacizumab will be compared with a maintenance treatment with bevacizumab alone or no maintenance treatment. Reinduction treatment will be done in case of progression.
Primary end-point: Time to failure of maintenance and reinduction treatment strategy measured from randomization.
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E.2.2 | Secondary objectives of the trial |
Secondary end-points: - Time to failure of strategy from enrolment - Toxicity: Incidence, onset, duration, severity - Quality of life - Progression-free survival (PFS 1) - Progression-free survival during reinduction treatment (PFS 2) - Objective response rate due to first induction - Objective response rate on reinduction treatment - Treatment free interval / duration of maintenance therapy - Secondary resection rate with curative intent - Reasons for discontinuation of treatment - Overall survival - Translational research: immunohistochemistry, protein and gene expression parameters, proteomics and epigenetics; circulating tumour cells.
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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 |
1.) Full title: Quality of life supplementary study (LQ-KRK0207) to the AIO Trial KRK 0207: Randomized three arm phase III trial on induction treatment with 5-fluorouracil / leucovorin and oxaliplatin or capecitabine and oxaliplatin, both in combination with bevacizumab, for 24 weeks followed by maintenance treatment with bevacizumab and 5-fluorouracil / leucovorin or capecitabine vs. bevacizumab alone vs. no maintenance treatment and reinduction in case of progression for first-line treatment of patients with metastatic colorectal cancer A cooperative project of the quality of life working group and the colorectal cancer study group of the AIO Version: FINAL 3, January 21,2010
2.) Translational Research – Biomarker Development The aim of the accompanying scientific project is the continuous collection, archiving and processing of tumour tissue material as well as whole blood and serum/plasma of patients treated within the AIO-KRK-0207 trial. Tumour tissue and non-tumour tissues will be investigated. Circulating tumour cells (CTC), assessable in peripheral blood, are a widely examined prognostic marker in breast cancer and other tumour types. In metastatic CRC, the role as a prognostic marker so far is discussed controversely. Recently, a large analysis comprising 430 patients from an phase III trial has shown that reduction of CTC during treatment may serve as prognostic marker and as a predictor for progression free survival and overall survival. Therefore, evaluation of CTC count and CTC reduction in terms of treatment de-escalation is planned for a subset of patients. The objectives of translational research on tumour tissue will be the investigation of the immunohistochemical expression of relevant biological markers as well as gene expression arrays and its correlation with outcome. Proteomic analyses could lead to the identification of proteins with prognostic or predictive potential. Genotyping of non-tumour tissues might allow predicting treatment-related toxicity, whereas the genotype of both tumour and non-tumour tissue influences treatment response. |
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E.3 | Principal inclusion criteria |
- Histologically confirmed and inoperable or irresectable metastatic colorectal cancer (stage IV)
- Measurable lesion according to RECIST measured within 4 weeks prior to registration of the subject for the study
Not allowed prior treatments - Previous chemotherapy for metastatic disease (adjuvant therapy for non-metastasized disease is allowed if terminated more than 6 months ago and without recurrence within 6 months after the end of adjuvant treatment) - Prior radiation of indicator lesion(s), except for documented progression during radiation and termination of radiotherapy at least 4 weeks prior to entry into the study
- 18 years and over
- ECOG 0-2
- No past or current history of malignancies except for the indication under this study and curatively treated: o Basal and squamous cell carcinoma of the skin o In-situ carcinoma of the cervix o Other malignant disease without recurrence after at least 5 years of follow-up - No severe internal disease (insufficiently treated or uncontrolled arterial hypertension, hemoptoe, NYHA grade II or greater congestive heart failure, symptomatic coronary heart disease, myocardial infarction (≤ 12 months prior to inclusion), serious cardiac arrhythmia requiring medication, peripheral arterial occlusive disease stage II or greater, uncontrolled severe disease) - No history or evidence upon physical examination of CNS disease unless adequately treated - No pre-existing neuropathy >= grade 1 (NCI CTCAE), except for loss of tendon reflex as the only symptom - No interstitial pneumonia or symptomatic fibrosis of the lung - No allogenic transplantation requiring immuno-suppressive therapy - No severe non-healing wounds, ulcers or bone fractions - No thrombosis or severe bleeding within 6 months prior to entry into the study (except for bleeding of the tumor before its surgical resection) and no evidence of bleeding diathesis or coagulopathy. - Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and aPTT < 1.5 ULN within 7 days prior to registration. The use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least two weeks at the time of registration.
Laboratory requirements - within 7 days prior to enrollment - Neutrophil count >= 1,500/µl - Platelets >= 100,000/µl - Hb >= 9g/dl (may be transfused to maintain or exceed this level) - Serum creatinine clearance > 50ml/min (Cockroft/Gault) - Serum total bilirubin: =< 1.5 x ULN - AST and ALT =< 2.5 x ULN; =< 5 x ULN in subjects with documented liver metastases
Lab requirements in fertile woman -within 2 days prior to treatment) - Negative serum pregnancy test
Other medication - No concomitant therapy with certain anti-viral medicines - No continuous medication with ASS > 325 mg or NSAIDs, known to inhibit platelet function
Other - No major surgical procedure, open biopsy, nor significant traumatic injury within 28 days prior to study treatment start, nor anticipation of the need for major surgical procedure during the course of the study except for surgery for colorectal cancer with curative intent and central venous line placement for chemotherapy administration, which must be inserted at least 2 days prior to treatment start. With the only exception of a high remission pressure in case of synchronous metastases in just resected colorectal cancer, treatment may be initiated without addition of bevacizumab at the 1st, and eventually second, administration, if the start of treatment could not be delayed until at least 28 days. In that case, the first application of chemotherapy may begin without bevacizumab as early as two weeks after surgery. - No pregnant or breastfeeding women - No women of child-bearing potential with positive or missing pregnancy test at study entry; post-menopausal women must have been amenorrheic for at least 12 months to be considered of non-child-bearing potential - No sexually active men or women of childbearing potential not willing to use effective means of contraception (intrauterine contraceptive device, implants, injectables, sexual abstinence or vasectomised partner) - No subjects with known allergy to the used study drugs or to any of its excipients - No known DPD deficiency - No proteinuria (>1+); if dipstick test of urine exceeds 1+, proteiunuria has to be below 1g protein in 24 hours urine - No concomitant treatment with preparations of St. John’s wort - No currently or recent (within the 28 days prior to starting study treatment) treatment of another investigational drug or participation in another investigational study - No known grade III/IV allergic reaction against monoclonal antibodies
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E.4 | Principal exclusion criteria |
See with E.2 Principal inclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
AIO-KRK-0207 (Main study): Time to failure of maintenance and reinduction treatment strategy measured from randomization. Quality of life evaluation: Difference in the mean value of the global quality of life dimension of the EORTC QLQ C30, calculated as the average of all available time points from 6 weeks to 24 weeks after start of maintenance treatment or treatment interruption. |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Substudies: Quality of life supplementary study (LQ-KRK0207); Translational Research (CTC,CEC) |
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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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Investigational arm 3: No maintenance treatment until progression |
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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 | 120 |
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
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This clinical trial starts with the first initiation visit and ends when all patients have finished the 24 months follow-up from registration and randomization and the database has been fully cleaned and frozen for this analysis. |
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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 | 5 |
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 | 5 |
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 |