| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The aim of this study is to investigate the following schedules for efficacy with regard to response rate in neoadjuvant treatment of patients with non-resectable liver metastases:
- Cetuximab/FOLFOXIRI and cetuximab/FOLFIRI in patients with ras wild type tumours and
- Bevacizumab/FOLFOXIRI and FOLFOXIRI in patients with ras mutant tumours. |
|
| E.1.1.1 | Medical condition in easily understood language |
| neoadjuvant treatment of non-resectable colorectal liver metastases |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027457 |
| E.1.2 | Term | Metastases to liver |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months |
|
| E.2.2 | Secondary objectives of the trial |
-Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)
-Rate of liver resection with macroscopically tumour free margins and/or RFA (all patients with R0 or R1 resection and/or complete RFA of all lesion, ITT- population)
-Progression free survival (Kaplan-Meier-estimation, ITT- population)
-Disease free survival after resection (Kaplan-Meier-estimation, resected patients)
-Overall survival (Kaplan-Meier-estimation, ITT- population)
-Toxicity (safety population)
-Pathological response in resected tumour tissue
-Evaluation of molecular predictive markers for response (i.e. other mutations in EGFR pathway, EGFR ligands) and toxicity
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients can be enrolled, if all of these conditions apply:
1)Non-resectable, histologically confirmed, synchronous or metachronous colorectal liver metastases.
2)Non-resectability will be documented by a local multidisciplinary tumour board with participation of a surgeon experienced in liver surgery. Patients can be enrolled if they
a)are technically non-resectable (locally determined by a multi-disciplinary team discussion based on remaining functional liver tissue after resection, i.e.
i)involvement of both portal veins, all hepatic veins, portal vein of the liver lobe and hepatic veins draining the segments of the other liver lobe, or
ii)other reasons for less than 30% remaining functional liver tissue after resection)
and / or
b)have ≥ 5 liver metastases
and / or
c)are regarded as non-resectable for other reasons (description necessary)
3)Patients with simultaneous liver metastases are eligible,
a)if the primary tumour was resected at least 1 month prior to chemotherapy
or
b)all of the following conditions apply:
i)the primary tumour is clearly resectable,
ii)no radiation therapy is planned,
iii)liver resection is planned before resection of the primary or at the same operation as the resection of the primary,
iv)no two-stage liver resection is planned, and
v)all efforts were made to exclude additional distant metastases.
4)WHO PS ≤ 1
5)Written informed consent
6)Adequate bone marrow function, liver function (neutrophils > 1.5 x 109/l; platelets > 100 x 109/l; haemoglobin > 5.0 mmol/l (8.0 g/dl); bilirubin ≤ ULN or ≤ 1.5 x ULN and not increasing more than 25 % within the last 4 weeks; SGOT and SGPT < 5 x UNL)
7)Age ≥ 18 years
|
|
| E.4 | Principal exclusion criteria |
1)Any evidence of extrahepatic metastases, distant lymph node metastases and primary tumour recurrence
2)(deleted)
3)Prior systemic anti-tumour therapy with anti- EGFR-, anti-angiogenetic drugs or with chemotherapy (except adjuvant chemotherapy with an interval of ≥ 6 months or in combination with radiation as radio sensitizer)
4)Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic interventions or venous port implantation) ≤ 4 weeks before study entry
5)Renal insufficiency with serum creatinine ≥ 1.5 x UNL. If serum creatinine is between 1.0 and 1.5 x UNL, the creatinine clearance according to the Cockroft-Gault formula should be ≥ 60 ml/min
6)Hypertension with an arterial blood pressure > 150/90 mmHg
7)Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last 12 months, significant arrhythmias)
8)Known proteinuria > 1 g/day (to be tested if proteinuria more than 1+ in the urinary dipstick analysis)
9)Peripheral neuropathy > CTC grade I
10)Concurrent systemic immune therapy, chemotherapy, hormone therapy, or patients receiving immune suppressive treatment (i.e. for transplantation, severe rheumatologic disease)
11)Participation in clinical trials with investigational agents within 30 days before start of the treatment in study
12)Active treatment of
a)peptic ulcers or bleeding erosive esophagitis / gastritis within 3 months before study
b)pulmonary embolism, severe or unstable angina pectoris or myocardial infarction, stroke or transient ischemic attack within 12 months before study
c)deep vein thrombosis within 4 weeks before study
13)Inflammatory bowel disease
14)History of other malignancies, from which the patient is not 5 years disease free, with the exception of colorectal cancer, or adequately treated basal cell or squamous cell carcinoma of skin or in-situ cervical cancer within 5 years before study
15)History of brain metastases
16)History of severe psychiatric illness
17)Active drug- or alcohol abuse
18)Known hepatitis B or C or HIV infection
19)Breast- feeding or pregnant women
20)Lack of effective contraception (for male and female patients)
21)Known intolerance to one of the following drugs: cetuximab, bevacizumab, oxaliplatin, irinotecan, 5-FU, folinic acid
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of patients with partial or complete response according to modified RECIST criteria 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Rate of patients who had a R0 resection of all lesions and are disease free for at least 6 months
-Resection rate, defined as patients with microscopically complete (R0) resection (ITT- population)
-Rate of liver resection with macroscopically tumour free margins and/or RFA (all patients with R0 or R1 resection and/or complete RFA of all lesion, ITT- population)
-Progression free survival (Kaplan-Meier-estimation, ITT- population)
-Disease free survival after resection (Kaplan-Meier-estimation, resected patients)
-Overall survival (Kaplan-Meier-estimation, ITT- population)
-Toxicity (safety population)
-Pathological response in resected tumour tissue
-Evaluation of molecular predictive markers for response (i.e. other mutations in EGFR pathway, EGFR ligands) and toxicity
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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