| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resectable liver metastases from colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with a metastatic cancer of the colon or rectum wich is resectable at the time of diagnosis. |
|
| 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 | 15.0 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the efficacy of 5-Fluorouracil (5-FU) and oxaliplatin (FOLFOX-Regimen) for 6 months postoperatively compared to 5-FU, oxaliplatin and irinotecan (FOLFOXIRI-Regimen) with bevacizumab for three months pre- and three months postoperatively for resectable liver metastases from colorectal cancer. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are safety and tolerability of the treatment as well as the progression free survival, overall survival, achievability of R0/R1 resection, quality of life, overall (according to RECIST v1.1) and pathological response rate after preoperative treatment (Arm B) and perioperative morbidity. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Histological proven CRC with completely resectable metachronous or synchronous liver metastases (as judged by the treating surgeon).
-Patients must have undergone complete resection (R0) of the primary tumor at least 4 weeks before randomization. Or in case of synchronous disease with intact primary; the primary tumor have to be R0 resectable together with the liver metastases and the patient has a non-obstructive primary tumor and is able to receive preoperative chemotherapy before surgery. Synchronous rectal primary is not allowed.
-Measurable hepatic disease by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
-Ability to undergo anaesthesia and hepatic resection.
-Patients must be from 18 to 75 years.
-ECOG Performance status ≤ 1
-Previous adjuvant oxaliplatin-containing chemotherapy for primary CRC is allowed, if completed at least 12 months before inclusion in this study.
-All the following tests should be done within 4 weeks prior to randomization
a. Absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L, and hemoglobin > 9 g/dL or 5.59 mmol/l.
b. Serum creatinine less than 1.5 times the upper limit of normal (ULN) (to exclude severe renal impairment); no significant proteinuria (urine dipstick for proteinuria ³ 2+. If urine dipstick is ³ 2+, 24-hour urine must demonstrate £ 1 g of protein in 24 hours for patient to be eligible).
c. Absence of major hepatic insufficiency (bilirubin < 1.5 x ULN and aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) < 5 x ULN).
d. 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.
- Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women < 1 year after the onset of menopause is required before entering in the trial. Note: a negative test has to be reconfirmed by a urine test, should the 7-day window be exceeded.
-Adequate contraception is required during and for 3 months after study treatment for both male and female patients if the risk of conception exists.
-Signed written informed consent before randomization according to ICH/EU GCP, and local, national and international regulations. |
|
| E.4 | Principal exclusion criteria |
- Evidence of extra-hepatic metastasis of CRC.
- Previous chemotherapy for metastatic disease. Radiotherapy alone is allowed if given pre or post protocol treatment.
- Pregnancy or breast feeding
- Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization.
- Previous exposure to VEGF/VEGFR-targeting therapy within the last 12 months.
- Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study.
- Past or current history (within the last 2 years prior to treatment start) of other malignancies except metastatic colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible).
- 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.
- Peripheral neuropathy NCI CTCAE-grade ≥ 1, active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as > 4 loose stools per day), serious wound complications, ulcers, or bone fractures.
- History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) hemoptoe or evidence of interstitial lung disease on baseline chest X-ray or CT scan.
- Clinically significant cardiovascular disease, including: uncontrolled hypertension, New York Heart Association (NYHA) class II-IV heart failure, unstable angina pectoris within the past 12 months, peripheral vascular disease ≥ grade 2, serious cardiac arrhythmia requiring medication, myocardial infarction within the past 12 months, cerebrovascular accident or transient ischemic attack within the past 12 months, other clinically significant cardiovascular disease.
- Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
- Known hypersensitivity or contraindication to the drugs used in the trial (eg: 5-FU, folinic acid/ leucovorin, oxaliplatin, bevacizumab, irinotecan)
- Concomitant treatment with ASS > 325 mg or NSAIDs, known to inhibit platelet function, sorivudin or analog compounds or preparations of St. John’s wort |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Failure Free Survival Rate at 18 months. (Failure will be defined as no macroscopically complete resection (R0/1), local or distant recurrence or death from any cause) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 18 months (from randomization) |
|
| E.5.2 | Secondary end point(s) |
- Progression free survival (PFS)
- Overall Survival (OS)
- Perioperative morbidity
- Toxicity (Safety assessments will include physical examinations (blood pressure, heart rate, respiratory rate), vital signs, ECOG, clinical laboratory profile and monitoring of adverse events, according to NCI CTCAE v4.0)
- Quality of life using the EORTC QLQ-C30 and the module CR29
- Achievability of R0/R1 resection
- Overall Response Rate (CR and PR) according to RECIST v1.1 and Pathological Response Rate in the patients treated preoperatively (Arm B)
- Survival and efficacy of the treatment according to KRAS and BRAF status.
- Retrospective analysis of resectability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 18 months (from randomization) |
|
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 60 |
| 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 | 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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