E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resectable liver metastases from wild type KRAS and NRAS colorectal cancer. |
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E.1.1.1 | Medical condition in easily understood language |
Resectable liver metastases from wild type KRAS and NRAS colorectal cancer. |
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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 | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024700 |
E.1.2 | Term | Liver metastases |
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 | 17.0 |
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) |
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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 |
The primary objective is to detect an increase in progression free survival (PFS*, see chapter 7.3.6) rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) compared to mFOLFOX6 alone arm as perioperative treatment for resectable liver metastasis from wild type Kirsten rat sarcoma viral oncogene homolog (KRAS) and NRAS colorectal cancer (CRC). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the pathological response rate and detect an increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm. Others objectives are correlation between pathological response and disease free survival (DFS), resection rate, response rate, PFS*, overall survival and safety. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Histologically proven CRC with 1 to 8 metachronous or synchronous liver metastases considered to be completely resectable.
-Primary tumor (or liver metastasis) of CRC must be KRAS and NRAS status “wild type”.
-Patients must have undergone complete resection (R0) of the primary tumor at least 4 weeks before randomization. Or for patients with synchronous metastases the primary tumor can be resected (R0) at the same time as the liver metastases if: the patient has a non-obstructive primary tumor and is able to receive preoperative chemotherapy (3-4 months) before surgery.
-Measurable hepatic disease by RECIST version 1.1.
-Patients must be 18 years old or older.
-A WHO performance status of 0 or 1. Radiotherapy alone is allowed if given pre or post protocol treatment.
-Previous adjuvant chemotherapy for primary CRC is allowed if completed at least 12 months before inclusion in this study.
-Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 14 days prior to the first dose of study treatment.
-Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
-Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
-Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
-No previous chemotherapy for metastatic disease or surgical treatment (e.g. surgical resection or radiofrequency ablation) for liver metastasis.
-No evidence of extra-hepatic metastasis (of CRC).
-No previous exposure to EGFR or VEGF/VEGFR targeting therapy within the last 12 months.
-No major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization.
-No regular use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). No bleeding diathesis (e.g. hemoptysis of ≥ 1/2 teaspoon or 2.5mL), coagulopathy, or need for administration of full-dose anti-coagulant(s).
-Presence of peripheral neuropathy > grade 1 (Common Terminology Criteria for Adverse Events, v4.0) serious wound complications, ulcers, or bone fractures.
-Clinically significant cardiovascular disease, including: uncontrolled hypertension, New York Heart Association (NYHA) class II-IV heart failure, myocardial infarction or unstable angina pectoris, cerebrovascular accident or transient ischemic attack within the past 12 months, peripheral vascular disease ≥ grade 2, serious cardiac arrhythmia requiring medication and other clinically significant cardiovascular disease.
-Presence of symptomatic diverticulitis or active or uncontrolled gastroduodenal ulceration.
-History or evidence of interstitial lung disease (e.g. pneumonitis, pulmonary fibrosis).
-Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
-Significant disease that, in the investigator’s opinion, would exclude the patient from the study. Including known allergy or any other adverse reaction to any of the study drugs (including any of the excipients) or to any related compound, including hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies.
-Participation in another clinical study (except sub studies of this protocol) within the 30 days before randomization and during this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point: to detect an increase in progression free survival rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) compared to mFOLFOX6 alone arm as perioperative treatment for resectable liver metastasis from wild type Kirsten rat sarcoma viral oncogene homolog (KRAS) and NRAS colorectal cancer (CRC). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
To assess the pathological response rate and detect an increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm. Others objectives are correlation between pathological response and disease free survival (DFS), resection rate, response rate, PFS*, overall survival and safety. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-For all patients: After 3 years of accrual and 1 additional year of follow-up in the FOLFOX alone arm and in each experimental arm.
-After protocol treatment patients without progression will be followed-up every 3 months in the first 2 years and every 6 months thereafter for a further 3 years or until progression.
-All patients will be followed for survival |
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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 | No |
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 | No |
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 |
FOLFOX-6 (Fluorouracil, Folinic Acid, Oxaliplatin) |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 | No |
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 |
Austria |
Belgium |
France |
Germany |
Netherlands |
Norway |
Spain |
Switzerland |
United Kingdom |
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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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End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment.
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol.
3. 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 | 4 |
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 | 4 |
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 |