| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| colorectal cancer with liver metastases |
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| E.1.1.1 | Medical condition in easily understood language |
| cancer of the bowel with liver secondaries |
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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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | 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 |
MAIN STUDY:
Primary objectives:
• Progression free survival (PFS) of FOLFIRI plus cetuximab versus FOLFIRI plus aflibercept in patients with liver metastases deemed to be inoperable or unsuitable for upfront resection and with with RAS wild type (WT) disease.
• In patients with RAS mutant CRC, to compare progression free survival of FOLFOXIRI versus FOLFIRI plus aflibercept or FOLFOXIRI plus aflibercept in patients with liver metastases deemed to be inoperable or unsuitable for upfront resection.
The primary Endpoint of the study is one year-PFS
The genetic material (DNA) in cancer cells can influence whether cancer responds to anti-cancer treatments. One of those characteristics is determined by examining a gene called RAS. RAS is an important downstream protein in the epridermal growth factor receptor (EGFR) pathway. Previous research has shown that testing for RAS can help guide treatment for mCRC. If no mutations are identified in the RAS genes, the tumour is referred |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study include, Overall survival (OS),Resection margins, radiological objective response rate (ORR), data on use of locoregional treatment options like radiofrequency ablation (RFA), patterns of failur, quality of life data and data on health economics.
OS is measured from the time of randomisation of the study to the date of death from any cause; surviving patients will be censored at date last known to be alive.
The resection margins are very important in determining the outcome of the patients recruited into this study. We will there report the R0 (no microscopic disease), R1 (microscopic disease, which is only detected under the microscopic examination of the resected tissue but is not visible to the naked eye of the operating surgeon) and R2 (macroscopic disease, which is visible to the naked eye of the operating surgeon) resection rates. Other secondary objectives/endpoints include relapse free survival for patients who have undergone R0 or R |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
MAIN STUDY AND SAFETY RUN-IN PHASE OF THE STUDY:
A patient may be included if the answer to all of the following statements is “yes”.
• Signed and dated informed consent, and willing and able to comply with protocol requirements,
• Histologically proven adenocarcinoma of the colon and/or rectum,
• Metastatic disease confirmed, with liver-only metastatic disease except in the safety run-in phase of the study, where extra-hepatic disease in the presence of liver metastases will be allowed. Presence of metachronous or synchronous liver metastases will be allowed. For patients enrolled in the safety run-in phase of the study, they will be required to have at least one liver metastasis but they will not have to meet the liver resectibility criteria set out for the main study.
• Liver metastases considered to be unresectable at randomisation based on at least one of the following:
i) No upfront R0/R1 resection of all hepatic lesions possible
Note: a patient with bilobar disease suitable for a two-stage resection would still fulfill the inclusion criteria for unresectability.
ii) Less than 30% estimated residual liver after resection
iii) Disease in contact with major vessels of the remnant liver (vessels remaining after potential hepatectomy).
These criteria should be discussed and agreed at an MDM in a local hepatopancreaticobiliary (HPB) centre.
• Presence of synchronous colorectal primary cancer will be allowed.
• General condition considered feasible for major abdominal surgery after first-line chemotherapy.
• No evidence of extrahepatic metastatic disease as determined by CT CAP or other investigations such as PET scan or biopsy (if required). However, for the SAFETY RUN-IN PHASE of FOLFOXIRI + aflibercept, all comers with metastatic colorectal cancer will be allowed, irrespective of their RAS mutation status. These patients must have hepatic metastatic disease with or without extra-hepatic metastatic disease. The patients included in the safety run-in phase of the study with extra-hepatic disease will not be included in the final analysis but will be followed up according to the trial follow up plan.
• Age ≥18 years
• WHO Performance status (PS) 0-2,
• Patients with adequate haematological, renal and liver functions as defined in the protocol.
• Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour.
• Regular follow-up feasible.
• For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment,
• Female patients must commit to using reliable and appropriate methods of contraception until at least six months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial and for six months after the last study drug treatment.
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| E.4 | Principal exclusion criteria |
A patient will not be eligible to enter the study if the answer to any of the following statement is “yes”.
• Pre-existing permanent neuropathy (NCI grade ≥2)
• Uncontrolled hypercalcemia,
• Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy,
• Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
• Treatment with any other investigational medicinal product within 28 days prior to study entry.
• Other serious and uncontrolled non-malignant disease,
• History or evidence upon physical examination of CNS metastasis
• Intolerance to atropine sulfate or loperamide
• Known dihydropyrimidine dehydrogenase deficiency
• Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumour), treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis.
• Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >6months, Adjuvant or neo-adjuvant chemotherapy for prior tumour should be completed for more than 6 months of randomisation. In case of synchronous rectal cancer, radiotherapy with or without chemotherapy for primary rectal cancer will be allowed.
• Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days
• Pregnant or breastfeeding women,
• Patients with known allergy to study drugs,
• History of myocardial infarction and/or stroke within 6 months prior to randomization. This includes, but is not limited to, the following examples: cerebrovascular accidents (≤ 6 months prior to registration), myocardial infarction (≤ 6 year prior to registration), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, clinically significant ECG findings (e.g. QTc ≥ 460 or ≥ 2º AV Block, etc.). Patients who suffer from serious cardiac arrhythmia requiring medication can enter the study only if they are considered to be in a stable condition regarding both the arrhythmia and their medication. Patients with pacemakers are allowed to enter the study only if they are considered as being in a stable condition. In case of doubt, the investigator should obtain a consultation with a local cardiologist.
• Bowel obstruction.
• Medical or psychiatric conditions that compromises the patient’s ability to give informed consent.
• Serious, non-healing wound, ulcer or bone fracture
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization
• Immunocompromised patients e.g. human immunodeficiency virus (HIV). Patients with hepatic disease e.g. patients with known serologically positive
Hepatitis B or Hepatitis C.
• Treatment with strong CYP3A4 inducers (e.g. Avasimibe,(5) carbamazepine, phenytoin, rifampin, St. John’s wort) unless discontinued > 7 days prior to randomization. For more detailed information on CYP3A4 inducers, please see:http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm
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| E.5 End points |
| E.5.1 | Primary end point(s) |
FOR MAIN STUDY:
To measure 1-year progression free survival (PFS) in patients treated on the study. This will be measured from date of randomisation to date of first appearance of disease progression, relapse, death from any cause; patients alive without progression or relapse will be censored at date last known to be alive.
FOR SAFETY RUN-IN PHASE:
In patients with metastatic colorectal cancer (CRC), to find the maximum tolerated dose (MTD)of FOLFOXIRI plus aflibercept |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 100 |
| 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 | 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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| Patient follow up will continue for five years or until death whichever comes first, to evaluate the secondary end points of the trial. Therefore the ‘end of study’for the purposes of the European Clinical Trials Directive will be defined as five years after the last patient has had their last active study treatment. The sponsor will inform the MHRA and REC within 90 days of the ‘end of trial’ that the trial has closed. |
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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 | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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