| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal adenocarcinoma with metastases involving the liver only |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10010035 |
| E.1.2 | Term | Colorectal cancer stage IV |
|
| 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 |
| To evaluate the response rate of patients with previously untreated unresectable liver-only metastases from colorectal cancer treated with neoadjuvant capecitabine and oxaliplatin plus bevacizumab. |
|
| E.2.2 | Secondary objectives of the trial |
•Safety and feasibility of bevacizumab in combination with capecitabine/oxaliplatin in patients receiving neoadjuvant treatment, including:grade 3/4 toxicity during perioperative chemotherapy;perioperative complications of liver failure, bleeding at surgical site, reoperation rate for bleeding, wound healing complications, blood transfusions; treatment related death; post-operative mortality.
•Complete (R0) resection rate
•Rate of patients proceeding to resection
•Progression-free survival of all patients enrolled into study
•Disease-free survival of patients who had complete resections (R0) only
•Overall survival of all patients and of subgroup who had complete resection (R0)
•Patterns of recurrence of disease
•To correlate radiological response evaluation of liver metastases with histopathology.
•To evaluate the effects of neoadjuvant treatment on the non tumour liver parenchyma.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Histologically proven diagnosis of colorectal adenocarcinoma
•Metastatic disease present in the liver only.
•Absence of extrahepatic metastases excluded by CT chest, abdomen and pelvis. Indeterminate CT findings may require verification by FDG-PET scanning.
•Liver-only metastases determined to be unresectable at presentation on a pre-treatment liver MRI with an appropriate liver specific contrast (eg. TESLA) by a specialist multidisciplinary team (consisting of medical oncologist, hepatic surgeon and radiologist). Guidelines for determining unresectability include:presence of >4 metastases;size >5cm;location and distribution of metastatic disease within the liver unsuitable for resection with clear margins (eg. Involvement of both lobes of liver; invasion of intrahepatic vascular structures);extent of liver involvement precluding resection with adequate post-resection residual liver parenchyma volume for viable liver function in the immediate post-operative period;inability to retain adequate vascular in flow and out flow to maintain viable liver function; any liver-only metastases diagnosed synchronously with the primary tumour.
•No previous treatment for metastatic colorectal cancer, including chemotherapy, targeted or experimental therapies (e.g. anti-VEGF or anti-EGFR), radiotherapy to the liver, or surgery or radiofrequency ablation to liver metastases.
•If the primary colorectal tumour is in situ, the primary tumour must also be resectable with curative intent
•Patients presenting with liver metastases only relapse after initially curative resection of their primary colorectal cancer followed by treatment with adjuvant chemotherapy may not be entered into the study if the relapse has occurred within 12 months of completion of adjuvant treatment
•Adequate medical fitness to undergo neoadjuvant treatment and surgery with curative intent (hepatectomy +/- resection of primary tumour, if required)
•Absence of pre-existing liver dysfunction of Childs Pugh Grade B or greater. Patients who are suspected of having pre-existing liver dysfunction due to clinical, biochemical or radiological findings, should have significant liver disease excluded by a liver biopsy prior to study entry.
|
|
| E.4 | Principal exclusion criteria |
•No major surgery, major trauma or open biopsy within 28 days prior to study entry. Patients requiring insertion of central venous access for treatment (e.g. due to poor venous access) should have the procedure performed at least 2 days before starting treatment
•No serious, non-healing wound, ulcer, or bone fracture
•Absence of obvious risk of requiring emergency surgery after commencement of study treatment, such as impending bowel obstruction
•Absence of clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents ( ≤ 6 months prior to randomisation), myocardial infarction (≤ 1 year prior to randomisation), uncontrolled hypertension while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication
•No recent history of any active gastrointestinal inflammatory condition such as peptic ulcer disease, diverticulitis or inflammatory bowel disease. If patients have a known diagnosis of any of the above, evidence of disease control is required by negative endoscopy within the past 28 days
•No evidence of bleeding diathesis or coagulopathy
•No recent commencement of full dose oral anticoagulation (warfarin), unless stable and within therapeutic range for at least 10 days. INR must be monitored closely after commencement of treatment due to potential for interaction between warfarin and capecitabine
•No thrombolytic therapy within 10 days prior to commencement of study treatment
•No chronic, daily treatment with high-dose aspirin (> 325mg/day) or nonsteroidal anti-inflammatory medications (those known to inhibit platelet function at doses used to treat chronic inflammatory diseases)
•No chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids)
•No known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other components of the study drugs
•No proteinuria at baseline as defined by >1g of protein/24 hr by a 24-hour urine collection
•No known peripheral neuropathy ≥ CTCAE v 3.0 Grade 1 (absence of deep tendon reflexes (DTRs) as the sole neurological abnormality does not render the patient ineligible)
•No known dihydropyrimidine dehydrogenase (DPD) deficiency
•Absence of contraindications to MRI (eg. patients with pacemakers)
•WHO performance status 0-2
•Adequate bone marrow function with platelets > 100 x 109/l; WBC > 3 x 109/l; neutrophils > 1.5 x 109/l
•Serum bilirubin < 1.5 × upper limit of institutional normal range (ULN) and transaminases < 2.5 ULN (see exclusion criteria for hepatic dysfunction)
•Serum creatinine less than ULN or calculated creatinine clearance >50ml/min (Cockcroft and Gault formula).
•Absence of lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication
•In females of childbearing potential, pregnancy must be excluded, either with a negative pregnancy test within 7 days prior of commencing treatment or history of amenorrhea greater than 2 years. Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception may not enter the study
•No other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix)
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate according to RECIST criteria. |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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 | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | Information not present in EudraCT |
| 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
|
| After completion of protocol treatment, patients will be followed up for 5 years as is standard with patients who have received curative treatment for colorectal cancer. The end of the trial will be when the last subject attends their last follow up visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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