E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Third line colorectal liver metastases |
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E.1.1.1 | Medical condition in easily understood language |
Bowel cancer with liver secondaries |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 assess whether an absence of vascular (blood-supply) shutdown in the tumour, in metastatic colorectal cancer, using contrast enhanced ultrasound, in patients taking Axitinib will quickly select out patients who are not going to obtain benefit from this drug. This group of non-responsive patients should have a similar overall survival as the placebo group, whereas the patients on Axitinib who do have vascular tumour shutdown on contrast enhanced ultrasound should obtain significant benefit. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows: -To compare overall survival between Axitinib and 'dummy treatment' (placebo) -To compare disease progression free survival between Axitinib and placebo -To evaluate the use of 2 week contrast enhanced ultrasound assessing response when compared to an 8 week CT scan response criteria (RECIST)and see whether this correlates to the blood levels of Axitinib (PK levels) -To compare overall survival in patients who develop raised diastolic blood pressure (>90mmHg) on Axitinib compared to those who do not including the placebo group -To collect the side-effect profile for Axitinib and compare this to the placebo receiving patients |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants must meet all of the following inclusion criteria to elgible for enrollment into the trial: • Histologically or cytologically confirmed adenocarcinoma of the colon or rectum with liver metastas(es). At least one of which should not have had any focal therapy including radiofrequency ablation, chemoembolization, ethanol or cryoablation. • Failed at least 2 chemotherapy regimens in advanced disease. • Evidence of unidimensionally measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). • 18 years of age or older. • ECOG performance status of 0 or 1. • Resolution of all acute toxic effects of prior therapy e.g. radiotherapy or surgical procedure to NCI CTCv4 grade ≤1. • Adequate organ function as defined by the following criteria: Serum aspartate aminotransferase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine aminotransferase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤2.5 x upper limit of normal (ULN). For patients with liver metastases, <5 x ULN. Total serum bilirubin <1.5 x ULN Serum albumin ≥3.0 g/dL Absolute neutrophil count ≥1500/µL Platelets ≥100,000/µL Haemoglobin ≥9.0 g/dL Serum creatinine ≤1.5 x ULN • Signed and dated informed consent form • Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures • At least 2 weeks since the end of prior systemic treatment (4 weeks for Bevacizumab-containing regimens), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 3.0 grade ≤1 or back to baseline except for alopecia or hypothyroidism. • No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible. • Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment. • Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrolment. |
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E.4 | Principal exclusion criteria |
Participants must be excluded if they present with any of the following exclusion criteria: • Non-exposed to both oxaliplatin and irinotecan FP based cytotoxic chemotherapy (prior pelvic radiation therapy including adjuvant or neoadjuvant chemo-radiation therapy for resected rectal cancer is allowed provided it is completed within 4 weeks prior to study entry) • Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John’s wort). • Any of the following within the 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism. • Non-English speaking • Pregnancy, breastfeeding, or unwillingness/inability to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for up to 3 months after discontinuing study drug if of reproductive potential. • Hypertension uncontrolled by medication (>150/100 mmHg despite optimal medical therapy). • Diagnosis of any second malignancy within the last 3 years that is potentially liable to interfere with study outcomes (basal cell carcinoma, squamous cell skin cancer, or in situ carcinoma and hormone controlled locally advanced prostate cancer that has been adequately treated with no evidence of recurrent disease for 12 months, are allowed) • Prior surgery or IMP within 4 weeks prior to study entry • Current treatment within another therapeutic clinical trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome anticipated is that we expect a shorter median overall survival in participants exhibiting a ≤20% reduction from baseline in Contrast Enhanced Hepatic Perfusion Index (CEPHI) on Axitinib compared to those on Axitinib or placebo who have a >20% reduction in CEPHI. Overall survival is defined as the time from randomization to date of death due to any cause. |
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E.5.2 | Secondary end point(s) |
• Median overall survival between the Axitinib and placebo arms (with an intention to treat analysis). • Comparison of disease progression in patients who fail to display reduction in CEHPI at 2 weeks (RECIST v1.1). • Best overall response rate (CR+PR) in Axitinib versus placebo groups. • Best overall response rate (CR+PR) in CEHPI responders versus non-responders. • Progression free survival and 6 and 9 month survival percentages and duration on study treatment between Axitinib and placebo. • Progression free survival and 6 and 9 month survival percentages and ‘duration on study treatment’ between CEHPI responders and non-responders. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
40 weeks from last randomisation. |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker of efficacy and toxicity |
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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 | No |
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) | No |
E.8.2.2 | Placebo | Yes |
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 | 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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LVLS, i.e. at the latest 1 year from randomisation of last patient. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 2 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 2 |