E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced BRAF mutant melanoma |
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E.1.1.1 | Medical condition in easily understood language |
advanced melanoma that has a gene mutation called BRAF. |
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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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Is the combination of axitinib and metformin efficacious in BRAF mutant advanced melanoma? |
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E.2.2 | Secondary objectives of the trial |
What is the toxicity of the combination? What molecular changes result in tumours as a consequence? |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Advanced melanoma defined as unresectable locally advanced or metastatic disease 2.The presence of one or more clinically or radiologically measurable lesions at least 10mm in size 3.Age 18 or greater 4.ECOG performance status 0 or 1 5.Life expectancy greater than 12 weeks 6.At least 28 days since any major surgery 7.The capacity to understand the patient information sheet and ability to provide written informed consent 8.Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures 9.Women must not be pregnant or lactating with no intention of pregnancy during study treatment. Women of child bearing potential must have a negative serum pregnancy test prior to study entry (even if surgically sterilised). Men and women of childbearing potential must use adequate birth control measures (e.g. abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, implantable or injectable contraceptives or surgical sterilisation) for the duration of the study and should continue such precautions for 6 months after receiving the last study treatment 10.Serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), total serum bilirubin ≤1.5 x ULN 11.Serum creatinine ≤1.5 x ULN 12.Serum lipase and amylase <1.5 x ULN 13.Haemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5 x 109/L, platelets ≥100 x 109/L 14.Prothrombin time (PT) ≤1.5 x ULN 15.Able to swallow and retain oral medication. |
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E.4 | Principal exclusion criteria |
1.Intracranial disease, unless there has been radiological evidence of stable intracranial disease > 6 months. In the case of a solitary brain metastasis, evidence of a disease-free interval of at least 3 months post surgery. All patients previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days 2.Women who are pregnant, nursing, or planning to become pregnant during the course of the trial 3.Men who plan to father a child during the course of the trial 4.Use of any investigational drug within 30 days prior to screening (both cancer and non cancer treatments) 5.Use of herbal or chinese medication 6.Use of therapeutic coumarin derivatives (ie warfarin, acenoucumarol, phenprocoumon) 7.Significant cardiac disease 8.Severe and/or uncontrolled medical disease 9.Known chronic liver disease 10.Known HIV infection 11.Previous radiotherapy to 25% or more of the bone marrow 12.Radiation therapy in the 4 weeks prior to study entry 13.Any malabsorption syndrome (i.e. partial gastrectomy, small bowel resection, Crohn’s disease or ulcerative colitis). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy of the combination of axitinib and metformin |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Proportion of patients who have progression free survival after 6 months.Progression free survival times will be measured from the date of enrolment into the treatment phase until the first date (following start of treatment) of either death or confirmed progressive disease according to RECIST. |
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E.5.2 | Secondary end point(s) |
1.Response rate at 12 weeks 2.Overall survival 3.Toxicity of treatment 4.Correlation between molecular changes and response to treatment and survival |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
There will be too few instances of progression/death in 24 patients in each cohort to be able to make confident statements about the relationship of outcome to these factors using PFS at 6 months as an endpoint. The effect sizes from such analyses will therefore only be presented together with their 95% confidence intervals as a guide to the ranges within which these effects might lie. |
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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 | Yes |
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 | No |
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 | No |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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
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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 | 2 |
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 | 2 |
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 |