| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic uveal melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the eye that has spread to other parts of the body. |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068117 |
| E.1.2 | Term | Metastatic ocular melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To assess progression-free survival time between selumetinib alone or combination selumetinib in either a continuous or intermittent schedule with weekly paclitaxel. |
|
| E.2.2 | Secondary objectives of the trial |
• Overall Survival time
• RECIST Response Rate
• Safety and toxicity
Exploratory Endpoints
Exploratory endpoints will include, but not be confined to:
• GNAQ/GNA11 mutation status
• MEK transcriptional signature
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically or cytologically confirmed metastatic uveal melanoma.
• Patients must have measurable disease, defined by RECIST 1.1.
• Age ≥18 years.
• ECOG performance status 0-2.
• Life expectancy of greater than 3 months.
• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• All prior treatment-related toxicities must be CTCAE v4 grade ≤ 1 (except alopecia) at the time of randomization.
• Laboratory values as listed below (SI units):
- Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN).
- Aspartate aminotransferase or alanine aminotransferase >2.5 x ULN (or ≥5 ULN in presence of liver metastases).
- Haemoglobin ≥9.0 g/dL.
- Platelets >100x109/L (100,000 per mm3).
- Absolute neutrophil count >1.5x109/L (1500 per mm3).
- Creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault formula) ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min.
• Female patients of child-bearing potential should have a negative pregnancy test.
|
|
| E.4 | Principal exclusion criteria |
• Patients may not have received prior chemotherapy for uveal melanoma.This includes patients who have received isolated hepatic perfusion of chemotherapy. Patients who have received prior immunotherapy or non-chemotherapy locoregional therapy for liver metastases, but who have documented evidence of progression of metastatic disease would however be eligible.
• Patients who have a known or suspected brain metastases or spinal cord compression, unless asymptomatic, has been treated with surgery and / or radiation, and has been stable without requiring corticosteroids nor anti-convulsant medications for at least 4 weeks prior to the first dose of study medication.
• Prior exposure to MEK, Ras, or Raf inhibitors or history of hypersensitivity to any excipient agents.
• History of another malignancy unless disease-free for 3 years. Patients, who have had a completely resected non-melanoma skin cancer, are eligible.
• Any permitted previous treatment must have been greater than 21 days prior to study treatment starting and all toxicities from previous treatments should have resolved.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Treated brain metastases must have been stable for at least 1 month.
• Current use of a prohibited medication.
• Cardiac conditions as follows:
- Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).
- Acute coronary syndrome within 6 months prior to starting treatment.
- Baseline Left ventricular ejection fraction (LVEF) below the LLN or <55% measured by echocardiography or institution’s LLN for MUGA.
- Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest.
- Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy, or severe valvular heart disease (refer to Appendix 1).
- Prior or current cardiomyopathy including but not limited to the following:
− known hypertrophic cardiomyopathy
− known arrhythmogenic right ventricular cardiomyopathy
− previous moderate or severe impairment of left ventricular systolic function (LVEF <45% on echocardiography or equivalent on MuGA) even if full recovery has occurred.
- Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy, refer to Appendix 2).
- Acute coronary syndrome within 6 months prior to starting treatment.
- QTcF >450ms or other factors that increase the risk of QT prolongation.
• Ophthalmological conditions as follows (unless in the eye involved by uveal melanoma):
- Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure).
- Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy(CSR) or retinal vein occlusion.
• Uncontrolled intercurrent illness or uncontrolled systemic disease including, but not limited to, ongoing or active infection – including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV), symptomatic congestive heart failure, unstable/uncontrolled angina pectoris, uncontrolled cardiac arrhythmia, QTc prolongation, active bleeding diatheses, renal transplant or psychiatric illness/social situations that would limit compliance with study requirements.
• Female patients who are breast-feeding.
• Male or female patients of reproductive potential who are not employing an effective method of contraception.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) time. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Provided the trial has not been stopped early, the trial statistical analysis will be triggered when 68 progressions have been observed or 7 months after the last patient has been randomised whichever is earlier.
|
|
| E.5.2 | Secondary end point(s) |
To compare between the combination of selumetinib in either a continuous or intermittent schedule with weekly paclitaxel or with selumetinib alone:
• Overall Survival time
• RECIST Response Rate
• Safety and toxicity
Exploratory Endpoints
These will include, but not be confined to, the predictive value of GNAQ/GNA11 mutation status and a MEK transcriptional signature ( the latter performed using the nCounter analysis system from NanoString technologies). Both will be performed on samples obtained at the diagnostic (metastatic) biopsy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoint analysis will occur at the time of final database lock/end of trial.
The end of trial will be when all patients have been followed up until death or until 14 months from the time the last patient has completed trial treatment, if this occurs first. |
|
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 13 |
| 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
|
| The end of the trial is defined to be the date on which all patients have been followed up until death or until 14 months from the time the last patient has completed trial treatment, if this occurs first. |
|
| 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 | 1 |
| 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 | 1 |
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