E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic or unresectable cutaneous melanoma |
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E.1.1.1 | Medical condition in easily understood language |
metastatic or inoperable melanoma of the skin |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053571 |
E.1.2 | Term | Melanoma |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To determine whether treatment with MEK162 prolongs PFS as compared to dacarbazine in patients with advanced unresectable, or metastatic NRAS mutation-positive cutaneous or unknown primary melanoma who are previously untreated or who have progressed on or after treatment with any number of lines of immunotherapy for unresectable ormetastatic disease. |
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E.2.2 | Secondary objectives of the trial |
Key secondary:
To compare Overall Survival (OS) between treatment arms
Other secondary:
- To compare the Overall Response Rate (ORR) between treatment arms
- To describe the time to objective response (TTR) in the two treatment arms
- To describe the duration of objective response (DOR) between treatment arms
- To compare the disease control rate (DCR) between treatment arms
- To assess assess the safety and tolerability of MEK162 in this patient population using NCI CTCAE v4.03 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (AJCC Stage IIIC or IV)
•Presence of NRAS Q61 mutation in tumor tissue prior to randomization
•Naïve untreated patients or patients who have progressed on or after treatment with any number of immunotherapy for unresectable or metastatic melanoma
•Evidence of at least one measurable lesion as detected by radiological or photographic methods
•Adequate bone marrow, organ function, cardiac and laboratory parameters
•Normal functioning of daily living activities
Other protocol defined inclusion criteria may apply. |
|
E.4 | Principal exclusion criteria |
• Any untreated /non-stable brain lesion
* uveal or mucosal
• Non-cutaneous melanoma
• History of or current evidence of retinal vein occlusion (RVO)
• History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease.
• Patients with washout period < 6 weeks from the last dose of ipilimumab or other immunotherapy.
• Any Previous systemic chemotherapy for unresectable locally advanced or metastatic melanoma.
• History of Gilbert's syndrome
• Prior therapy with a MEK- inhibitor
• Impaired cardiovascular function or clinically significant cardiovascular diseases
• Uncontrolled arterial hypertension despite medical treatment
• HIV positive or active Hepatitis A or B
• Impairment of gastrointestinal function or gastrointestinal disease
• Patients with neuromuscular disorders that are associated with elevated CK.
• Pregnant or nursing (lactating) women
• Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
Other protocol defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (PFS)
PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined by a Blinded Independent Review Committee (BIRC). The local Investigator's assessments will be used as supportive analyses. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final PFS analysis is expected approximately 16 months after FPFV. |
|
E.5.2 | Secondary end point(s) |
1. Overall Survival (OS)
To compare OS between treatment arms. OS is calculated as the
timefrom date of randomization to date of death due to any cause.
2. Overall Response Rate (ORR)
ORR calculated as the proportion of patient with a best overall response of complete response (CR) or partial response (PR). ORR will be calculated for confirmed and unconfirmed responses separately.
3. Time to Objective Response (TTR)
TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response(PR).
4. Duration of objective response (DOR)
DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer
5. Disease control rate (DCR)
DCR calculated as the proportion of patient with a best overall response of CR, PR or stable disease (SD)
6. Number of patients with adverse events
To assess the safety and tolerability of MEK162 in this patient, changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), MUGA(Multi Gated Acquisition Scan)/echocardiogram and assessment of physical and ocular examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03
7. Number of patients with serious adverse events
To assess the safety and tolerability of MEK162 in this patient, changes in hematology and chemistry values, vital signs, ECGs, MUGA/echocardiogram and assessment of physical and ocular examinations graded according to the NCI CTCAE v4.03
8. Time to definitive 10% deterioration in the global health status score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
To compare the global health status between the treatments.
9. Change from baseline in the global health status score of the EORTC QLQ-C30
To compare the global health status between the treatment.
10. Change from baseline in the EQ-5D-5L (EuroQol Group standardised instrument for use as a measure of health outcome)
To compare the global health status between the treatment.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Final analysis is expected to occur 21 m after FPFV
2. Approximately 16 months after the FPFV
3. Approximately 16 months after the FPFV
4. Approximately 16 months after the FPFV
5. Approximately 16 months after the FPFV
6. Approximately 16 months after the FPFV
7. Approximately 16 months after the FPFV
8. Approximately 16 months after the FPFV
9. Approximately 16 months after the FPFV
10. Approximately 16 months after the FPFV |
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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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
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 | 2 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Czech Republic |
France |
Germany |
Greece |
Hungary |
Iceland |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
New Zealand |
Poland |
Portugal |
Russian Federation |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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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
|
final PFS analysis will take place when approximately 260 PFS events as per BIRC have been observed. This is estimated to occur around 16 months following the first patient first visit (FPFV). Subsequently, the study will remain open to collect additional survival and safety data until approximately 80% of the patients on the study (~314 patients) have died. |
|
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 | 7 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |