E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
unresectable or metastatic BRAF V600 mutant melanoma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 16.0 |
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 LGX818 plus MEK162 prolongs progression free survival (PFS) compared with vemurafenib, and/or whether treatment with LGX818 prolongs PFS compared with vemurafenib in patients with BRAF V600 mutant locally advanced unresectable or metastatic melanoma. |
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E.2.2 | Secondary objectives of the trial |
Key secondary:
To compare overall survival (OS) between study arms of LGX818 plus MEK162 and LGX818 versus vemurafenib.
Other secondary:
● To estimate the treatment effect of LGX818 plus MEK162 versus LGX818 in terms of progression free survival (PFS)
● To assess objective response rate (ORR) by treatment arms
● To describe the time to objective response (TTR)
● To assess disease control rate (DCR) by treatment arms
● To evaluate duration of response (DOR)
● To determine the safety and tolerability of LGX818 plus MEK162 and LGX818 in this patient population
● To compare the patient-reported outcomes (PRO) between the treatment arms
● To compare the ECOG PS between the treatment arms
● To characterize the pharmacokinetics of LGX818 and MEK162 in this patient population
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) Title: Pre-screening evaluation to determine the BRAF mutation status; 13.05.2013 - v.00; Objective: BRAF mutation status
2) Title: Biomarker evaluation to analyze BRAF mutation status in circulating tumor DNA and in corresponding tumor tissue; 13.05.2013 - v.00; Biomarker evaluation |
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E.3 | Principal inclusion criteria |
• Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma (AJCC Stage IIIB, IIIC, or IV)
• Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization
• Naïve untreated patients for unresectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy or radiotherapy)
• Evidence of at least one measurable lesion as detected by radiological or photographic methods
• ECOG performance status of 0 or 1
• Adequate bone marrow, organ function, cardiac and laboratory parameters
• Normal functioning of daily living activities
Other protocol-defined inclusion criteria may apply
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E.4 | Principal exclusion criteria |
• Any active/non-stable brain lesion
• Non-cutaneous melanoma
• History of leptomeningeal metastases
• History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease.
• Patients with washout period < 12 weeks from the last dose of ipilimumab or other immunotherapy.
• Any previous anti-cancer treatment, extensive radiotherapy or investigational agent for locally advanced unresectable or metastatic melanoma; prior systematic treatment in adjuvant setting (including ipilimumab) is allowed
• History of Gilbert's syndrome
• Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor
• Impaired cardiovascular function or clinically significant cardiovascular diseases
• Uncontrolled arterial hypertension despite medical treatment
• HIV positive or active Hepatitis B, and/or active Hepatitis C
• 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 for Combination versus vemurafenib and for LGX818 versus vemurafenib.
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 based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. 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 |
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E.5.2 | Secondary end point(s) |
1. Overall Survival (OS), to compare OS between study arms of Combination and LGX818 versus vemurafenib.
2. Progression free survival for Combination versus LGX818.
3. Overall Response Rate (ORR).
4. Time to Objective Response (TTR).
5. Disease control rate (DCR).
6. Duration of objective response (DOR).
7. Safety and tolerability of Combination and LGX818.
8. Quality of life according to the various questionnaires and scales(EORTC QLQC30; EQ-5D; FACT-M)
9. ECOG performance status
10. Pharmacokinetics of LGX818 and MEK162. Plasma concentration-profiles of LGX818 and MEK162
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 and 7. Up to approximatively 4 years
2. Approximately 2 years with update around 3 years
3-6 and 8-10. Approximately 2 years
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | 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) | 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 | 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 | 24 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 124 |
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 |
Belgium |
Brazil |
Canada |
China |
Colombia |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Poland |
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
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The end of study is defined as the final overall survival analysis timepoint. This analysis is planned when 670 deaths have occurred in the three treatment arms combined. |
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |