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 | 21.1 |
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 Combo 450 (LGX818 450mg QD plus MEK162 45mg BID) prolongs progression free survival (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 Part1 1) Determine the contribution of MEK162 to the Combo using PFS Combo450 vs. LGX818
Key Part2 2) Further quantify the contribution of MEK162 to the Combo using PFS Combo300 vs. LGX818 Other part specific -Compare / estimate the effect of (3) Combo450 vs. vemurafenib / (4) Combo450 vs. LGX818 in overall survival (OS) in Part1 -Estimate the safety and tolerability of (5) Combo450 and LGX818 in part1, (6) Combo300 vs. LGX818, (7) Combo300 vs. Combo450 in Part2 -Estimate the effect of (8) Combo300 vs. LGX818 in OS in Part2 -Estimate the effect in PFS and OS of (9) Combo300 vs. vemurafenib and (10) Combo300 vs. Combo450 in Part2
Other Part1 and 2 -Estimate (11) the effect of LGX818 vs. vemurafenib in PFS and OS -Assess (12) objective response rate, (14) disease control rate, (15) duration of response -Describe (13) time to objective response -Compare (16) patient-reported outcomes, (17) ECOG PS -Characterize (18) pharmacokinetics of LGX818 and MEK162 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma (AJCC Stage IIIB, IIIC, or IV) • Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to randomization • Naïve untreated patients or patients who have progressed on or after prior first-line immunotherapy for unresectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy or radiotherapy), except the administration of BRAF or MEK inhibitors. • 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 untreated central nervous system (CNS lesion) • Mucosal or uveal melanoma • History of leptomeningeal metastases • History of or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); • Patients with washout period <6 weeks from the last dose of ipilimumab or other immunotherapy. • Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma. • 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 • Patients with neuromuscular disorders that are associated with elevated CK. • Pregnant or nursing (lactating) women •Patients taking non-topical medication known to be a strong inhibitor of CYP3A4 • 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 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) |
-Overall survival: time from the date of randomization to date of death due to any cause -Safety and tolerability: Adverse events and serious adverse events, changes in laboratory values, vital signs, ECGs, MUGA/echocardiogram and assessment of physical, dermatological and ocular examinations graded according to the NCI CTCAE v4.03 -Objective response rate: 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. -Time to objective response: the time from date of randomization until first documented CR or PR. -Disease control rate: proportion of patient with a best overall response of CR, PR or stable disease (SD) -Duration of response: time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer -Time to definitive 10% deterioration in the FACT-M melanoma subscale and global health status score of the EORTC QLQ-C30. -Change from baseline in the FACT-M melanoma subscale, EQ- 5D-5L, global health status score of the EORTC QLQ-C30 other EORTC QLQ-C30 subscales. -Time to definitive 1 point deterioration in ECOG PS Change from baseline in ECOG PS -Plasma concentration-profiles of LGX818 and MEK162 and model based PK parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key Part1 1) about 2 years
Key Part2 2) about 3 years
Other part specific -(3), (4) about 5.5 years -(5)about 2 years -(6), (7) about 3 years -(8) about 5.5 years -(9) about 3 for PFS and 5.5 years for OS -(10) about 3 for PFS and 5.5 years for OS Other Part 1 and 2 -(11) about 2, 3 and 5 years -(12), (13), (14), (15), (16), (17) about 2 (for Combo450, LGX818 and vemurafenib evaluation) and 3 years (for Combo300 evaluation) -(18) about 2 (for Combo450 and LGX818 evaluation) and 3 years (for Combo300 evaluation) |
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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 | 4 |
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 | 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 |
Brazil |
Canada |
China |
Colombia |
Czechia |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Poland |
Portugal |
Russian Federation |
Singapore |
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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Part 1 and Part 2 of the study will each remain open to collect additional survival and safety data until the final OS update is performed when 80% of randomized patients in each part of the study have died, withdrawn consent for survival follow-up or are lost to follow-up. At the end of the study, access to Combo 450, Combo 300 and/or LGX818 treatment will be made available to patients who continue to derive benefit from Combo 450, Combo 300 and/or LGX818 study treatment.
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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 | 6 |
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 | 6 |
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 |