| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| unresectable or metastatic BRAF V600 mutant melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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. |
|
| 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
|
|
| 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)
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 |
|
| E.4 | Principal exclusion criteria |
• Any active/non-stable brain lesion
• Non-cutaneous melanoma
• History of leptomeningeal metastases
• History of or current evidence of retinal vein occlusion (RVO)
• Patients with washout period < 12 weeks from the last dose of
ipilimumab or other immunotherapy.
• Any previous 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 |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Key secondary: Overall Survival (OS), to compare OS between study arms of Combination and LGX818 versus vemurafenib.
OS is calculated as the time from date of randomization to date of death due to any cause.
2. Progression free survival for Combination versus LGX818.
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.
3. 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.
4. Time to Objective Response (TTR).
TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response(PR).
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. 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
7. Safety and tolerability of Combination and LGX818.
Number of patients with adverse events and serious adverse events , changes in laboratory values, vital signs, electrocardiograms (ECGs), MUGA(Multi Gated Acquisition Scan)/echocardiogram and assessment of physical,dermatological and ocular examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03
8. Time to definitive 10% deteriortaion in global health status (EORTC QLQC30)
Time to definitive 10% deterioration in the global health status score of the EORTC QLQ-C30 is the time from the date of randomization to the date of at least 10% relative to baseline worsening with no later improvement above this threshold observed during the course of the study or death due to any cause
9. Global health status (EORTC QLQC30).
Change from baseline in the global health status score of the EORTC QLQ-C30
10. Global health status (EQ-5D).
Change from baseline in the EQ-5D
11. Time to definitive 10% deterioration in the FACT-M melanoma subscale.
Time to definitive 10% deterioration in the FACT-M melanoma (subscale) is the time from the date of randomization to the date of at least 10% relative to baseline worsening with no later improvement above this threshold observed during the course of the study or death due to any cause.
12. Time to definitive 1 point deterioration in the ECOG performance status.
Time to definitive 1 point deterioration in the ECOG PS is defined as the time form date of randomization to definitive deterioration, where deteriorationis considered as definitive if no improvement in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.
13. ECOG performance status.
Change from baseline in the ECOG PS.
14. Pharmacokinetics of LGX818 and MEK162.
Plasma concentration-profiles of LGX818 and MEK162 and model based PK parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximatively 4 years
2. Approximately 2 years with update around 3 years
3. Approximately 2 years
4. Approximately 2 years
5. Approximately 2 years
6. Approximately 2 years
7. Up to approximatively 4 years
8. Approximately 2 years
9. Approximately 2 years
10. Approximately 2 years
11. Approximately 2 years
12. Approximately 2 years
13. Approximately 2 years
14. Approximately 2 years |
|
| 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 | 13 |
| 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 |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| South Africa |
| Turkey |
| United States |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Norway |
| Poland |
| Slovakia |
| Sweden |
| United Kingdom |
| Netherlands |
| Spain |
| Switzerland |
|
| 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
|
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. |
|
| 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 |
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