carbamates has been researched along with Emesis in 17 studies
Excerpt | Relevance | Reference |
---|---|---|
"In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300)." | 9.34 | Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. ( Arance, A; Ascierto, PA; de Groot, JWB; Dummer, R; Flaherty, KT; Garbe, C; Gogas, HJ; Gollerkeri, A; Gutzmer, R; Krajsova, I; Liszkay, G; Loquai, C; Mandala, M; Pickard, MD; Robert, C; Schadendorf, D, 2020) |
"The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat." | 7.74 | Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. ( Cross-Mellor, SK; Ossenkopp, KP; Parker, LA; Piomelli, D, 2007) |
"In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300)." | 5.34 | Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. ( Arance, A; Ascierto, PA; de Groot, JWB; Dummer, R; Flaherty, KT; Garbe, C; Gogas, HJ; Gollerkeri, A; Gutzmer, R; Krajsova, I; Liszkay, G; Loquai, C; Mandala, M; Pickard, MD; Robert, C; Schadendorf, D, 2020) |
"Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily." | 5.30 | Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. ( Arance, A; Ascierto, PA; de Groot, JWB; Dummer, R; Dutriaux, C; Flaherty, KT; Garbe, C; Gogas, HJ; Gollerkeri, A; Gutzmer, R; Krajsova, I; Liszkay, G; Loquai, C; Mandala, M; Pickard, MD; Robert, C; Schadendorf, D; Sileni, VC; Yamazaki, N, 2019) |
"Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi)." | 4.02 | Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report. ( Lankheet, NAG; Meussen, E; Mian, P; Piersma, D, 2021) |
"We evaluated the effectiveness of the potent selective monoacylglycerol lipase (MAGL) inhibitor, MJN110, which selectively elevates the endocannabinoid 2-AG, to suppress acute nausea and vomiting, as well as anticipatory nausea in rat and shrew models." | 3.81 | Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus. ( Abdullah, RA; Cravatt, BF; Downey, R; Lichtman, AH; Limebeer, CL; Morris, H; Niphakis, MJ; Parker, LA; Rock, EM; Sticht, MA, 2015) |
"The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat." | 3.74 | Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. ( Cross-Mellor, SK; Ossenkopp, KP; Parker, LA; Piomelli, D, 2007) |
"In human volunteers, studies to assess the adverse effects of the carbamate anticholinesterase physostigmine showed that the intramuscular dose observed to induce emesis in 50% of subjects tested (ED50) was 28." | 3.68 | A model for carbamate and organophosphate-induced emesis in humans. ( D'Mello, GD; Sidell, FR, 1991) |
"CNS excitation and seizures, manifestations of organochlorine intoxication, can occur following ingestion or inappropriate application of the 1 per cent topical formulation of lindane used to treat scabies and lice." | 2.37 | Management of acute childhood poisonings caused by selected insecticides and herbicides. ( Mortensen, ML, 1986) |
"The administration of emetic agents in dogs for the purpose of gastric decontamination is not without risk, although the incidence of adverse effects is unknown and likely under-reported." | 1.51 | Side effects of powdered sodium carbonate (washing or 'Lectric' soda) used as an oral emetic agent in five dogs. ( Indrawirawan, YH; Watson, AK, 2019) |
"Acute pancreatitis was diagnosed in 5 subjects." | 1.28 | Acute pancreatitis in children with anticholinesterase insecticide intoxication. ( Sofer, S; Weizman, Z, 1992) |
Timeframe | Studies, this research(%) | All Research% |
---|---|---|
pre-1990 | 5 (29.41) | 18.7374 |
1990's | 2 (11.76) | 18.2507 |
2000's | 3 (17.65) | 29.6817 |
2010's | 5 (29.41) | 24.3611 |
2020's | 2 (11.76) | 2.80 |
Authors | Studies |
---|---|
Gogas, HJ | 2 |
Flaherty, KT | 2 |
Dummer, R | 2 |
Ascierto, PA | 2 |
Arance, A | 2 |
Mandala, M | 2 |
Liszkay, G | 2 |
Garbe, C | 2 |
Schadendorf, D | 2 |
Krajsova, I | 2 |
Gutzmer, R | 2 |
Sileni, VC | 1 |
Dutriaux, C | 1 |
de Groot, JWB | 2 |
Yamazaki, N | 1 |
Loquai, C | 2 |
Gollerkeri, A | 2 |
Pickard, MD | 2 |
Robert, C | 2 |
Mian, P | 1 |
Meussen, E | 1 |
Piersma, D | 1 |
Lankheet, NAG | 1 |
Watson, AK | 1 |
Indrawirawan, YH | 1 |
Parker, LA | 3 |
Niphakis, MJ | 1 |
Downey, R | 1 |
Limebeer, CL | 2 |
Rock, EM | 2 |
Sticht, MA | 1 |
Morris, H | 1 |
Abdullah, RA | 1 |
Lichtman, AH | 1 |
Cravatt, BF | 1 |
Tongpoo, A | 1 |
Sriapha, C | 1 |
Wongvisawakorn, S | 1 |
Rittilert, P | 1 |
Trakulsrichai, S | 1 |
Wananukul, W | 1 |
Litt, DL | 1 |
Kwiatkowska, M | 1 |
Piomelli, D | 2 |
Percie du Sert, N | 1 |
Ho, WS | 1 |
Rudd, JA | 1 |
Andrews, PL | 1 |
Darmani, NA | 1 |
McClanahan, BA | 1 |
Trinh, C | 1 |
Petrosino, S | 1 |
Valenti, M | 1 |
Di Marzo, V | 1 |
Cross-Mellor, SK | 1 |
Ossenkopp, KP | 1 |
Weizman, Z | 1 |
Sofer, S | 1 |
D'Mello, GD | 1 |
Sidell, FR | 1 |
Mortensen, ML | 1 |
Gailani, S | 1 |
Blais, M | 1 |
Udall, ND | 1 |
Müntzing, J | 1 |
Shukla, SK | 1 |
Chu, TM | 1 |
Mittelman, A | 1 |
Murphy, GP | 1 |
Luce, JK | 1 |
Bodey, GP | 1 |
Trial | Phase | Enrollment | Study Type | Start Date | Status | ||
---|---|---|---|---|---|---|---|
A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma[NCT01909453] | Phase 3 | 921 participants (Actual) | Interventional | 2013-12-13 | Active, not recruiting | ||
A Phase 1B Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of the Combination of Encorafenib, Binimetinib and Palbociclib in Patients With BRAF-mutant Metastatic Melanoma (The CELEBRATE Study)[NCT04720768] | Phase 1/Phase 2 | 78 participants (Anticipated) | Interventional | 2020-06-04 | Recruiting | ||
[information is prepared from clinicaltrials.gov, extracted Sep-2024] |
DCR was calculated as the percentage of participants with a best overall response (BOR) of CR, PR, or stable disease (SD). CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Two sets of DCR were considered, one for confirmed and one for unconfirmed responses. Results are reported for confirmed and unconfirmed responses combined. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. DCR was based on central review. (NCT01909453)
Timeframe: From randomization until disease progression or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | percentage of participants (Number) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 92.2 |
Part 1: LGX818 300 mg | 84.0 |
Part 1: Vemurafenib 960 mg BID | 81.7 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 90.7 |
Part 2: LGX818 300 mg | 79.1 |
Part 1 + Part 2: LGX818 300 mg | 82.5 |
DOR was calculated, as the time from the date of first documented response (CR or PR) to the first documented progression or death due to underlying cancer. DOR was estimated for responders (i.e. participants achieving at least once CR or PR) only using a Kaplan-Meier method. CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. If a participant with a CR or PR had no progression or death due to underlying disease, the participant was censored at the date of last adequate tumor assessment. Results are based on confirmed BIRC response. (NCT01909453)
Timeframe: From randomization until disease progression, censoring date or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 16.6 |
Part 1: LGX818 300 mg | 15.2 |
Part 1: Vemurafenib 960 mg BID | 12.3 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 12.7 |
Part 2: LGX818 300 mg | 7.5 |
Part 1 + Part 2: LGX818 300 mg | 12.9 |
ORR, calculated as the percentage of participants with a best overall response of complete response (CR) or partial response (PR). CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Results are reported for confirmed BIRC response. (NCT01909453)
Timeframe: From randomization until disease progression, censoring date or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | percentage of participants (Number) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 63.0 |
Part 1: LGX818 300 mg | 50.5 |
Part 1: Vemurafenib 960 mg BID | 40.3 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 65.9 |
Part 2: LGX818 300 mg | 50.0 |
Part 1 + Part 2: LGX818 300 mg | 50.4 |
ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50 percent (%) of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. Definitive deterioration was defined as death due to any cause or decrease in ECOG PS by at least one category from baseline score with no subsequent improvement. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 36 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | NA |
Part 1: LGX818 300 mg | 26.7 |
Part 1: Vemurafenib 960 mg BID | 18.2 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | NA |
Part 2: LGX818 300 mg | 10.2 |
Part 1 + Part 2: LGX818 300 mg | 19.2 |
FACT-M:melanoma specific questionnaire to assess participant health-related quality of life. Melanoma specific subscale consists of 16 items related to signs,symptoms,physical/social activities most relevant to participants with advanced-stage melanoma. Other items include physical, functional and social/family well-being (7 items each),emotional well-being (6 items),surgery specific concerns related to melanoma(8 items,not included in this study). Each item range from 0(not at all) to 4(very much), combined to produce subscale scores.Total score range for FACT-M excluding surgery specific items is 0 to 172,higher scores represent better quality of life.Melanoma subscale score range from 0(worst response) to 64(best response),higher score indicated better quality of life. Time to definitive 10% deterioration:time from date of randomization to date of event with at least 10% relative to baseline worsening of corresponding scale score with no later improvement or death due to any cause. (NCT01909453)
Timeframe: Date of randomization to date of event or death due to any cause, which ever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | NA |
Part 1: LGX818 300 mg | 30.5 |
Part 1: Vemurafenib 960 mg BID | 22.1 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | NA |
Part 2: LGX818 300 mg | NA |
Part 1 + Part 2: LGX818 300 mg | 20.5 |
"EORTC QLQ-C30 is 30 item questionnaire composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/quality of life (QOL) subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4 point Likert scales with responses from not at all to very much and two 7 point Likert scales for global health and overall QOL. Global health status scale score ranged from 0 to 100. Higher score represented better level of functioning. Time to definitive 10% deterioration: time from date of randomization to date of event with at least 10% relative to baseline worsening of corresponding scale score with no later improvement or death due to any cause." (NCT01909453)
Timeframe: Date of randomization to date of event or death due to any cause, which ever occurred first (maximum up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 23.9 |
Part 1: LGX818 300 mg | 14.7 |
Part 1: Vemurafenib 960 mg BID | 16.6 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 18.4 |
Part 2: LGX818 300 mg | 9.5 |
Part 1 + Part 2: LGX818 300 mg | 11.1 |
TTR was the time between date of randomization until first documented response of CR or PR. Participants who did not achieve a PR or CR were censored at the last adequate tumor assessment date when they did not have a PFS event or at maximum follow-up (i.e. first patient first visit [FPFV] to last patient last visit [LPLV] used for the analysis) when they had a PFS event. CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. TTR was estimated in the treatment arms using a Kaplan-Meier method. TTR was based on central review. (NCT01909453)
Timeframe: From randomization until disease progression, censoring date or death, whichever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 1.9 |
Part 1: LGX818 300 mg | 2.0 |
Part 1: Vemurafenib 960 mg BID | 2.1 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 1.9 |
Part 2: LGX818 300 mg | 1.9 |
Part 1 + Part 2: LGX818 300 mg | 1.9 |
PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm^2. (NCT01909453)
Timeframe: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months), excluding Part 1: LGX818 300 mg group; up to 35 months for Part 1: LGX 300 mg group
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 14.9 |
Part 1: LGX818 300 mg | 9.6 |
PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC/central review and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 square millimeter (mm^2). (NCT01909453)
Timeframe: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months)
Intervention | months (Median) |
---|---|
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 14.9 |
Part 1: Vemurafenib 960 mg BID | 7.3 |
PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a participant did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm^2. (NCT01909453)
Timeframe: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 35 months)
Intervention | months (Median) |
---|---|
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 12.9 |
Part 2: LGX818 300 mg | 7.4 |
Part 1 + Part 2: LGX818 300 mg | 9.2 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at End of treatment visit | |
Part 2: LGX818 300 mg | 74.20 | 1.79 | 2.96 | -3.62 | -0.60 | -2.69 | -6.41 | -2.12 | 1.79 | 2.78 | 16.67 | 5.56 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 73.04 | 7.29 | 6.15 | 9.37 | 9.22 | 10.56 | 8.66 | 10.59 | 10.33 | 8.33 | 13.13 | -4.17 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at Cycle 23 Day 1 | Change at Cycle 25 Day 1 | Change at End of treatment visit | |
Part 1 + Part 2: LGX818 300 mg | 74.38 | 0.32 | 1.98 | -0.91 | 1.26 | -0.74 | 0.83 | 1.30 | 3.26 | 1.27 | -0.76 | 2.94 | -0.32 | -0.83 |
Part 1: LGX818 300 mg | 74.46 | -0.34 | 1.54 | 0.34 | 2.15 | 0.12 | 3.78 | 2.30 | 3.64 | 1.00 | -1.16 | 2.94 | -0.32 | -3.57 |
Part 1: Vemurafenib 960 mg BID | 72.31 | 1.88 | 2.03 | 2.71 | -0.17 | 4.53 | -2.25 | -5.46 | -1.39 | 0.38 | -3.13 | -0.69 | -1.19 | 12.50 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 74.68 | 3.23 | 5.37 | 5.42 | 4.47 | 4.81 | 3.52 | 7.35 | 5.33 | 4.25 | 4.17 | -1.74 | 3.92 | 41.67 |
EQ-5D-5L is a standardized participant completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS) in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated better health status. (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at End of treatment visit | |
Part 2: LGX818 300 mg | 0.73 | -0.06 | -0.06 | -0.16 | -0.11 | -0.16 | -0.20 | -0.26 | -0.20 | -0.11 | -0.11 | -0.06 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 0.75 | 0.06 | 0.07 | 0.06 | 0.07 | 0.06 | 0.05 | 0.05 | 0.06 | 0.05 | 0.12 | -0.27 |
EQ-5D-5L is a standardized participant completed questionnaire that measures health status in terms of a single index value or utility score. EQ-5D-5L consisted of two components: a health state profile (descriptive system) and a visual analogue scale (VAS) in which participants rate their overall health status from 0 (worst imaginable) to 100 (best imaginable), where higher scores indicated better health status. EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems. EQ-5D-5L health status index score range between 0 to 1. Higher score indicated better health status. (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at Cycle 23 Day 1 | Change at Cycle 25 Day 1 | Change at End of treatment visit | |
Part 1 + Part 2: LGX818 300 mg | 0.75 | -0.09 | -0.13 | -0.14 | -0.14 | -0.17 | -0.18 | -0.20 | -0.15 | -0.17 | -0.14 | -0.11 | -0.11 | -0.08 |
Part 1: LGX818 300 mg | 0.76 | -0.10 | -0.15 | -0.13 | -0.15 | -0.18 | -0.17 | -0.18 | -0.14 | -0.18 | -0.14 | -0.11 | -0.11 | -0.09 |
Part 1: Vemurafenib 960 mg BID | 0.73 | 0.00 | -0.04 | -0.03 | -0.04 | -0.01 | -0.02 | -0.07 | -0.02 | -0.02 | -0.04 | -0.05 | -0.17 | -0.14 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 0.74 | 0.05 | 0.04 | 0.05 | 0.03 | 0.04 | 0.05 | 0.05 | 0.07 | 0.03 | 0.07 | 0.04 | 0.07 | 0.03 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at End of treatment visit | |
Part 2: LGX818 300 mg | 67.39 | -4.95 | -4.72 | -7.08 | -8.73 | -7.53 | -9.29 | -12.75 | -7.14 | -0.93 | 0.00 | 4.17 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 65.95 | 4.47 | 5.61 | 5.01 | 4.94 | 4.76 | 5.89 | 6.11 | 5.86 | 1.23 | 3.03 | -6.25 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at Cycle 23 Day 1 | Change at Cycle 25 Day 1 | Change at End of treatment visit | |
Part 1 + Part 2: LGX818 300 mg | 66.48 | -6.81 | -7.87 | -8.53 | -10.96 | -10.13 | -8.80 | -10.56 | -7.85 | -8.05 | -10.80 | -5.64 | -7.05 | 4.63 |
Part 1: LGX818 300 mg | 66.07 | -7.64 | -9.24 | -9.21 | -12.03 | -11.27 | -8.59 | -9.91 | -8.03 | -9.33 | -11.05 | -5.64 | -7.05 | 4.76 |
Part 1: Vemurafenib 960 mg BID | 64.74 | -3.46 | -4.05 | -3.04 | -6.94 | -3.80 | -2.93 | -10.34 | -6.94 | -1.89 | -8.85 | -3.47 | -2.38 | -4.17 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 66.72 | 3.56 | 1.55 | 1.53 | -0.55 | 0.81 | 0.42 | 5.02 | 0.41 | -0.51 | 0.74 | -1.39 | 1.96 | 0.00 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represented a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at End of treatment visit | |
Part 2: LGX818 300 mg | 81.45 | -13.63 | -12.63 | -17.01 | -15.83 | -13.49 | -13.85 | -24.31 | -19.05 | -14.07 | -13.33 | -4.44 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 80.67 | 2.94 | 2.73 | 1.22 | 3.03 | 0.50 | 0.47 | -0.40 | -0.88 | -5.71 | -8.48 | -5.00 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represented a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at Cycle 23 Day 1 | Change at Cycle 25 Day 1 | Change at End of treatment visit | |
Part 1 + Part 2: LGX818 300 mg | 82.63 | -13.74 | -15.74 | -16.49 | -18.27 | -19.87 | -18.22 | -21.18 | -18.91 | -19.14 | -16.78 | -14.46 | -15.93 | -2.00 |
Part 1: LGX818 300 mg | 83.18 | -13.79 | -17.14 | -16.26 | -19.43 | -22.65 | -20.00 | -20.26 | -18.88 | -20.07 | -16.86 | -14.46 | -15.93 | -0.95 |
Part 1: Vemurafenib 960 mg BID | 80.71 | -2.90 | -7.45 | -6.98 | -6.82 | -4.11 | -6.30 | -6.22 | -3.27 | -1.90 | -4.90 | -2.22 | -4.76 | -15.00 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 82.10 | 0.20 | 0.15 | -1.93 | -0.45 | -0.85 | -1.25 | 0.29 | -0.03 | -1.22 | -0.95 | -5.00 | -5.49 | 33.33 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represented a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at End of treatment visit | |
Part 2: LGX818 300 mg | 78.31 | -10.00 | -5.11 | -13.89 | -9.52 | -12.37 | -5.77 | -15.69 | -7.14 | -12.96 | -33.33 | 0.00 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 81.37 | 4.05 | 3.37 | 3.05 | 3.66 | 1.95 | 1.75 | 2.86 | 1.59 | 1.23 | 4.55 | -16.67 |
"EORTC QLQ-C30 contains 30 items and is composed of multi-item and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life (QOL) scale. The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items converted to 0 to 100 scale. For functional and global QOL scales, higher scores represented a better level of functioning/QOL. For symptom-oriented scales, a higher score represented more severe symptoms." (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at Cycle 23 Day 1 | Change at Cycle 25 Day 1 | Change at End of treatment visit | |
Part 1 + Part 2: LGX818 300 mg | 80.09 | -10.59 | -9.80 | -11.11 | -13.70 | -12.54 | -9.74 | -11.78 | -10.54 | -12.43 | -15.15 | -6.37 | -7.05 | -13.33 |
Part 1: LGX818 300 mg | 80.91 | -10.86 | -11.92 | -9.80 | -15.71 | -12.62 | -11.38 | -10.63 | -11.42 | -12.33 | -14.73 | -6.37 | -7.05 | -19.05 |
Part 1: Vemurafenib 960 mg BID | 78.54 | -4.90 | -7.21 | -2.75 | -1.99 | -0.36 | -0.45 | -6.32 | 1.39 | 3.79 | -3.13 | 1.39 | 4.76 | -8.33 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 80.69 | -0.66 | 3.26 | 2.82 | 1.57 | -2.72 | -4.27 | 3.73 | 1.11 | -1.04 | -1.52 | -12.32 | -5.21 | 25.00 |
FACT-M: melanoma specific questionnaire to assess participant health-related quality of life. Melanoma specific subscale consists of 16 items related to signs, symptoms, physical/social activities most relevant to participants with advanced-stage melanoma. Other items include physical, functional and social/family well-being (7 items each),emotional well-being (6 items),surgery specific concerns related to melanoma(8 items, not included in this study). Each item range from 0(not at all) to 4(very much), combined to produce subscale scores. Total score range for FACT-M excluding surgery specific items is 0 to 172,higher scores represented better quality of life. Melanoma subscale score range from 0(worst response) to 64(best response),higher score indicated better quality of life. (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at End of treatment visit | |
Part 2: LGX818 300 mg | 51.13 | -2.16 | -0.60 | -3.14 | -1.83 | -2.41 | -3.31 | -4.14 | -2.64 | 0.00 | -2.00 | -1.61 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 52.08 | 2.79 | 2.58 | 2.64 | 3.23 | 2.54 | 1.97 | 2.08 | 2.45 | 1.23 | 2.58 | 6.58 |
FACT-M: melanoma specific questionnaire to assess participant health-related quality of life. Melanoma specific subscale consists of 16 items related to signs, symptoms, physical/social activities most relevant to participants with advanced-stage melanoma. Other items include physical, functional and social/family well-being (7 items each),emotional well-being (6 items),surgery specific concerns related to melanoma(8 items, not included in this study). Each item range from 0(not at all) to 4(very much), combined to produce subscale scores. Total score range for FACT-M excluding surgery specific items is 0 to 172,higher scores represented better quality of life. Melanoma subscale score range from 0(worst response) to 64(best response),higher score indicated better quality of life. (NCT01909453)
Timeframe: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)
Intervention | units on a scale (Mean) | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline | Change at Cycle 3 Day 1 | Change at Cycle 5 Day 1 | Change at Cycle 7 Day 1 | Change at Cycle 9 Day 1 | Change at Cycle 11 Day 1 | Change at Cycle 13 Day 1 | Change at Cycle 15 Day 1 | Change at Cycle 17 Day 1 | Change at Cycle 19 Day 1 | Change at Cycle 21 Day 1 | Change at Cycle 23 Day 1 | Change at Cycle 25 Day 1 | Change at End of treatment visit | |
Part 1: Vemurafenib 960 mg BID | 52.01 | -1.55 | -1.90 | -2.19 | -1.90 | -0.51 | -0.97 | -1.72 | 0.70 | 0.23 | -3.33 | -0.17 | -0.14 | -2.31 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 52.39 | 0.92 | -0.01 | 1.35 | 0.52 | 0.18 | -0.33 | 0.40 | 0.27 | -0.59 | -0.69 | -1.67 | -1.83 | 18.50 |
Part 1 + Part 2: LGX818 300 mg | 52.24 | -3.14 | -2.78 | -3.08 | -2.39 | -3.29 | -2.88 | -2.88 | -1.88 | -2.38 | -2.58 | -1.38 | -1.00 | -3.81 |
Part 1: LGX818 300 mg | 52.76 | -3.58 | -3.77 | -3.05 | -2.69 | -3.67 | -2.71 | -2.48 | -1.66 | -2.80 | -2.59 | -1.38 | -1.00 | -5.18 |
ECOG: participant's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50% of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. (NCT01909453)
Timeframe: Part 1 and Part 2: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 31)
Intervention | Participants (Count of Participants) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Baseline: ECOG score 0 | Baseline: ECOG score 1 | Cycle 2 Day 1: ECOG score 0 | Cycle 2 Day 1: ECOG score 1 | Cycle 2 Day 1: ECOG score 2 | Cycle 2 Day 1: ECOG score 3 | Cycle 2 Day 1: ECOG score 4 | Cycle 3 Day 1: ECOG score 0 | Cycle 3 Day 1: ECOG score 1 | Cycle 3 Day 1: ECOG score 2 | Cycle 4 Day 1: ECOG score 0 | Cycle 4 Day 1: ECOG score 1 | Cycle 4 Day 1: ECOG score 2 | Cycle 4 Day 1: ECOG score 3 | Cycle 5 Day 1: ECOG score 0 | Cycle 5 Day 1: ECOG score 1 | Cycle 5 Day 1: ECOG score 2 | Cycle 5 Day 1: ECOG score 3 | Cycle 5 Day 1: ECOG score 4 | Cycle 6 Day 1: ECOG score 0 | Cycle 6 Day 1: ECOG score 1 | Cycle 6 Day 1: ECOG score 2 | Cycle 6 Day 1: ECOG score 3 | Cycle 6 Day 1: ECOG score 4 | Cycle 7 Day 1: ECOG score 0 | Cycle 7 Day 1: ECOG score 1 | Cycle 7 Day 1: ECOG score 2 | Cycle 8 Day 1: ECOG score 0 | Cycle 8 Day 1: ECOG score 1 | Cycle 8 Day 1: ECOG score 2 | Cycle 8 Day 1: ECOG score 3 | Cycle 9 Day 1: ECOG score 0 | Cycle 9 Day 1: ECOG score 1 | Cycle 9 Day 1: ECOG score 2 | Cycle 9 Day 1: ECOG score 3 | Cycle 9 Day 1: ECOG score 4 | Cycle 9 Day 1: ECOG score 5 | Cycle 10 Day 1: ECOG score 0 | Cycle 10 Day 1: ECOG score 1 | Cycle 10 Day 1: ECOG score 2 | Cycle 10 Day 1: ECOG score 3 | Cycle 11 Day 1: ECOG score 0 | Cycle 11 Day 1: ECOG score 1 | Cycle 11 Day 1: ECOG score 2 | Cycle 11 Day 1: ECOG score 3 | Cycle 12 Day 1: ECOG score 0 | Cycle 12 Day 1: ECOG score 1 | Cycle 12 Day 1: ECOG score 2 | Cycle 12 Day 1: ECOG score 3 | Cycle 12 Day 1: ECOG score 4 | Cycle 13 Day 1: ECOG score 0 | Cycle 13 Day 1: ECOG score 1 | Cycle 13 Day 1: ECOG score 2 | Cycle 13 Day 1: ECOG score 4 | Cycle 14 Day 1: ECOG score 0 | Cycle 14 Day 1: ECOG score 1 | Cycle 14 Day 1: ECOG score 2 | Cycle 14 Day 1: ECOG score 3 | Cycle 14 Day 1: ECOG score 4 | Cycle 15 Day 1: ECOG score 0 | Cycle 15 Day 1: ECOG score 1 | Cycle 15 Day 1: ECOG score 2 | Cycle 15 Day 1: ECOG score 3 | Cycle 15 Day 1: ECOG score 4 | Cycle 16 Day 1: ECOG score 0 | Cycle 16 Day 1: ECOG score 1 | Cycle 16 Day 1: ECOG score 2 | Cycle 16 Day 1: ECOG score 3 | Cycle 17 Day 1: ECOG score 0 | Cycle 17 Day 1: ECOG score 1 | Cycle 17 Day 1: ECOG score 2 | Cycle 18 Day 1: ECOG score 0 | Cycle 18 Day 1: ECOG score 1 | Cycle 18 Day 1: ECOG score 2 | Cycle 18 Day 1: ECOG score 3 | Cycle 19 Day 1: ECOG score 0 | Cycle 19 Day 1: ECOG score 1 | Cycle 19 Day 1: ECOG score 2 | Cycle 20 Day 1: ECOG score 0 | Cycle 20 Day 1: ECOG score 1 | Cycle 20 Day 1: ECOG score 2 | Cycle 20 Day 1: ECOG score 3 | Cycle 21 Day 1: ECOG score 0 | Cycle 21 Day 1: ECOG score 1 | Cycle 21 Day 1: ECOG score 2 | Cycle 22 Day 1: ECOG score 0 | Cycle 22 Day 1: ECOG score 1 | Cycle 22 Day 1: ECOG score 3 | Cycle 22 Day 1: ECOG score 4 | Cycle 23 Day 1: ECOG score 0 | Cycle 23 Day 1: ECOG score 1 | Cycle 24 Day 1: ECOG score 0 | Cycle 24 Day 1: ECOG score 1 | Cycle 25 Day 1: ECOG score 0 | Cycle 25 Day 1: ECOG score 1 | Cycle 26 Day 1: ECOG score 0 | Cycle 26 Day 1: ECOG score 1 | Cycle 26 Day 1: ECOG score 2 | Cycle 27 Day 1: ECOG score 0 | Cycle 27 Day 1: ECOG score 1 | Cycle 28 Day 1: ECOG score 0 | Cycle 28 Day 1: ECOG score 1 | Cycle 29 Day 1: ECOG score 0 | Cycle 29 Day 1: ECOG score 1 | Cycle 30 Day 1: ECOG score 0 | Cycle 30 Day 1: ECOG score 1 | Cycle 31 Day 1: ECOG score 0 | Cycle 31 Day 1: ECOG score 1 | |
Part 1 + Part 2: LGX818 300 mg | 199 | 77 | 142 | 111 | 7 | 2 | 0 | 130 | 113 | 6 | 128 | 96 | 7 | 1 | 118 | 100 | 6 | 0 | 0 | 97 | 90 | 6 | 1 | 1 | 95 | 87 | 2 | 77 | 70 | 6 | 1 | 72 | 67 | 1 | 1 | 0 | 0 | 70 | 53 | 2 | 0 | 61 | 56 | 4 | 0 | 55 | 49 | 2 | 1 | 0 | 55 | 46 | 3 | 0 | 62 | 37 | 2 | 0 | 1 | 54 | 37 | 2 | 0 | 0 | 52 | 30 | 4 | 0 | 48 | 33 | 2 | 41 | 29 | 0 | 0 | 40 | 26 | 1 | 34 | 22 | 2 | 0 | 31 | 20 | 1 | 27 | 16 | 1 | 1 | 26 | 12 | 23 | 10 | 23 | 8 | 21 | 8 | 0 | 20 | 6 | 18 | 6 | 13 | 5 | 9 | 3 | 7 | 3 |
Part 1: LGX818 300 mg | 139 | 53 | 98 | 79 | 3 | 2 | 0 | 90 | 81 | 4 | 93 | 66 | 4 | 1 | 85 | 69 | 4 | 0 | 0 | 68 | 65 | 3 | 0 | 1 | 68 | 60 | 1 | 55 | 49 | 3 | 1 | 50 | 47 | 1 | 0 | 0 | 0 | 52 | 35 | 1 | 0 | 44 | 40 | 1 | 0 | 44 | 31 | 1 | 1 | 0 | 41 | 31 | 1 | 0 | 47 | 27 | 0 | 0 | 1 | 41 | 30 | 1 | 0 | 0 | 41 | 23 | 3 | 0 | 39 | 27 | 1 | 36 | 24 | 0 | 0 | 38 | 20 | 1 | 31 | 19 | 2 | 0 | 29 | 19 | 1 | 27 | 16 | 1 | 1 | 26 | 12 | 23 | 10 | 23 | 8 | 21 | 8 | 0 | 20 | 6 | 18 | 6 | 13 | 5 | 9 | 3 | 7 | 3 |
Part 1: Vemurafenib 960 mg BID | 135 | 51 | 113 | 64 | 4 | 0 | 0 | 107 | 64 | 4 | 98 | 52 | 4 | 4 | 82 | 52 | 7 | 1 | 1 | 78 | 46 | 1 | 1 | 0 | 74 | 35 | 2 | 58 | 33 | 4 | 0 | 55 | 30 | 4 | 1 | 0 | 0 | 43 | 26 | 2 | 1 | 39 | 20 | 2 | 1 | 32 | 16 | 2 | 1 | 0 | 27 | 18 | 2 | 0 | 25 | 19 | 2 | 0 | 0 | 22 | 18 | 1 | 0 | 0 | 24 | 10 | 1 | 0 | 21 | 11 | 1 | 18 | 11 | 1 | 1 | 20 | 9 | 1 | 19 | 8 | 0 | 0 | 15 | 8 | 0 | 11 | 6 | 0 | 0 | 10 | 5 | 9 | 5 | 9 | 2 | 7 | 2 | 0 | 3 | 4 | 4 | 1 | 5 | 0 | 4 | 0 | 2 | 0 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 136 | 56 | 142 | 44 | 1 | 0 | 1 | 131 | 53 | 1 | 128 | 50 | 1 | 0 | 128 | 42 | 3 | 1 | 0 | 124 | 45 | 0 | 0 | 0 | 111 | 46 | 1 | 112 | 33 | 2 | 1 | 102 | 36 | 4 | 0 | 1 | 1 | 94 | 32 | 3 | 0 | 88 | 30 | 2 | 0 | 84 | 25 | 1 | 0 | 0 | 77 | 22 | 1 | 0 | 74 | 23 | 0 | 0 | 0 | 72 | 20 | 1 | 1 | 0 | 64 | 24 | 1 | 0 | 65 | 16 | 1 | 60 | 14 | 1 | 0 | 54 | 9 | 2 | 53 | 7 | 0 | 1 | 36 | 10 | 9 | 29 | 8 | 0 | 0 | 24 | 6 | 21 | 7 | 17 | 3 | 14 | 3 | 1 | 5 | 3 | 5 | 3 | 1 | 2 | 0 | 0 | 0 | 0 |
Part 2: LGX818 300 mg | 60 | 24 | 44 | 32 | 4 | 0 | 0 | 40 | 32 | 2 | 35 | 30 | 3 | 0 | 33 | 31 | 2 | 0 | 0 | 29 | 25 | 3 | 1 | 0 | 27 | 27 | 1 | 22 | 21 | 3 | 0 | 22 | 20 | 0 | 1 | 0 | 0 | 18 | 18 | 1 | 0 | 17 | 16 | 3 | 0 | 11 | 18 | 1 | 0 | 0 | 14 | 15 | 2 | 0 | 15 | 10 | 2 | 0 | 0 | 13 | 7 | 1 | 0 | 0 | 11 | 7 | 1 | 0 | 9 | 6 | 1 | 5 | 5 | 0 | 0 | 2 | 6 | 0 | 3 | 3 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 189 | 68 | 193 | 62 | 1 | 0 | 0 | 197 | 55 | 1 | 189 | 56 | 4 | 1 | 181 | 55 | 2 | 1 | 0 | 168 | 58 | 3 | 1 | 1 | 158 | 58 | 2 | 140 | 58 | 1 | 1 | 135 | 52 | 0 | 0 | 1 | 0 | 121 | 46 | 3 | 1 | 116 | 42 | 0 | 0 | 113 | 38 | 0 | 0 | 1 | 102 | 39 | 1 | 1 | 100 | 33 | 2 | 1 | 0 | 82 | 27 | 1 | 0 | 1 | 64 | 23 | 0 | 1 | 52 | 15 | 1 | 34 | 11 | 1 | 0 | 22 | 7 | 1 | 15 | 5 | 0 | 0 | 11 | 2 | 0 | 4 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 4.03 were graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift from baseline in laboratory parameter = worsening by at least 2 grades or to >=grade 3. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | Participants (Count of Participants) | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Hemoglobin (hypo) | Prothrombin international normalized ratio increased | Lymphocytes (hypo) | Lymphocytes (hyper) | Neutrophils (hypo) | Platelets (hypo) | Leukocytes (hypo) | Albumin (hypo) | Alkaline phosphatase | Alanine aminotransferase | Aspartate aminotransferase | Bilirubin | Creatine (phospho)kinase | Corrected Calcium (hypo) | Corrected Calcium (hyper) | Creatinine | Gamma-glutamyl transferase | Glucose serum fasting (hypo) | Glucose serum fasting (hyper) | Magnesium (hypo) | Magnesium (hyper) | Phosphate (hypo) | Potassium (hypo) | Potassium (hyper) | Sodium (hypo) | |
Part 1: LGX818 300 mg | 11 | 1 | 15 | 11 | 5 | 1 | 3 | 5 | 3 | 8 | 4 | 0 | 1 | 1 | 0 | 15 | 29 | 4 | 12 | 1 | 0 | 25 | 1 | 4 | 1 |
Part 1: Vemurafenib 960 mg BID | 13 | 3 | 41 | 5 | 3 | 1 | 4 | 2 | 4 | 8 | 4 | 13 | 1 | 3 | 2 | 48 | 15 | 3 | 12 | 0 | 1 | 35 | 3 | 6 | 1 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 19 | 0 | 20 | 14 | 14 | 2 | 5 | 3 | 6 | 15 | 12 | 1 | 32 | 1 | 0 | 35 | 43 | 2 | 20 | 0 | 2 | 18 | 1 | 6 | 7 |
AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Dermatologic-related AESI included rash, photosensitivity, nail disorders, skin infections, severe cutaneous adverse reactions and Palmar-plantar erythrodysaesthesia (PPE) syndrome. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this outcome measure. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | Participants (Count of Participants) | |||||
---|---|---|---|---|---|---|
Rash | Skin infections | PPE syndrome | Photosensitivity | Nail disorders | Severe cutaneous adverse reactions | |
Part 1: LGX818 300 mg | 10 | 1 | 26 | 0 | 0 | 1 |
Part 1: Vemurafenib 960 mg BID | 25 | 0 | 2 | 3 | 0 | 5 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 2 | 4 | 0 | 1 | 0 | 0 |
Newly occurring notable ECG values were reported for QT (millisecond [ms]), QTcF (millisecond), QTcB (millisecond) and heart rate (beats per minute). Newly occurring was defined as participants not meeting criterion at baseline and meeting criterion post-baseline. Ranges for newly occurring notable ECG values (QT, QTcF, QTcB) are New greater than (>) 450, New >480, New >500, Increase from baseline >30, Increase from baseline >60. Heart rate: New <60, New >100 was considered as newly occurring notable value. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | Participants (Count of Participants) | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
QT: Increase >30 ms | QT: Increase >60 ms | QT: New >450 ms | QT: New >480 ms | QT: New >500 ms | QTcF: Increase >30 ms | QTcF: Increase >60 ms | QTcF: New >450 ms | QTcF: New >480 ms | QTcF: New >500 ms | QTcB: Increase >30 ms | QTcB: Increase >60 ms | QTcB: New >450 ms | QTcB: New >480 ms | QTcB: New >500 ms | Heart rate: New <60 bpm | Heart rate: New <100 bpm | |
Part 1: LGX818 300 mg | 68 | 19 | 15 | 4 | 2 | 56 | 7 | 39 | 7 | 5 | 74 | 15 | 76 | 23 | 10 | 37 | 23 |
Part 1: Vemurafenib 960 mg BID | 81 | 24 | 17 | 3 | 2 | 76 | 10 | 42 | 5 | 3 | 78 | 14 | 65 | 20 | 8 | 16 | 18 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 105 | 27 | 23 | 5 | 2 | 50 | 10 | 25 | 7 | 1 | 47 | 11 | 47 | 12 | 3 | 58 | 14 |
Notably abnormal vital signs were: Low/high systolic blood pressure (SBP) (millimeter of mercury [mmHg]): less than or equal to (<=) 90 mmHg with decrease from baseline of greater than or equal to (>=) 20 mmHg/>= 160 mmHg with increase from baseline of >=20 mmHg. Low/high diastolic blood pressure (DBP) [mmHg]: <= 50 mmHg with decrease from baseline of >=15 mmHg/>=100 mmHg with increase from baseline of >=15 mmHg. Low/high Pulse rate: <=50 beats per minute (bpm) with decrease from baseline of >=15 bpm/>= 120 bpm with increase from baseline of >=15 bpm. Low/high Weight [kilogram]: >=20 percent (%) decrease from baseline/>= 10% increase from baseline. Low/high Body temperature degree Celsius (C): <= 36 degree C/>= 37.5 degree C. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | Participants (Count of Participants) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Sitting Pulse Rate (bpm): High | Sitting Pulse Rate (bpm): Low | Sitting Systolic Blood Pressure (mmHg): High | Sitting Systolic Blood Pressure (mmHg): Low | Sitting Diastolic Blood Pressure (mmHg): High | Sitting Diastolic Blood Pressure (mmHg): Low | Weight (kg): High | Weight (kg): Low | Body temperature (degree C): High | Body temperature (degree C): Low | |
Part 1: LGX818 300 mg | 7 | 8 | 14 | 4 | 5 | 7 | 10 | 8 | 11 | 74 |
Part 1: Vemurafenib 960 mg BID | 8 | 2 | 31 | 1 | 13 | 5 | 8 | 13 | 17 | 57 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 1 | 3 | 27 | 7 | 23 | 9 | 44 | 2 | 19 | 76 |
AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Ocular-related AESI included retinopathy excluding retinal vein occlusion (RVO), RVO and uveitis-type events. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this outcome measure. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | Participants (Count of Participants) | ||
---|---|---|---|
Retinopathy excluding RVO | RVO | Uveitis-type events | |
Part 1: LGX818 300 mg | 0 | 1 | 0 |
Part 1: Vemurafenib 960 mg BID | 0 | 0 | 0 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 5 | 0 | 1 |
Participants with worst post-baseline LVEF Values were graded as Grade 0: Non missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute reduction from baseline >=10% and < 20%; Grade 3: LVEF between 20% and 39% or absolute reduction from baseline >=20%; Grade 4: LVEF lower than 20%. Baseline was defined as the last non-missing value prior to the first dose of study treatment. Missing data were due to participants who died or withdrew consent prior to the first scheduled evaluation or missed evaluations as protocol deviations. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | Participants (Count of Participants) | ||||
---|---|---|---|---|---|
Grade 0 | Grade 2 | Grade 3 | Grade 4 | Missing | |
Part 1: LGX818 300 mg | 161 | 17 | 4 | 0 | 10 |
Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 127 | 56 | 3 | 0 | 6 |
Part 1: Vemurafenib 960 mg BID | 161 | 16 | 2 | 0 | 7 |
AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; results in persistent/significant disability/incapacity; results in congenital anomaly/birth defect or that is considered to be important medical event. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence; Grade 5: death. AEs of all grades were reported. (NCT01909453)
Timeframe: Baseline up to 30 days from last dose of study drug (up to 30 months), excluding Part 1: LGX818 300 mg group; up to 36 months for Part 1 LGX 300 mg group
Intervention | percentage of participants (Number) | |
---|---|---|
Participants with AEs | Participants with SAEs | |
Part 1: LGX818 300 mg | 99.5 | 34.9 |
Part 1: Vemurafenib 960 mg BID | 99.5 | 37.1 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 98.4 | 34.4 |
(NCT01909453)
Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose
Intervention | nanogram per milliliter (Mean) | |||||
---|---|---|---|---|---|---|
Cycle 1 Day 1: pre-dose | Cycle 1 Day 1: 0.5 hours post dose | Cycle 1 Day 1: 1.5 hours post dose | Cycle 1 Day 1: 4 to 8 hours post dose | Cycle 2 Day 1: pre-dose | Cycle 3 Day 1: pre-dose | |
Part 1: LGX818 300 mg | 58.1 | 1190 | 4090 | 1850 | 73.6 | 53.8 |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 18.6 | 1640 | 6860 | 3400 | 119 | 150 |
(NCT01909453)
Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8, hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose
Intervention | nanogram per milliliter (Mean) | |||||
---|---|---|---|---|---|---|
Cycle 1 Day 1: pre-dose | Cycle 1 Day 1: 0.5 hours post dose | Cycle 1 Day 1: 1.5 hours post dose | Cycle 1 Day 1: 4 to 8 hours post dose | Cycle 2 Day 1: pre-dose | Cycle 3 Day 1: pre-dose | |
Part 1:LGX818 450 mg QD+MEK162 45 mg BID (Combo 450) | 2.95 | 426 | 832 | 330 | 81.0 | 68.1 |
Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 4.0 were graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift from baseline in laboratory parameter = worsening by at least 2 grades or to >=grade 3. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | Participants (Count of Participants) | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Hemoglobin (hypo) | Prothrombin international normalized ratio increased | Lymphocytes (hypo) | Lymphocytes (hyper) | Neutrophils (hypo) | Platelets (hypo) | Leukocytes (hypo) | Albumin (hypo) | Alkaline phosphatase (hyper) | Alanine aminotransferase | Aspartate aminotransferase | Bilirubin | Creatine kinase | Corrected Calcium (hypo) | Creatinine | Gamma-glutamyl transferase | Glucose serum fasting (hypo) | Glucose serum fasting (hyper) | Magnesium (hypo) | Magnesium (hyper) | Phosphate (hypo) | Potassium (hypo) | Potassium (hyper) | Sodium (hypo) | Sodium (hyper) | |
Part 1 + Part 2: LGX818 300 mg | 16 | 1 | 25 | 13 | 9 | 2 | 5 | 9 | 4 | 9 | 5 | 0 | 1 | 2 | 26 | 38 | 4 | 17 | 1 | 0 | 33 | 1 | 7 | 3 | 0 |
Part 2: LGX818 300 mg | 5 | 0 | 10 | 2 | 4 | 1 | 2 | 4 | 1 | 1 | 1 | 0 | 0 | 1 | 11 | 9 | 0 | 5 | 0 | 0 | 8 | 0 | 3 | 2 | 0 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 16 | 4 | 28 | 11 | 19 | 1 | 3 | 7 | 11 | 18 | 15 | 2 | 40 | 4 | 44 | 38 | 3 | 27 | 0 | 3 | 26 | 2 | 8 | 4 | 2 |
AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Dermatologic-related AESI included rash, photosensitivity, nail disorders, skin infections, severe cutaneous adverse reactions and PPE syndrome. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported are reported in this outcome measure. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | Participants (Count of Participants) | |||||
---|---|---|---|---|---|---|
Rash | Skin infection | PPE syndrome | Photosensitivity | Nail disorders | Severe cutaneous adverse reactions | |
Part 1 + Part 2: LGX818 300 mg | 13 | 1 | 30 | 0 | 0 | 1 |
Part 2: LGX818 300 mg | 3 | 0 | 4 | 0 | 0 | 0 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 2 | 7 | 1 | 0 | 0 | 0 |
Newly occurring notable ECG values were reported for QT (ms), QTcF (ms), QTcB (ms) and heart rate (bpm). Newly occurring was defined as participants not meeting criterion at baseline and meeting criterion post-baseline. Ranges for newly occurring notable ECG values (QT, QTcF, QTcB) are New >450, New >480, New >500, increase from baseline >30, Increase from baseline >60. Heart rate: New < 60, New >100 was considered as newly occurring notable value. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | Participants (Count of Participants) | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
QT (ms): Increase from baseline > 30 | QT (ms): Increase from baseline > 60 | QT (ms): New > 450 | QT (ms): New > 480 | QT (ms): New > 500 | QTcF (ms): Increase from baseline > 30 | QTcF (ms): Increase from baseline > 60 | QTcF (ms): New > 450 | QTcF (ms): New > 480 | QTcF (ms): New > 500 | QTcB (ms): New > 450 | QTcB (ms): New > 480 | QTcB (ms): New > 500 | QTcB (ms): Increase from baseline > 30 | QTcB (ms): Increase from baseline > 60 | Heart rate (bpm): New < 60 | Heart rate (bpm): New > 100 | |
Part 1 + Part 2: LGX818 300 mg | 95 | 25 | 20 | 6 | 2 | 76 | 14 | 50 | 12 | 6 | 104 | 29 | 11 | 98 | 23 | 42 | 33 |
Part 2: LGX818 300 mg | 27 | 6 | 5 | 2 | 0 | 20 | 7 | 11 | 5 | 1 | 28 | 6 | 1 | 24 | 8 | 5 | 10 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 132 | 34 | 34 | 9 | 4 | 59 | 13 | 36 | 11 | 2 | 70 | 23 | 10 | 69 | 22 | 82 | 8 |
Notably abnormal vital signs were: Low/high systolic blood pressure (SBP) in millimeter of mercury (mmHg): less than or equal to (<=) 90 mmHg with decrease from baseline of greater than or equal to (>=) 20 mmHg/>= 160 mmHg with increase from baseline of >=20 mmHg, Low/high diastolic blood pressure (DBP) [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg/>=100 mmHg with increase from baseline of >=15 mmHg, Low/high pulse rate [bpm]: <=50 bpm with decrease from baseline of >=15 bpm/>=120 bpm with increase from baseline of >=15 bpm, Low/high weight (kg): >=20 % decrease from baseline/>= 10% increase from baseline Low/high Body temperature degree C): <= 36°C/>= 37.5 degree C. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | Participants (Count of Participants) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Sitting Pulse Rate (bpm): High | Sitting Pulse Rate (bpm): Low | Sitting Systolic Blood Pressure (mmHg): High | Sitting Systolic Blood Pressure (mmHg): Low | Sitting Diastolic Blood Pressure (mmHg): High | Sitting Diastolic Blood Pressure (mmHg): Low | Weight (kg): High | Weight (kg): Low | Body temperature (°C): High | Body temperature (°C): Low | |
Part 1 + Part 2: LGX818 300 mg | 10 | 9 | 17 | 8 | 7 | 9 | 11 | 9 | 16 | 96 |
Part 2: LGX818 300 mg | 3 | 1 | 3 | 4 | 2 | 2 | 1 | 1 | 5 | 22 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 7 | 11 | 40 | 10 | 41 | 7 | 46 | 0 | 14 | 120 |
AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Ocular-related AESI included retinopathy excluding RVO, RVO and uveitis-type events. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this outcome measure. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | Participants (Count of Participants) | ||
---|---|---|---|
Retinopathy excluding RVO | RVO | Uveitis-type events | |
Part 1 + Part 2: LGX818 300 mg | 0 | 1 | 0 |
Part 2: LGX818 300 mg | 0 | 0 | 0 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 4 | 0 | 4 |
Participants with worst post-baseline LVEF Values were graded as Grade 0: Non missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute reduction from baseline >=10% and < 20%;Grade 3: LVEF between 20% and 39% or absolute reduction from baseline >=20%; Grade 4: LVEF lower than 20%. Baseline was defined as the last non-missing value prior to the first dose of study treatment. Missing data were due to participants who died or withdrew consent prior to the first scheduled evaluation or missed evaluations as protocol deviations. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | Participants (Count of Participants) | ||||
---|---|---|---|---|---|
Grade 0 | Grade 2 | Grade 3 | Grade 4 | Missing | |
Part 1 + Part 2: LGX818 300 mg | 235 | 22 | 4 | 0 | 15 |
Part 2: LGX818 300 mg | 74 | 5 | 0 | 0 | 5 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 181 | 71 | 3 | 0 | 2 |
AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; results in persistent/significant disability/incapacity; results in congenital anomaly/birth defect or that is considered to be important medical event. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence; Grade 5: death. AEs of all grades were reported. (NCT01909453)
Timeframe: Baseline up to 30 days after last dose of study drug (up to 36 months)
Intervention | percentage of Participants (Number) | |
---|---|---|
AEs | SAEs | |
Part 1 + Part 2: LGX818 300 mg | 98.6 | 33.3 |
Part 2: LGX818 300 mg | 96.4 | 29.8 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 98.1 | 29.2 |
(NCT01909453)
Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose
Intervention | nanogram per milliliter (Mean) | |||||
---|---|---|---|---|---|---|
Cycle 1 Day 1: pre-dose | Cycle 1 Day 1: 0.5 hours post dose | Cycle 1 Day 1: 1.5 hours post dose | Cycle 1 Day 1: 4 to 8 hours post dose | Cycle 2 Day 1: pre-dose | Cycle 3 Day 1: pre-dose | |
Part 1 + Part 2: LGX818 300 mg | 39.7 | 1250 | 4170 | 1980 | 60.1 | 60.6 |
Part 2: LGX818 300 mg | 0.0145 | 1370 | 4310 | 2250 | 29.5 | 79.5 |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 5.02 | 1360 | 4390 | 2420 | 121 | 74.1 |
(NCT01909453)
Timeframe: Cycle 1 Day 1: pre-dose, 0.5, 1.5, 4 to 8, hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose
Intervention | nanogram per milliliter (Mean) | |||||
---|---|---|---|---|---|---|
Cycle 1 Day 1: pre-dose | Cycle 1 Day 1: 0.5 hours post dose | Cycle 1 Day 1: 1.5 hours post dose | Cycle 1 Day 1: 4 to 8 hours post dose | Cycle 2 Day 1: pre-dose | Cycle 3 Day 1: pre-dose | |
Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300) | 1.68 | 366 | 642 | 287 | 72.3 | 73.2 |
1 review available for carbamates and Emesis
Article | Year |
---|---|
Management of acute childhood poisonings caused by selected insecticides and herbicides.
Topics: Absorption; Adolescent; Animals; Anticonvulsants; Atropine; Carbamates; Central Nervous System; Chil | 1986 |
4 trials available for carbamates and Emesis
Article | Year |
---|---|
Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Fatigue; Female; Humans; | 2019 |
Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carb | 2020 |
Clinical trial of acetylenic carbamate: 1,1-diphenyl-2-propynyl cyclohexanecarbamate (NSC-112682).
Topics: Adolescent; Adult; Aged; Alkynes; Antineoplastic Agents; Carbamates; Carcinoma, Bronchogenic; Carcin | 1970 |
Initial clinical trials with 1,1-diphenyl-2-propynyl cyclohexanecarbamate (NCS-112682).
Topics: Alkynes; Antineoplastic Agents; Bone Marrow; Carbamates; Clinical Trials as Topic; Cyclohexanes; Eva | 1970 |
12 other studies available for carbamates and Emesis
Article | Year |
---|---|
Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; C | 2021 |
Side effects of powdered sodium carbonate (washing or 'Lectric' soda) used as an oral emetic agent in five dogs.
Topics: Animals; Carbamates; Dog Diseases; Dogs; Emetics; Fatal Outcome; Female; Male; Powders; Vomiting | 2019 |
Effect of selective inhibition of monoacylglycerol lipase (MAGL) on acute nausea, anticipatory nausea, and vomiting in rats and Suncus murinus.
Topics: Animals; Carbamates; Disease Models, Animal; Female; Male; Monoacylglycerol Lipases; Nausea; Rats; R | 2015 |
OCCUPATIONAL CARBAMATE POISONING IN THAILAND.
Topics: Adolescent; Adult; Aged; Agricultural Workers' Diseases; Carbamates; Carbofuran; Child; Diarrhea; Fe | 2015 |
The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew).
Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Carbamates; Cisplatin; Drug Interactions; E | 2009 |
Cannabinoid-induced reduction in antral pacemaker frequency: a telemetric study in the ferret.
Topics: Amidohydrolases; Animals; Apomorphine; Benzamides; Biological Clocks; Body Temperature; Cannabinoids | 2010 |
Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew.
Topics: Analysis of Variance; Animals; Apomorphine; Arachidonic Acids; Benzamides; Benzyl Compounds; Brain; | 2005 |
Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat.
Topics: Amidohydrolases; Animals; Arachidonic Acids; Association Learning; Avoidance Learning; Benzamides; C | 2007 |
Acute pancreatitis in children with anticholinesterase insecticide intoxication.
Topics: Abdominal Pain; Acute Disease; Amylases; Blood Glucose; Butyrylcholinesterase; Carbamates; Child; Ch | 1992 |
A model for carbamate and organophosphate-induced emesis in humans.
Topics: Adolescent; Adult; Animals; Atropine; Behavior, Animal; Callitrichinae; Carbamates; Cholinesterases; | 1991 |
The toxicity of the molluscicides metaldehyde and methiocarb to dogs.
Topics: Acetaldehyde; Animals; Atropine; Carbamates; Dog Diseases; Dogs; Gluconates; Glucose; Hyperemia; Kid | 1973 |
Pharmacoclinical study of oral estramustine phosphate (Estracyt) in advanced carcinoma of the prostate.
Topics: Acid Phosphatase; Administration, Oral; Antineoplastic Agents; Carbamates; Carcinoembryonic Antigen; | 1974 |