Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)

• ClinicalTrials.gov Identifier: NCT01909453
• Recruitment Status: Active, not recruiting
• First Posted: July 26, 2013
• Results First Posted: July 12, 2021
• Last Update Posted: April 26, 2024
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: July 24, 2013
• First Posted Date: July 26, 2013
• Results First Submitted Date: May 5, 2021
• Results First Posted Date: July 12, 2021
• Last Update Posted Date: April 26, 2024
• Actual Study Start Date: September 16, 2013
• Actual Primary Completion Date: November 9, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 9, 2021)

• Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to Vemurafenib Group [ Time Frame: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months) ]
  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).
• Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to LGX818 Group [ Time Frame: 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 ]
  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.

Original Primary Outcome Measures (submitted: July 24, 2013)

Progression free survival (PFS) [ Time Frame: Approximately 2 years after first patient randomized ]

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.

Current Secondary Outcome Measures (submitted: July 9, 2021)

• Part 2: Progression Free Survival (PFS) by BIRC in Combo 300 Group as Compared to LGX818 Group [ Time Frame: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 35 months) ]
  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.
• Part 1: Overall Survival (OS) [ Time Frame: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 38 months) ]
  Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a death had not been observed by the date of analysis cutoff, OS was censored at the date of last contact.
• Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [ Time Frame: 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 ]
  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.
• Part 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 4.03 [ Time Frame: 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 ]
  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.
• Part 1: Number of Participants With Newly Occurring Notably Abnormal Vital Signs [ Time Frame: 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 ]
  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.
• Part 1: Number of Participants With Newly Occurring Notable Electrocardiogram (ECG) Values [ Time Frame: 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 ]
  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.
• Part 1: Number of Participants With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade [ Time Frame: 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 ]
  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.
• Part 1: Number of Participants With Dermatologic-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 [ Time Frame: 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 ]
  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.
• Part 1: Number of Participants With Ocular-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 [ Time Frame: 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 ]
  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.
• Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: 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 [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: Number of Participants With Newly Occurring Notably Abnormal Vital Signs [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: Number of Participants With Newly Occurring Notable ECG Values [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: Number of Participants With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: Number of Participants With Dermatologic-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: Number of Participants With Ocular-related Adverse Events of Special Interest (AESI) Graded According to the National Cancer Institute Common Terminology Criteria (NCI-CTCAE) v4.03 [ Time Frame: Baseline up to 30 days after last dose of study drug (up to 36 months) ]
  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.
• Part 2: Overall Survival (OS) [ Time Frame: From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 38 months) ]
• Part 1 and Part 2: Objective Response Rate (ORR) [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Time to Objective Response (TTR) [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Disease Control Rate (DCR) [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Duration of Response (DOR) [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Change From Baseline in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit [ Time Frame: 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) ]
  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.
• Part 1 and Part 2: Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: Part 1 and Part 2: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 31) ]
  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.
• Part 1: Plasma Concentrations of LGX 818 [ Time Frame: 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 ]
• Part 2: Plasma Concentrations of LGX 818 [ Time Frame: 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 ]
• Part 1: Plasma Concentrations of MEK162 [ Time Frame: 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 ]
• Part 2: Plasma Concentrations of MEK162 [ Time Frame: 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 ]
• Part 1 and Part 2: Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: 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) ]
  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.

Original Secondary Outcome Measures (submitted: July 24, 2013)

• Overall Survival (OS) [ Time Frame: Up to approximately 4 years after first patient randomized ]
  OS is calculated as the time from date of randomization to date of death due to any cause.
• Progression Free Survival (PFS) [ Time Frame: Approximately 2 years with update around 3 years after first patient randomized ]
  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.
• Objective Response Rate (ORR) [ Time Frame: Approximately 2 years after first patient randomized ]
  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.
• Time To Response (TTR) [ Time Frame: Approximately 2 years after first patient randomized ]
  TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response(PR).
• Disease Control Rate (DCR) [ Time Frame: Approximately 2 years after first patient randomized ]
  DCR calculated as the proportion of patient with a best overall response of CR, PR or stable disease (SD)
• Duration of objective response (DOR) [ Time Frame: Approximately 2 years after first patient randomized ]
  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
• Safety and tolerability of combination and LGX818 [ Time Frame: Up to approximately 4 years after first patient randomized ]
  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
• ECOG Performance status (PS) [ Time Frame: Approximatley 2 years after first patient randomized ]
  Change from baseline in the ECOG PS
• Time to definitive 1 point deterioration in ECOG performance status [ Time Frame: Approximatley 2 years after first patient randomized ]
  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.
• Pharmacokinetics of LGX818 and MEK162 [ Time Frame: Approximatley 2 years after first pateint randomized ]
  Plasma concentration-profiles of LGX818 and MEK162 and model based PK parameters
• Time to definitive 10% deteriortaion in global health status (EORTC QLQC30) [ Time Frame: Approximately 2 years after first patient randomized ]
  Time to definitive 10% deterioration in the global health status score of theEORTC 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
• Global health status (EORTC QLQC30) [ Time Frame: Approximately 2 years after first patient randomized ]
  Change from baseline in the global health status score of the EORTC QLQ-C30
• Time to definitive 10% deterioration in the FACT-M melanoma subscale [ Time Frame: Approximately 2 years after first patient randomized ]
  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
• Global health status (EQ-5D) [ Time Frame: Approximately 2 years after first patient randomized ]
  Change from baseline in the EQ-5D

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma
• Official Title: 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

Brief Summary

This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized.

Part 1:

Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms:

1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm)
2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or
3. vemurafenib 960 mg BID (denoted as vemurafenib arm)

Part 2:

Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms:

1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or
2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: LGX818
  LGX818- Orally 100 mg and 50 mg capsules
• Drug: MEK162
  MEK162- Orally 15 mg tablets
• Drug: vemurafenib
  Tablets in bottles or blisters 240 mg
  Other Names:

  • Zelboraf
  • PLX4032
  • RO5185426

Study Arms

• Experimental: LGX818 450 mg + MEK162
  LGX818 450 mg QD + MEK162 45 mg BID
  Interventions:

  • Drug: LGX818
  • Drug: MEK162
• Active Comparator: Vemurafenib
  Vemurafenib 960 mg BID
  Intervention: Drug: vemurafenib
• Experimental: LGX818 300 mg + MEK162
  LGX818 300 mg QD + MEK162 45 mg BID
  Interventions:

  • Drug: LGX818
  • Drug: MEK162
• Experimental: LGX818
  LGX818 300 mg QD
  Intervention: Drug: LGX818

Publications *

• Dummer R, Flaherty KT, Robert C, Arance A, de Groot JWB, Garbe C, Gogas HJ, Gutzmer R, Krajsova I, Liszkay G, Loquai C, Mandala M, Schadendorf D, Yamazaki N, di Pietro A, Cantey-Kiser J, Edwards M, Ascierto PA. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol. 2022 Dec 20;40(36):4178-4188. doi: 10.1200/JCO.21.02659. Epub 2022 Jul 21. Erratum In: J Clin Oncol. 2023 Apr 20;41(12):2301.
• Gogas H, Dummer R, Ascierto PA, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Sileni VC, Dutriaux C, Yamazaki N, Loquai C, Queirolo P, Jan de Willem G, Sellier AT, Suissa J, Murris J, Gollerkeri A, Robert C, Flaherty KT. Quality of life in patients with BRAF-mutant melanoma receiving the combination encorafenib plus binimetinib: Results from a multicentre, open-label, randomised, phase III study (COLUMBUS). Eur J Cancer. 2021 Jul;152:116-128. doi: 10.1016/j.ejca.2021.04.028. Epub 2021 Jun 4. Erratum In: Eur J Cancer. 2022 Jan;160:287-288.
• Gogas HJ, Flaherty KT, Dummer R, Ascierto PA, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Sileni VC, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Gollerkeri A, Pickard MD, Robert C. Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. Eur J Cancer. 2019 Sep;119:97-106. doi: 10.1016/j.ejca.2019.07.016. Epub 2019 Aug 19.
• Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Oct;19(10):1315-1327. doi: 10.1016/S1470-2045(18)30497-2. Epub 2018 Sep 12. Erratum In: Lancet Oncol. 2018 Oct;19(10):e509.
• Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 25, 2024): 921
• Original Estimated Enrollment (submitted: July 24, 2013): 900
• Estimated Study Completion Date: July 15, 2024
• Actual Primary Completion Date: November 9, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV)
• Presence of BRAF V600E 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 resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), 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

Exclusion Criteria:

• Any untreated central nervous system (CNS) lesion
• Uveal and mucosal melanoma
• History of leptomeningeal metastases
• History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease
• 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; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 weeks prior to randomization
• 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
• 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 inclusion/exclusion criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Canada, Colombia, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Norway, Poland, Portugal, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01909453
• Other Study ID Numbers: CMEK162B2301; C4221004 ( Other Identifier: Alias Study Number ); 2013-001176-38 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Novartis Pharmaceuticals
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2024