Melanoma and Metastatic Colorectal Cancer
Conditions
Keywords
BRAF mutant,, BRAF mutated,, melanoma,, metastatic,, advanced,, RAF kinase inhibitor, BRAF V600 mutation
Brief summary
CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.
Interventions
DRUGLGX818
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For the dose escalation phase: 1. Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer \[AJCC\]). For the dose expansion phase: (i) Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer \[AJCC\]), or (ii) confirmed diagnosis and non-resectable advanced metastatic colorectal cancer (mCRC) for which no further effective standard therapy exists. 2. Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation. 3. Evidence of measurable disease
Exclusion criteria
1. Previous therapy with a MEK inhibitor. 2. Symptomatic or untreated leptomeningeal disease. 3. Symptomatic or untreated brain metastasis.Patients previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging. 4. Known acute or chronic pancreatitis. 5. Clinically significant cardiac disease 6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818 7. Previous or concurrent malignancy. Exceptions to this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | Up to 28 days | DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: \>=grade (G)3 neutropenia or thrombocytopenia for \>7 days; G4 thrombocytopenia; febrile neutropenia; \>=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (\>=G3 for \> 7 consecutive days or G4); \>=G3 ALT or AST and \>=G2 blood bilirubin; \>=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for \>7 consecutive days; \>= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; \>=G3 pancreatitis, rash/photosensitivity (G3 for \> 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders. |
| Number of Participants With DLT During Dose Expansion Phase | Up to 28 days | DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: \>=grade (G)3 neutropenia or thrombocytopenia for \>7 days; G4 thrombocytopenia; febrile neutropenia; \>=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (\>=G3 for \> 7 consecutive days or G4); \>=G3 ALT or AST and \>=G2 blood bilirubin; \>=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for \>7 consecutive days; \>= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; \>=G3 pancreatitis, rash/photosensitivity (G3 for \> 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS): Dose Escalation Phase | From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure) | PFS was defined as time from date of first study treatment intake to date of first documented disease progression (PD) or death due to any cause. If a participant did not have an event, data censoring was done at the date of last adequate tumor assessment. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of greater than or equal to (\>=) 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier method. |
| PFS: Dose Expansion Phase | From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively) | PFS was defined as time from date of first study treatment intake to date of first documented PD or death due to any cause. If a participant did not have an event, data censoring was done at the date of last adequate tumor assessment. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier method. |
| Duration of Response (DOR): Dose Escalation Phase | From first observation of response until first time of PD or death due to any cause (Maximum of 556.1 weeks of treatment exposure) | DOR was defined as the time from first observation of response CR or partial response \[PR\]) to the first time of progression or death. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion. |
| Time to Response (TTR): Dose Escalation Phase | From date of start of treatment until CR or PR or censoring date (maximum of 556.1 weeks of treatment exposure) | TTR was defined as the time from date of treatment until first documented response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. Individual participant data have been reported for this outcome measure. |
| DOR: Dose Expansion Phase | From first observation of response until first time of PD or death due to any cause (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively) | DOR was defined as the time from first observation of response (CR or PR\] to the first time of progression or death. CR was defined as complete disappearance of all target and non-target lesions and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to (\<10 mm. PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion. |
| TTR: Dose Expansion Phase | From date of start of treatment until CR or PR or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively) | TTR was defined as the time from date of treatment until first documented response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. Individual participant data have been reported for this outcome measure. |
| Overall Survival (OS): Dose Expansion Phase | From start of study treatment until date of death or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively) | Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. |
| Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | — |
| Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | — |
| Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | AUC (inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. |
| Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | — |
| Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | t1/2 was the time measured for the plasma concentration to decrease by one half. Terminal phase half-life expressed in hours (hr). |
| Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | From start of study treatment until 30 days after last dose of study treatment (maximum of 556.1 weeks of treatment exposure) | An AE was defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions. An SAE was defined as one of the following: fatal or life-threatening; resulted in significant disability/incapacity; congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization unless for routine treatment, elective or pre-planned treatment for a pre-existing condition, treatment on an emergency outpatient basis, social reasons and respite care in the absence of any deterioration in the participants general condition, any SAEs that were expected due to the condition being treated. |
| Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | — |
| Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure) | Tumor response included: CR, PR, stable disease and disease progression (PD). CR=complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion. |
| Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | — |
| Vz/F of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | — |
| Tmax of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | Tmax was the time required to reach the maximum plasma concentration (Cmax). First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in hours (hr). |
| AUCinf of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | AUC (inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time. |
| AUCtau of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | — |
| t1/2 of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | — |
| CL/F of LGX818: Dose Expansion Phase | Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days) | — |
| Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | (Baseline) last non-missing value prior to the first dose (Baseline) | Number of participants according to BRAF V600 mutation status as V600E (i.e., mutation of the BRAF gene in which valine \[V\] was substituted by glutamic acid \[E\] at amino acid 600) or other is reported in this outcome measure. |
| Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively) | umor response included: CR, PR, stable disease and disease progression (PD). CR=complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion. |
| Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days) | — |
| Number of Participants With AEs and SAEs During Dose Expansion Phase | From start of study treatment until 30 days after last dose of study treatment (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively) | An AE was defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions. An SAE was defined as one of the following: fatal or life-threatening; resulted in significant disability/incapacity; congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization unless for routine treatment, elective or pre-planned treatment for a pre-existing condition, treatment on an emergency outpatient basis, social reasons and respite care in the absence of any deterioration in the participants general condition, any SAEs that were expected due to the condition being treated. |
Countries
Australia, France, Japan, Norway, Spain, Switzerland, United States
Participant flow
Pre-assignment details
A total of 107 participants (54 in dose escalation and 53 in dose expansion) were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| 50 mg of Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 50 mg encorafenib (LGX818) orally once daily (QD) in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity | 4 |
| 100 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 100 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 10 |
| 150 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 150 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 6 |
| 75 mg Encorafenib BID Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 75 mg encorafenib orally twice daily (BID) in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 3 |
| 200 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 200 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 4 |
| 100 mg Encorafenib BID Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 100 mg encorafenib twice daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 5 |
| 300 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 300 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 5 |
| 150 mg Encorafenib BID Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 150 mg encorafenib twice daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 4 |
| 450 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 450 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 6 |
| 550 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 550 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 5 |
| 700 mg Encorafenib QD Participants with advanced or metastatic melanoma harboring BRAF V600 (E, K, D, R) mutations received 700 mg encorafenib orally once daily in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 2 |
| Mel Naive 300 mg Encorafenib Participants with advanced melanoma harboring BRAF V600 (E, K, D, R) mutations naive to a selective BRAF inhibitor received 300 mg encorafenib orally QD in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 9 |
| Mel Naive 450 mg Encorafenib Participants with advanced melanoma harboring BRAF V600 (E, K, D, R) mutations naive to a selective BRAF inhibitor received 450 mg encorafenib orally QD in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 6 |
| Mel Pre-treated: 300 mg Encorafenib Participants with advanced melanoma harboring BRAF V600 (E, K, D, R) mutations pre-treated to a selective BRAF inhibitor received 300 mg encorafenib orally QD in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 2 |
| Mel Pre-treated: 450 mg Encorafenib Participants with advanced melanoma harboring BRAF V600 (E, K, D, R) mutations pre-treated to a selective BRAF inhibitor received 450 mg encorafenib orally QD in each 28-day treatment cycle until disease progression, withdrawal of consent or, unacceptable toxicity. | 16 |
| Mel Stepwise: 450 mg Encorafenib Participants with advanced melanoma harboring BRAF V600 (E, K, D, R) mutations received 450 mg encorafenib orally QD in a two-step manner in each 28-day treatment cycle until disease progression, withdrawal of consent or unacceptable toxicity. | 2 |
| Metastatic Colorectal Cancer: 300 mg Encorafenib Participants with metastatic colorectal cancer received 300 mg encorafenib orally QD in each 28-day treatment cycle until disease progression, withdrawal of consent or unacceptable toxicity. | 6 |
| Metastatic Colorectal Cancer: 450 mg Encorafenib Participants with metastatic colorectal cancer received 450 mg encorafenib orally QD in each 28-day treatment cycle until disease progression, withdrawal of consent or unacceptable toxicity. | 12 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose Escalation | Administrative problems | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation | Death | 1 | 3 | 1 | 0 | 2 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation | Lost to Follow-up | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation | New anti-cancer therapy | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Escalation | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Expansion | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Expansion | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 3 | 0 | 3 | 3 |
| Dose Expansion | Disease progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 0 | 1 | 0 | 0 | 1 |
| Dose Expansion | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Dose Expansion | New cancer therapy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 | 0 | 0 | 0 |
| Dose Expansion | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 2 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | 100 mg Encorafenib QD | 150 mg Encorafenib QD | 75 mg Encorafenib BID | 50 mg of Encorafenib QD | 200 mg Encorafenib QD | 100 mg Encorafenib BID | 300 mg Encorafenib QD | 150 mg Encorafenib BID | 450 mg Encorafenib QD | 550 mg Encorafenib QD | 700 mg Encorafenib QD | Mel Naive 300 mg Encorafenib | Mel Naive 450 mg Encorafenib | Mel Pre-treated: 300 mg Encorafenib | Mel Pre-treated: 450 mg Encorafenib | Mel Stepwise: 450 mg Encorafenib | Metastatic Colorectal Cancer: 300 mg Encorafenib | Metastatic Colorectal Cancer: 450 mg Encorafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >=65 years | 29 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 0 Participants | 2 Participants | 4 Participants |
| Age, Customized Between 18 and 44 years | 27 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 1 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 7 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized Between 45 and 64 years | 51 Participants | 4 Participants | 3 Participants | 1 Participants | 3 Participants | 0 Participants | 5 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 7 Participants | 3 Participants | 0 Participants | 4 Participants | 1 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Caucasian | 100 Participants | 10 Participants | 6 Participants | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants | 6 Participants | 4 Participants | 2 Participants | 6 Participants | 5 Participants | 1 Participants | 16 Participants | 2 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Others | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 48 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 1 Participants | 4 Participants | 1 Participants | 1 Participants | 13 Participants | 1 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 59 Participants | 7 Participants | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants | 2 Participants | 4 Participants | 1 Participants | 5 Participants | 5 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 3 / 10 | 1 / 6 | 0 / 3 | 1 / 4 | 1 / 5 | 2 / 5 | 1 / 4 | 1 / 6 | 0 / 5 | 0 / 2 | 2 / 9 | 3 / 6 | 1 / 2 | 11 / 16 | 1 / 2 | 5 / 6 | 8 / 12 |
| other Total, other adverse events | 4 / 4 | 10 / 10 | 6 / 6 | 3 / 3 | 4 / 4 | 5 / 5 | 5 / 5 | 4 / 4 | 6 / 6 | 5 / 5 | 2 / 2 | 8 / 9 | 5 / 6 | 2 / 2 | 15 / 16 | 2 / 2 | 6 / 6 | 12 / 12 |
| serious Total, serious adverse events | 3 / 4 | 7 / 10 | 3 / 6 | 2 / 3 | 4 / 4 | 2 / 5 | 4 / 5 | 2 / 4 | 2 / 6 | 3 / 5 | 1 / 2 | 2 / 9 | 4 / 6 | 2 / 2 | 9 / 16 | 2 / 2 | 3 / 6 | 6 / 12 |
Outcome results
Primary
Number of Participants With DLT During Dose Expansion Phase
DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: \>=grade (G)3 neutropenia or thrombocytopenia for \>7 days; G4 thrombocytopenia; febrile neutropenia; \>=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (\>=G3 for \> 7 consecutive days or G4); \>=G3 ALT or AST and \>=G2 blood bilirubin; \>=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for \>7 consecutive days; \>= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; \>=G3 pancreatitis, rash/photosensitivity (G3 for \> 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders.
Time frame: Up to 28 days
Population: DDS consisted of all participants from the safety set who either met the following minimum exposure criterion (received at least 75% of the planned doses of encorafenib in Cycle 1; observed for at least 1 cycle and considered to have sufficient safety data to conclude that a DLT did not occur in cycle 1) and had completed scheduled safety evaluations or experienced a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg Encorafenib QD | Number of Participants With DLT During Dose Expansion Phase | 2 Participants |
| 100 mg Encorafenib QD | Number of Participants With DLT During Dose Expansion Phase | 2 Participants |
| 150 mg Encorafenib QD | Number of Participants With DLT During Dose Expansion Phase | 0 Participants |
| 75 mg Encorafenib BID | Number of Participants With DLT During Dose Expansion Phase | 4 Participants |
| 200 mg Encorafenib QD | Number of Participants With DLT During Dose Expansion Phase | 1 Participants |
| 100 mg Encorafenib BID | Number of Participants With DLT During Dose Expansion Phase | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants With DLT During Dose Expansion Phase | 3 Participants |
Primary
Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase
DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: \>=grade (G)3 neutropenia or thrombocytopenia for \>7 days; G4 thrombocytopenia; febrile neutropenia; \>=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (\>=G3 for \> 7 consecutive days or G4); \>=G3 ALT or AST and \>=G2 blood bilirubin; \>=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for \>7 consecutive days; \>= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; \>=G3 pancreatitis, rash/photosensitivity (G3 for \> 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders.
Time frame: Up to 28 days
Population: Dose-Determining Set (DDS) consisted of all participants from the safety set who either met the following minimum exposure (received at least 75% of the planned doses of encorafenib in Cycle 1; observed for at least 1 cycle and considered to have sufficient safety data to conclude that a DLT did not occur in cycle 1) and had completed scheduled safety evaluations or experienced a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 0 Participants |
| 100 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 1 Participants |
| 150 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 0 Participants |
| 75 mg Encorafenib BID | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 0 Participants |
| 200 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 0 Participants |
| 100 mg Encorafenib BID | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 1 Participants |
| 300 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 1 Participants |
| 150 mg Encorafenib BID | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 1 Participants |
| 450 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 0 Participants |
| 550 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 1 Participants |
| 700 mg Encorafenib QD | Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase | 2 Participants |
Secondary
Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 9.14 Liter/hour | — |
| 50 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 18.8 Liter/hour | — |
| 100 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 21.3 Liter/hour | Geometric Coefficient of Variation 70.37 |
| 100 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 44.7 Liter/hour | Geometric Coefficient of Variation 19.67 |
| 150 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 13 Liter/hour | Geometric Coefficient of Variation 83.44 |
| 150 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 18.8 Liter/hour | Geometric Coefficient of Variation 36.58 |
| 75 mg Encorafenib BID | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 19.8 Liter/hour | Geometric Coefficient of Variation 39.57 |
| 75 mg Encorafenib BID | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 34.6 Liter/hour | Geometric Coefficient of Variation 37.55 |
| 200 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 31.5 Liter/hour | Geometric Coefficient of Variation 12.25 |
| 200 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 15.8 Liter/hour | Geometric Coefficient of Variation 20.11 |
| 100 mg Encorafenib BID | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter/hour | — |
| 100 mg Encorafenib BID | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 33.8 Liter/hour | Geometric Coefficient of Variation 53.66 |
| 300 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 20.2 Liter/hour | Geometric Coefficient of Variation 26.24 |
| 300 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 39.5 Liter/hour | Geometric Coefficient of Variation 35.79 |
| 150 mg Encorafenib BID | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 22.7 Liter/hour | Geometric Coefficient of Variation 69.51 |
| 150 mg Encorafenib BID | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter/hour | — |
| 450 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 15 Liter/hour | Geometric Coefficient of Variation 33.36 |
| 450 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 29.6 Liter/hour | Geometric Coefficient of Variation 53.35 |
| 550 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter/hour | — |
| 550 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 16.8 Liter/hour | Geometric Coefficient of Variation 50 |
| 700 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 34.3 Liter/hour | Geometric Coefficient of Variation 34.85 |
| 700 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 13.6 Liter/hour | Geometric Coefficient of Variation 70.34 |
| 550 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 17.2 Liter/hour | Geometric Coefficient of Variation 45.51 |
| 550 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 36 Liter/hour | Geometric Coefficient of Variation 36.38 |
| 700 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter/hour | — |
| 700 mg Encorafenib QD | Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 10.9 Liter/hour | Geometric Coefficient of Variation 1.75 |
Secondary
Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 57.8 Liter | — |
| 50 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 112 Liter | — |
| 100 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 274 Liter | Geometric Coefficient of Variation 7.68 |
| 100 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 120 Liter | Geometric Coefficient of Variation 56.42 |
| 150 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 67 Liter | Geometric Coefficient of Variation 79.38 |
| 150 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 103 Liter | Geometric Coefficient of Variation 36.42 |
| 75 mg Encorafenib BID | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 182 Liter | Geometric Coefficient of Variation 33.22 |
| 75 mg Encorafenib BID | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 104 Liter | Geometric Coefficient of Variation 35.34 |
| 200 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 188 Liter | Geometric Coefficient of Variation 43.23 |
| 200 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 84.5 Liter | Geometric Coefficient of Variation 28.15 |
| 100 mg Encorafenib BID | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 116 Liter | Geometric Coefficient of Variation 27.23 |
| 100 mg Encorafenib BID | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter | — |
| 300 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 177 Liter | Geometric Coefficient of Variation 31 |
| 300 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 91.9 Liter | Geometric Coefficient of Variation 39.62 |
| 150 mg Encorafenib BID | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter | — |
| 150 mg Encorafenib BID | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 73.8 Liter | Geometric Coefficient of Variation 39.95 |
| 450 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 76.5 Liter | Geometric Coefficient of Variation 33.65 |
| 450 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 128 Liter | Geometric Coefficient of Variation 12.49 |
| 550 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 53.9 Liter | Geometric Coefficient of Variation 49.07 |
| 550 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter | — |
| 700 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 60.5 Liter | Geometric Coefficient of Variation 53.31 |
| 700 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 157 Liter | Geometric Coefficient of Variation 38.55 |
| 550 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 84.8 Liter | Geometric Coefficient of Variation 41.99 |
| 550 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 221 Liter | Geometric Coefficient of Variation 75.92 |
| 700 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 50.7 Liter | Geometric Coefficient of Variation 10.87 |
| 700 mg Encorafenib QD | Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Liter | — |
Secondary
Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase
AUC (inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2700 Hours*Nanogram per milliliter | — |
| 50 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 5470 Hours*Nanogram per milliliter | — |
| 100 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 1130 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 20.1 |
| 100 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2340 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 70.37 |
| 150 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 5380 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 36.87 |
| 150 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 7660 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 83.44 |
| 75 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2900 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 37.88 |
| 75 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 5050 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 39.57 |
| 200 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 9520 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 20.11 |
| 200 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 4830 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 11.11 |
| 100 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2220 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 53.66 |
| 100 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 300 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 5080 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 35.87 |
| 300 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 9910 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 26.24 |
| 150 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 4410 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 69.51 |
| 150 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 450 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 10200 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 53.84 |
| 450 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 20000 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 33.36 |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 8940 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 50 |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 33100 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 70.34 |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 13200 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 34.77 |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 15600 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 36.58 |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 31900 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 45.51 |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 64400 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 1.75 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 5360 Hours*Nanogram per milliliter | — |
| 50 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2660 Hours*Nanogram per milliliter | — |
| 100 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2330 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 69.89 |
| 100 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 1120 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 19.67 |
| 150 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 7610 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 82.98 |
| 150 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 5330 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 36.58 |
| 75 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 5010 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 39.39 |
| 75 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2890 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 37.55 |
| 200 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 4750 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 12.25 |
| 200 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 9400 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 20.06 |
| 100 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3210 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 92.21 |
| 100 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 300 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 9860 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 26.5 |
| 300 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 5060 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 35.79 |
| 150 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 4780 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 52.49 |
| 150 mg Encorafenib BID | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 450 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 20300 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 29.06 |
| 450 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 10100 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 53.35 |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 8690 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 49.73 |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 13100 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 34.85 |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 32800 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 69.05 |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 15300 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 36.38 |
| 550 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 31700 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 45.33 |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 700 mg Encorafenib QD | Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 63900 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 1.41 |
Secondary
AUCinf of LGX818: Dose Expansion Phase
AUC (inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. 'Overall Number of Participants Analyzed' signifies number of participants with evaluable data for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 4290 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 30.9 |
| 50 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 2050 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 43.71 |
| 50 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 18200 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 32.37 |
| 150 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 70900 Hours*Nanogram per milliliter | — |
| 75 mg Encorafenib BID | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 16600 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 23.69 |
| 75 mg Encorafenib BID | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 33300 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 39.98 |
| 75 mg Encorafenib BID | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 4960 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 32.64 |
| 200 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA Hours*Nanogram per milliliter | — |
| 200 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA Hours*Nanogram per milliliter | — |
| 200 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Hours*Nanogram per milliliter | — |
| 100 mg Encorafenib BID | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 1040 Hours*Nanogram per milliliter | — |
| 300 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 54400 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 42.97 |
| 300 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 17300 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 38.06 |
| 300 mg Encorafenib QD | AUCinf of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 16400 Hours*Nanogram per milliliter | Geometric Coefficient of Variation 34.68 |
Secondary
AUCtau of LGX818: Dose Expansion Phase
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 18100 hours*nanogram per milliliter | Geometric Coefficient of Variation 32.22 |
| 50 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 7380 hours*nanogram per milliliter | Geometric Coefficient of Variation 60.51 |
| 50 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 4290 hours*nanogram per milliliter | Geometric Coefficient of Variation 30.9 |
| 100 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 35300 hours*nanogram per milliliter | — |
| 150 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 69300 hours*nanogram per milliliter | — |
| 75 mg Encorafenib BID | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 16600 hours*nanogram per milliliter | Geometric Coefficient of Variation 23.69 |
| 75 mg Encorafenib BID | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 17600 hours*nanogram per milliliter | Geometric Coefficient of Variation 25.65 |
| 75 mg Encorafenib BID | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 33200 hours*nanogram per milliliter | Geometric Coefficient of Variation 39.86 |
| 200 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA hours*nanogram per milliliter | — |
| 200 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA hours*nanogram per milliliter | — |
| 200 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA hours*nanogram per milliliter | — |
| 100 mg Encorafenib BID | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 10400 hours*nanogram per milliliter | — |
| 300 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 17300 hours*nanogram per milliliter | Geometric Coefficient of Variation 37.9 |
| 300 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 54400 hours*nanogram per milliliter | Geometric Coefficient of Variation 42.97 |
| 300 mg Encorafenib QD | AUCtau of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 16400 hours*nanogram per milliliter | Geometric Coefficient of Variation 34.67 |
Secondary
CL/F of LGX818: Dose Expansion Phase
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. 'Overall Number of Participants Analyzed' signifies number of participants with evaluable data for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 16.5 liter/hour | Geometric Coefficient of Variation 32.37 |
| 50 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 70.1 liter/hour | Geometric Coefficient of Variation 30.98 |
| 50 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 40.7 liter/hour | Geometric Coefficient of Variation 60.51 |
| 150 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 4.23 liter/hour | — |
| 75 mg Encorafenib BID | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 27.2 liter/hour | Geometric Coefficient of Variation 23.63 |
| 75 mg Encorafenib BID | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 13.5 liter/hour | Geometric Coefficient of Variation 39.98 |
| 75 mg Encorafenib BID | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 25.6 liter/hour | Geometric Coefficient of Variation 25.65 |
| 200 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA liter/hour | — |
| 200 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA liter/hour | — |
| 200 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA liter/hour | — |
| 100 mg Encorafenib BID | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 29.9 liter/hour | — |
| 300 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 26 liter/hour | Geometric Coefficient of Variation 37.9 |
| 300 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 8.27 liter/hour | Geometric Coefficient of Variation 42.97 |
| 300 mg Encorafenib QD | CL/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 27.4 liter/hour | Geometric Coefficient of Variation 34.67 |
Secondary
DOR: Dose Expansion Phase
DOR was defined as the time from first observation of response (CR or PR\] to the first time of progression or death. CR was defined as complete disappearance of all target and non-target lesions and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to (\<10 mm. PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.
Time frame: From first observation of response until first time of PD or death due to any cause (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Population: FAS included all participants who received at least one dose of encorafenib.'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. Only participants with complete or partial response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 mg Encorafenib QD | DOR: Dose Expansion Phase | NA Months |
| 100 mg Encorafenib QD | DOR: Dose Expansion Phase | NA Months |
| 75 mg Encorafenib BID | DOR: Dose Expansion Phase | NA Months |
| 200 mg Encorafenib QD | DOR: Dose Expansion Phase | NA Months |
| 100 mg Encorafenib BID | DOR: Dose Expansion Phase | NA Months |
Secondary
Duration of Response (DOR): Dose Escalation Phase
DOR was defined as the time from first observation of response CR or partial response \[PR\]) to the first time of progression or death. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.
Time frame: From first observation of response until first time of PD or death due to any cause (Maximum of 556.1 weeks of treatment exposure)
Population: FAS included all participants who received at least one dose of encorafenib. Here 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. Only participants with complete or partial response were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 mg Encorafenib QD | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 100 mg Encorafenib QD | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 150 mg Encorafenib QD | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 75 mg Encorafenib BID | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 200 mg Encorafenib QD | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 100 mg Encorafenib BID | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 150 mg Encorafenib BID | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 450 mg Encorafenib QD | Duration of Response (DOR): Dose Escalation Phase | NA Months |
| 550 mg Encorafenib QD | Duration of Response (DOR): Dose Escalation Phase | NA Months |
Secondary
Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase
t1/2 was the time measured for the plasma concentration to decrease by one half. Terminal phase half-life expressed in hours (hr).
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 50 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 4.14 Hours |
| 50 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 4.38 Hours |
| 100 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.71 Hours |
| 100 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.77 Hours |
| 150 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.99 Hours |
| 150 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.47 Hours |
| 75 mg Encorafenib BID | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.61 Hours |
| 75 mg Encorafenib BID | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.7 Hours |
| 200 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.65 Hours |
| 200 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.66 Hours |
| 100 mg Encorafenib BID | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2.82 Hours |
| 100 mg Encorafenib BID | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 300 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.13 Hours |
| 300 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.3 Hours |
| 150 mg Encorafenib BID | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2.53 Hours |
| 150 mg Encorafenib BID | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 450 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.57 Hours |
| 450 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.42 Hours |
| 550 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2.16 Hours |
| 550 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 700 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2.92 Hours |
| 700 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.19 Hours |
| 550 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.32 Hours |
| 550 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3.25 Hours |
| 700 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3.25 Hours |
| 700 mg Encorafenib QD | Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
Secondary
Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: Pharmacokinetic Analysis Set (PAS) consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 465 Nanogram per milliliter | — |
| 50 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 970 Nanogram per milliliter | — |
| 100 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 334 Nanogram per milliliter | Geometric Coefficient of Variation 57.7 |
| 100 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 846 Nanogram per milliliter | Geometric Coefficient of Variation 82.92 |
| 150 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 959 Nanogram per milliliter | Geometric Coefficient of Variation 25.19 |
| 150 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 1630 Nanogram per milliliter | Geometric Coefficient of Variation 42.36 |
| 75 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 949 Nanogram per milliliter | Geometric Coefficient of Variation 27.4 |
| 75 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 1020 Nanogram per milliliter | Geometric Coefficient of Variation 49.06 |
| 200 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 1570 Nanogram per milliliter | Geometric Coefficient of Variation 28.82 |
| 200 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 1300 Nanogram per milliliter | Geometric Coefficient of Variation 29.08 |
| 100 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 733 Nanogram per milliliter | Geometric Coefficient of Variation 46.32 |
| 100 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Nanogram per milliliter | — |
| 300 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 1300 Nanogram per milliliter | Geometric Coefficient of Variation 1220 |
| 300 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 1850 Nanogram per milliliter | Geometric Coefficient of Variation 28.06 |
| 150 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Nanogram per milliliter | — |
| 150 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 1200 Nanogram per milliliter | Geometric Coefficient of Variation 28.06 |
| 450 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2920 Nanogram per milliliter | Geometric Coefficient of Variation 34.41 |
| 450 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 3310 Nanogram per milliliter | Geometric Coefficient of Variation 42.54 |
| 550 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2510 Nanogram per milliliter | Geometric Coefficient of Variation 58.15 |
| 550 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Nanogram per milliliter | — |
| 700 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 5970 Nanogram per milliliter | Geometric Coefficient of Variation 56.35 |
| 700 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 3950 Nanogram per milliliter | Geometric Coefficient of Variation 49.12 |
| 550 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 4170 Nanogram per milliliter | Geometric Coefficient of Variation 48.94 |
| 550 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 5360 Nanogram per milliliter | Geometric Coefficient of Variation 36.87 |
| 700 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 8980 Nanogram per milliliter | Geometric Coefficient of Variation 13.5 |
| 700 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Nanogram per milliliter | — |
Secondary
Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 4310 Nanogram per milliliter | Geometric Coefficient of Variation 31.6 |
| 50 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 1060 Nanogram per milliliter | Geometric Coefficient of Variation 41.1 |
| 50 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 2050 Nanogram per milliliter | Geometric Coefficient of Variation 43.71 |
| 100 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 5650 Nanogram per milliliter | — |
| 150 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 7790 Nanogram per milliliter | — |
| 75 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 5590 Nanogram per milliliter | Geometric Coefficient of Variation 22.56 |
| 75 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 6580 Nanogram per milliliter | Geometric Coefficient of Variation 34.24 |
| 75 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 4960 Nanogram per milliliter | Geometric Coefficient of Variation 32.64 |
| 200 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Nanogram per milliliter | — |
| 200 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA Nanogram per milliliter | — |
| 200 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA Nanogram per milliliter | — |
| 100 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 1040 Nanogram per milliliter | — |
| 100 mg Encorafenib BID | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 1340 Nanogram per milliliter | — |
| 300 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 8380 Nanogram per milliliter | Geometric Coefficient of Variation 32.93 |
| 300 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 5650 Nanogram per milliliter | Geometric Coefficient of Variation 79.98 |
| 300 mg Encorafenib QD | Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 5130 Nanogram per milliliter | Geometric Coefficient of Variation 48.81 |
Secondary
Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion
Number of participants according to BRAF V600 mutation status as V600E (i.e., mutation of the BRAF gene in which valine \[V\] was substituted by glutamic acid \[E\] at amino acid 600) or other is reported in this outcome measure.
Time frame: (Baseline) last non-missing value prior to the first dose (Baseline)
Population: FAS included all participants who received at least one dose of Encorafenib
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 50 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 8 Participants |
| 50 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 1 Participants |
| 100 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 5 Participants |
| 100 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 1 Participants |
| 150 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 1 Participants |
| 150 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 1 Participants |
| 75 mg Encorafenib BID | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 16 Participants |
| 75 mg Encorafenib BID | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 0 Participants |
| 200 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 1 Participants |
| 200 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 1 Participants |
| 100 mg Encorafenib BID | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 6 Participants |
| 100 mg Encorafenib BID | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | V600E | 12 Participants |
| 300 mg Encorafenib QD | Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion | Others | 0 Participants |
Secondary
Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation
Tumor response included: CR, PR, stable disease and disease progression (PD). CR=complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.
Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure)
Population: FAS included all participants who received at least one dose of encorafenib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 1 Participants |
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 0 Participants |
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 2 Participants |
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 1 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 1 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 2 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 5 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 3 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 2 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 1 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 1 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 0 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 2 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 1 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 1 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 0 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 2 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 1 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 1 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 2 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 2 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 2 Participants |
| 150 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 1 Participants |
| 150 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 2 Participants |
| 150 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 1 Participants |
| 150 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 0 Participants |
| 450 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 1 Participants |
| 450 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 450 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 2 Participants |
| 450 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 2 Participants |
| 550 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 1 Participants |
| 550 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 2 Participants |
| 550 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 550 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 1 Participants |
| 700 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Partial Response (PR) | 0 Participants |
| 700 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Complete Response (CR) | 0 Participants |
| 700 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Progressive Disease (PD) | 0 Participants |
| 700 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation | Stable Disease (SD) | 1 Participants |
Secondary
Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion
umor response included: CR, PR, stable disease and disease progression (PD). CR=complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.
Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Population: FAS included all participants who received at least one dose of encorafenib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 0 Participants |
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 1 Participants |
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 1 Participants |
| 50 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 6 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 0 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 1 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 2 Participants |
| 100 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 0 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 0 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 0 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 2 Participants |
| 150 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 0 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 4 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 0 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 2 Participants |
| 75 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 8 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 0 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 1 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 1 Participants |
| 200 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 0 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 0 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 1 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 3 Participants |
| 100 mg Encorafenib BID | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 1 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Partial Response (PR) | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Complete Response (CR) | 0 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Progressive Disease (PD) | 3 Participants |
| 300 mg Encorafenib QD | Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion | Stable Disease (SD) | 8 Participants |
Secondary
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase
An AE was defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions. An SAE was defined as one of the following: fatal or life-threatening; resulted in significant disability/incapacity; congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization unless for routine treatment, elective or pre-planned treatment for a pre-existing condition, treatment on an emergency outpatient basis, social reasons and respite care in the absence of any deterioration in the participants general condition, any SAEs that were expected due to the condition being treated.
Time frame: From start of study treatment until 30 days after last dose of study treatment (maximum of 556.1 weeks of treatment exposure)
Population: Safety set included all participants who received at least one dose of encorafenib and had at least one valid post-baseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 50 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 3 Participants |
| 50 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 4 Participants |
| 100 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 7 Participants |
| 100 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 10 Participants |
| 150 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 3 Participants |
| 150 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 6 Participants |
| 75 mg Encorafenib BID | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 3 Participants |
| 75 mg Encorafenib BID | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 200 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 4 Participants |
| 200 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 4 Participants |
| 100 mg Encorafenib BID | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 100 mg Encorafenib BID | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 5 Participants |
| 300 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 4 Participants |
| 300 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 5 Participants |
| 150 mg Encorafenib BID | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 4 Participants |
| 150 mg Encorafenib BID | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 450 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 6 Participants |
| 450 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 550 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 3 Participants |
| 550 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 5 Participants |
| 700 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Serious Adverse Events (SAEs) | 1 Participants |
| 700 mg Encorafenib QD | Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase | Adverse Events (AEs) | 2 Participants |
Secondary
Number of Participants With AEs and SAEs During Dose Expansion Phase
An AE was defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions. An SAE was defined as one of the following: fatal or life-threatening; resulted in significant disability/incapacity; congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization unless for routine treatment, elective or pre-planned treatment for a pre-existing condition, treatment on an emergency outpatient basis, social reasons and respite care in the absence of any deterioration in the participants general condition, any SAEs that were expected due to the condition being treated.
Time frame: From start of study treatment until 30 days after last dose of study treatment (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Population: Safety set included all participants who received at least one dose of encorafenib and had at least one valid post-baseline safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 50 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 9 Participants |
| 50 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 100 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 6 Participants |
| 100 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 4 Participants |
| 150 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 2 Participants |
| 150 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 75 mg Encorafenib BID | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 16 Participants |
| 75 mg Encorafenib BID | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 9 Participants |
| 200 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 2 Participants |
| 200 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 2 Participants |
| 100 mg Encorafenib BID | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 6 Participants |
| 100 mg Encorafenib BID | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 3 Participants |
| 300 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Adverse Events (AEs) | 12 Participants |
| 300 mg Encorafenib QD | Number of Participants With AEs and SAEs During Dose Expansion Phase | Serious Adverse Events (SAEs) | 6 Participants |
Secondary
Overall Survival (OS): Dose Expansion Phase
Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until date of death or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Population: FAS included all participants who received at least one dose of encorafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 mg Encorafenib QD | Overall Survival (OS): Dose Expansion Phase | NA Months |
| 100 mg Encorafenib QD | Overall Survival (OS): Dose Expansion Phase | 12.5 Months |
| 150 mg Encorafenib QD | Overall Survival (OS): Dose Expansion Phase | NA Months |
| 75 mg Encorafenib BID | Overall Survival (OS): Dose Expansion Phase | 9.5 Months |
| 200 mg Encorafenib QD | Overall Survival (OS): Dose Expansion Phase | NA Months |
| 100 mg Encorafenib BID | Overall Survival (OS): Dose Expansion Phase | 7.2 Months |
| 300 mg Encorafenib QD | Overall Survival (OS): Dose Expansion Phase | 8.0 Months |
Secondary
PFS: Dose Expansion Phase
PFS was defined as time from date of first study treatment intake to date of first documented PD or death due to any cause. If a participant did not have an event, data censoring was done at the date of last adequate tumor assessment. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of \>= 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Population: FAS included all participants who received at least one dose of encorafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 mg Encorafenib QD | PFS: Dose Expansion Phase | 16.5 Months |
| 100 mg Encorafenib QD | PFS: Dose Expansion Phase | 19.3 Months |
| 150 mg Encorafenib QD | PFS: Dose Expansion Phase | 0.6 Months |
| 75 mg Encorafenib BID | PFS: Dose Expansion Phase | 2.0 Months |
| 200 mg Encorafenib QD | PFS: Dose Expansion Phase | 20.1 Months |
| 100 mg Encorafenib BID | PFS: Dose Expansion Phase | 4.5 Months |
| 300 mg Encorafenib QD | PFS: Dose Expansion Phase | 4.0 Months |
Secondary
Progression Free Survival (PFS): Dose Escalation Phase
PFS was defined as time from date of first study treatment intake to date of first documented disease progression (PD) or death due to any cause. If a participant did not have an event, data censoring was done at the date of last adequate tumor assessment. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of greater than or equal to (\>=) 5 mm, or appearance of \>=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure)
Population: Full Analysis Set (FAS) included all participants who received at least one dose of encorafenib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 50 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 75.0 Months |
| 100 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 10.0 Months |
| 150 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 50.0 Months |
| 75 mg Encorafenib BID | Progression Free Survival (PFS): Dose Escalation Phase | 33.3 Months |
| 200 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 50.0 Months |
| 100 mg Encorafenib BID | Progression Free Survival (PFS): Dose Escalation Phase | 40.0 Months |
| 300 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 0.0 Months |
| 150 mg Encorafenib BID | Progression Free Survival (PFS): Dose Escalation Phase | 75.0 Months |
| 450 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 33.3 Months |
| 550 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 20.0 Months |
| 700 mg Encorafenib QD | Progression Free Survival (PFS): Dose Escalation Phase | 0.0 Months |
Secondary
t1/2 of LGX818: Dose Expansion Phase
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 50 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 4.33 Hours |
| 50 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 3.36 Hours |
| 50 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 2.41 Hours |
| 100 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 4.04 Hours |
| 150 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 4.14 Hours |
| 75 mg Encorafenib BID | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 3.07 Hours |
| 75 mg Encorafenib BID | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 1.66 Hours |
| 75 mg Encorafenib BID | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 3.37 Hours |
| 200 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA Hours |
| 200 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA Hours |
| 200 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Hours |
| 100 mg Encorafenib BID | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 4.51 Hours |
| 300 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 3.13 Hours |
| 300 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 1.76 Hours |
| 300 mg Encorafenib QD | t1/2 of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 3.63 Hours |
Secondary
Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase
Time frame: Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 50 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 50 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2 Hours |
| 100 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 0.5 Hours |
| 100 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 0.5 Hours |
| 150 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 150 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2.99 Hours |
| 75 mg Encorafenib BID | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 75 mg Encorafenib BID | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 0.5 Hours |
| 200 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2 Hours |
| 200 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 100 mg Encorafenib BID | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 100 mg Encorafenib BID | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2.02 Hours |
| 300 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 300 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2 Hours |
| 150 mg Encorafenib BID | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 150 mg Encorafenib BID | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 450 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 450 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2 Hours |
| 550 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 550 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 1.25 Hours |
| 700 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2 Hours |
| 700 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 550 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2 Hours |
| 550 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | 2 Hours |
| 700 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 15 | NA Hours |
| 700 mg Encorafenib QD | Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase | Cycle 1 Day 1 | 2.04 Hours |
Secondary
Time to Response (TTR): Dose Escalation Phase
TTR was defined as the time from date of treatment until first documented response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. Individual participant data have been reported for this outcome measure.
Time frame: From date of start of treatment until CR or PR or censoring date (maximum of 556.1 weeks of treatment exposure)
Population: FAS included all participants who received at least one dose of encorafenib.'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. Only participants with complete or partial response were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 2 | 952 Days |
| 50 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 1 | 57 Days |
| 50 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 3 | 22 Days |
| 100 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 4 | 55 Days |
| 150 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 5 | 897 Days |
| 150 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 6 | 21 Days |
| 150 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 7 | 72 Days |
| 75 mg Encorafenib BID | Time to Response (TTR): Dose Escalation Phase | Participant 13 | 28 Days |
| 200 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 8 | 27 Days |
| 200 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 9 | 57 Days |
| 100 mg Encorafenib BID | Time to Response (TTR): Dose Escalation Phase | Participant 14 | 280 Days |
| 100 mg Encorafenib BID | Time to Response (TTR): Dose Escalation Phase | Participant 15 | 22 Days |
| 150 mg Encorafenib BID | Time to Response (TTR): Dose Escalation Phase | Participant 16 | 22 Days |
| 150 mg Encorafenib BID | Time to Response (TTR): Dose Escalation Phase | Participant 17 | 29 Days |
| 150 mg Encorafenib BID | Time to Response (TTR): Dose Escalation Phase | Participant 18 | 727 Days |
| 450 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 10 | 57 Days |
| 450 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 11 | 627 Days |
| 550 mg Encorafenib QD | Time to Response (TTR): Dose Escalation Phase | Participant 12 | 56 Days |
Secondary
Tmax of LGX818: Dose Expansion Phase
Tmax was the time required to reach the maximum plasma concentration (Cmax). First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in hours (hr).
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 50 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 1.97 Hours |
| 50 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 1.92 Hours |
| 50 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 1.9 Hours |
| 100 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Hours |
| 100 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 2.08 Hours |
| 150 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Hours |
| 150 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 3.97 Hours |
| 75 mg Encorafenib BID | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 1.93 Hours |
| 75 mg Encorafenib BID | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 2 Hours |
| 75 mg Encorafenib BID | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 2 Hours |
| 200 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA Hours |
| 200 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA Hours |
| 200 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Hours |
| 100 mg Encorafenib BID | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 4 Hours |
| 300 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 2 Hours |
| 300 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 2 Hours |
| 300 mg Encorafenib QD | Tmax of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 2 Hours |
Secondary
TTR: Dose Expansion Phase
TTR was defined as the time from date of treatment until first documented response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. Individual participant data have been reported for this outcome measure.
Time frame: From date of start of treatment until CR or PR or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Population: FAS included all participants who received at least one dose of encorafenib. 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure. Only participants with complete or partial response were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 1 | 211 Days |
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 6 | 23 Days |
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 7 | 56 Days |
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 2 | 22 Days |
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 3 | 23 Days |
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 4 | 22 Days |
| 50 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 5 | 56 Days |
| 100 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 9 | 111 Days |
| 100 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 8 | 78 Days |
| 75 mg Encorafenib BID | TTR: Dose Expansion Phase | Participant 11 | 22 Days |
| 75 mg Encorafenib BID | TTR: Dose Expansion Phase | Participant 13 | 28 Days |
| 75 mg Encorafenib BID | TTR: Dose Expansion Phase | Participant 10 | 391 Days |
| 75 mg Encorafenib BID | TTR: Dose Expansion Phase | Participant 12 | 32 Days |
| 200 mg Encorafenib QD | TTR: Dose Expansion Phase | Participant 14 | 25 Days |
| 100 mg Encorafenib BID | TTR: Dose Expansion Phase | Participant 15 | 53 Days |
Secondary
Vz/F of LGX818: Dose Expansion Phase
Time frame: Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Population: PAS consisted of all participants who had at least one blood sample providing evaluable pharmacokinetic (PK) data. 'Overall Number of Participants Analyzed' signifies number of participants with evaluable data for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 219 Liter | Geometric Coefficient of Variation 41.9 |
| 50 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 79.1 Liter | Geometric Coefficient of Variation 29.82 |
| 50 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 243 Liter | Geometric Coefficient of Variation 79 |
| 150 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 25.3 Liter | — |
| 75 mg Encorafenib BID | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 66.1 Liter | Geometric Coefficient of Variation 23.07 |
| 75 mg Encorafenib BID | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 130 Liter | Geometric Coefficient of Variation 20.81 |
| 75 mg Encorafenib BID | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 59.7 Liter | Geometric Coefficient of Variation 35.42 |
| 200 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | NA Liter | — |
| 200 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | NA Liter | — |
| 200 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | NA Liter | — |
| 100 mg Encorafenib BID | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 194 Liter | — |
| 300 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 15 | 110 Liter | Geometric Coefficient of Variation 32.51 |
| 300 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 1 | 44.6 Liter | Geometric Coefficient of Variation 26.6 |
| 300 mg Encorafenib QD | Vz/F of LGX818: Dose Expansion Phase | Cycle 1 Day 8 | 70 Liter | Geometric Coefficient of Variation 40.28 |