Brain Metastases
Conditions
Keywords
BRAFV600-mutant, melanoma, brain metastasis
Brief summary
This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and pharmacokinetic (PK) of 2 dosing regimens of encorafenib + binimetinib combination in patients with BRAFV600-mutant melanoma with brain metastasis. Approximately 100 patients will be enrolled, including 9 patients in a Safety Lead-in of the high-dose treatment arm. After a Screening Period, treatment will be administered in 28-day cycles and will continue until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent anticancer therapy, death.
Interventions
DRUGencorafenib
taken orally
DRUGbinimetinib
taken orally
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain. * Presence of B-RAF proto-oncogene, V600 mutant (BRAFV600) mutation in tumor tissue previously determined by a local PCR or NGS-based assay at any time prior to Screening or by a central laboratory during Screening. * Must have at least 1 parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as a magnetic resonance imaging (MRI) contrast-enhancing lesion that may be accurately measured in at least 1 dimension. (Measurable intracranial lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions). * Patients may have received the following prior therapies: 1. Safety Lead-in, Phase 2 Randomized , Phase 2 Arm A Cohort 1: May have received prior local therapy for brain metastases including but not restricted to brain surgery, whole brain radiotherapy, stereotactic radiotherapy or stereotactic radiosurgery. Multiple local (brain) therapies or combinations of local therapies are allowed. For patients receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (\> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For patients receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated. 2. Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery, craniotomy, SRS or SRT) for brain metastases. 3. All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy. 4. All patients (Safety Lead-In and Phase 2): If receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 2 weeks prior to first dose of study treatment (up to a total daily dose of 4mg of dexamethasone or equivalent). * An Eastern Cooperation Oncology Group Performance Status (ECOG PS) of 0 or 1 and Karnofsky score ≥ 80 * Adequate bone marrow, organ function and laboratory parameters Key
Exclusion criteria
* Patients with symptomatic brain metastasis. * Uveal or mucosal melanoma. * History of or current leptomeningeal metastases. * Treatment with SRS or craniotomy within 14 days prior to start of study treatment, or treatment with whole-brain radiation within 28 days prior to study treatment. Patients who received local therapy should have complete recovery with no neurological sequelae. * Either of the following: 1. Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start of study treatment; 2. Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent (or within 4 weeks prior to start of study treatment, when half-life is unknown). * Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) \< 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded. * Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase | Cycle 1 of SLI phase (up to 28 days) | DLT: any adverse event (AE) or laboratory abnormality not explained by underlying disease/disease progression/intercurrent illness/concomitant therapies/resulting in inability to tolerate 75% of planned dose of binimetinib or encorafenib during Cycle 1. Left ventricular ejection fraction (LVEF) \>10%, Grade (G)\>=3 cardiac disorders; G3/4 hypertension vascular disorders; G3/4 rash, hand foot skin reaction, photosensitivity; G3/4 diarrhea, nausea/vomiting Total bilirubin (TBL) G\>=3 (\>3.0\*upper limit of normal \[ULN)\]);AST/ALT\>5-8\*ULN\>5 days,\>8\*ULN,\>3\*ULN concurrent TBL\>2\*ULN;G\>=3 serum creatinine, CK elevation, ECG QTcF prolonged,G3 troponin, electrolyte\>72 hours,G3/4 amylase/lipase.G4 ANC, platelet count\>7 days;G3/4 platelet count, other AE except lymphopenia. G\>=3 retinopathy, other disorder\>21 days; G2 uveitis/eye pain/blurred vision/decreased visual acuity; G4 other disorder; Other hematologic/non hematologic G\>=3 AE. This outcome measure was planned to be analyzed in SLI phase only. |
| Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase | Day 1 of dosing up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs: events between first dose of study drug up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy minus 1 day, whichever occurred first. Grades by NCI CTCAE v.4.03: Grade 1= asymptomatic or mild , clinical or diagnostic observations only, intervention not indicated; Grade 2= moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3= severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4= life-threatening consequence, urgent intervention indicated; Grade 5= death related to AE. Number of participants with AEs per maximum grades were reported. |
| Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase | Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | Hepatology laboratory abnormalities included following parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT or AST greater than or equal to (\>=) 3\*upper limit normal (ULN), \>=5\*ULN, \>=10\*ULN, \>=20\*ULN; total bilirubin (TBILI): \>=2\*ULN; ALT \>=3\*ULN and TBILI \>=2\*ULN; AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \>2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \<=2\*ULN or missing. Only those laboratory test parameters in which at least 1 participant had data were reported. |
| Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported. |
| Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | Biochemistry laboratory test included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine kinase (CK) increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, and serum amylase increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for biochemistry laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported. |
| Number of Participants With Notable Abnormal Vital Signs: SLI Phase | Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | Vital signs included: systolic and diastolic blood pressure (BP),pulse rate,weight and temperature.Systolic and diastolic BP was measured in millimeters of mercury (mmHg) based on criteria:High Systolic BP:\>=160 mmHg and increase \>=20 mmHg from baseline;High Diastolic BP:\>=100 mmHg and increase\>=15 mmHg from baseline;Low Systolic BP:\<=90 mmHg with decrease from baseline of \>=20 mmHg;Low Diastolic BP:\<=50 mmHg with decrease from baseline of \>=15 mmHg;Pulse rate was measured in beats per minute (bpm) based on criteria:High pulse rate \>=120 bpm with increase from baseline of \>=15 bpm;Low pulse rate \<=50 bpm with decrease from baseline of \>=15 bpm;Weight was measured in in kilogram (kg) based on criteria:Increase from baseline of \>=10%,:\>=20% decrease from baseline;Temperature was measured in degree Celsius (C) based on criteria:High body temperature \>=37.5 degree C,Low body temperature \<=36 degree C.Only those vital signs parameters in which at least 1 participant had data were reported. |
| Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase | Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | In this outcome measure, number of participants with notable abnormal ECG values included: Fridericia's Correction Formula (QTcF) values in millisecond (msec) based on following criteria: 1) Increase from baseline \>30 msec; 2) Increase from baseline \>60 msec; 3) New \>450 msec; 4) New \>480 msec; and 5) New \>500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline \>25% and to a value \>100; 2) Decrease from baseline \>25% and to a value \<50. Only those ECG parameters in which at least 1 participant had data were reported. |
| Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase | Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months | An AE is any untoward medical occurrence in clinical investigation participant administered a product or medical device; event need not necessarily to have a causal relationship with treatment or usage. In this outcome measure, number of participants with incidence of dose interruptions, dose modifications and discontinuations due to AEs were reported. |
| Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2 | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in Phase 2 (approximately up to 8.3 months) | BMRR was reported in terms of percentage of participants who achieved a confirmed best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurred first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS for Global Tumor Assessment: SLI Phase and Phase 2 | From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm. Global tumor assessment consists of brain metastasis and extracranial lesions. If a participant did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. |
| BMRR Based on mRECIST v1.1: SLI Phase | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) | BMRR: percentage of participants who achieved a confirmed best overall response (BOR) of confirmed CR or PR in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurs first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: Disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (e.g., percent change from baseline). |
| Overall Survival: SLI Phase and Phase 2 | From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | Overall survival (OS) was defined as the time from date of the first dose of study treatment to the date of death due to any cause. If a death was not observed by the date of the analysis cutoff, OS was censored at the date of last contact. OS (months) = (date of death or censoring - date of first dose +1)/30.4375 |
| Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2 | Day 1 of dosing up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months | AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.TEAEs were events between 1st dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy minus 1 day, whichever occurs first.Severity was graded by NCI CTCAE v.4.03.Grade 1:asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2:moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3:severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL;Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to AE. Only those categories in which at least 1 participant had data were reported. |
| Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months | Hepatology laboratory abnormalities included following parameters: ALT, AST, ALT or AST \>=3\*ULN, \>=5\*ULN, \>=10\*ULN, \>=20\*ULN; TBILI: \>=2\*ULN; ALT \>=3\*ULN and TBILI \>=2\*ULN; AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \>2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \<=2\*ULN or missing. Only those laboratory test parameters in which at least 1 participant had data were reported. |
| Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months | Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported. |
| Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months | Biochemistry laboratory test included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, CK increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, and serum amylase increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for biochemistry laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported. |
| Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2 | Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months | In this outcome measure, number of participants with notable abnormal vital signs included: systolic and diastolic BP in mmHg based on following criteria: 1) High Systolic BP: \>=160 mmHg and an increase \>=20 mmHg from baseline; 2) High Diastolic BP: \>=100 mmHg and an increase \>=15 mmHg from baseline; 3) Low Systolic BP: \<=90 mmHg with decrease from baseline of \>=20 mmHg; 4) Low Diastolic BP: \<=50 mmHg with decrease from baseline of \>=15 mmHg; pulse rate in bpm based on following criteria: 1) High pulse rate \>=120 bpm with increase from baseline of \>=15 bpm; 2) Low pulse rate \<=50 bpm with decrease from baseline of \>=15 bpm; weight in kg based on following criteria: 1) Weight: Increase from baseline of \>=10%, 2) Weight: \>=20 % decrease from baseline; temperature in degree C based on following criteria: 1) High body temperature \>=37.5 degree C, 2) Low body temperature \<=36 degree C. Only those vital signs parameters in which at least 1 participant had data were reported. |
| Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2 | Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months | In this outcome measure, number of participants with notable abnormal ECG values included: QTcF values in msec based on following criteria: 1) increase from baseline \>30 msec; 2) increase from baseline \>60 msec; 3) new \>450 msec; 4) new \>480 msec; and 5) new \>500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline \>25% and to a value \>100; 2) Decrease from baseline \>25% and to a value \<50. Only those vital ECG parameters in which at least 1 participant had data were reported. |
| Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1 | In this outcome measure, plasma concentrations (in nanogram per milliliter \[ng/mL\]) of encorafenib and its metabolite LHY746 at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), Cycle 2 Day 1 (C2D1), and Cycle 3 Day 1 (C3D1) at different time points were reported. |
| Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1 | In this outcome measure, plasma concentrations of binimetinib and its metabolite AR00426032 at C1D1, C1D15, C2D1, and C3D1 at different time points were reported. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of encorafenib and its metabolite LHY746 in nanogram\*hour per milliliter (ng\*hr/mL) at C1D1, and C1D15 were assessed. |
| AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. |
| AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. |
| AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed. |
| Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, maximum observed plasma concentration (Cmax) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. |
| Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, maximum observed plasma concentration (Cmax) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. |
| Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, minimum observed plasma concentration (Cmin) after administration of encorafenib and its metabolite LHY746 at C1D15 were assessed. |
| Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, minimum observed plasma concentration (Cmin) after administration of binimetinib and its metabolite AR00426032 at C1D15 were assessed. |
| Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1 | In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of encorafenib and its metabolite LHY746 at C1D15 were assessed. |
| Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1 | In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of binimetinib and its metabolite AR00426032 at C1D15 were assessed. |
| Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2 | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | Extracranial response rate was defined as the percentage of participants with a BOR of confirmed CR or confirmed PR in extracranial lesions by investigator assessment per RECIST v1.1. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hrs (+/- 20 minutes [min]) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs (+/- 20 min) post-dose | In this outcome measure, time to reach maximum concentration (Tmax) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. |
| Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6, 24 hrs post-dose | In this outcome measure, time of last PK sample (Tlast) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. As outlined in the prespecified Statistical Analysis Plan for the study, since encorafenib was administered in continuous cycles, the pre-dose sample on Cycle 2 Day 1 was assumed to be at steady state and was interpolated as the concentration on 24 hours for encorafenib and LHY746 on Cycle 1 Day 15 during the analysis. In doing so, the reported Tlast values from the noncompartmental analysis (NCA) are 24 hours for encorafenib and LHY746. |
| Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6, 12 hrs post-dose | In this outcome measure, time of last PK sample (Tlast) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. As outlined in the prespecified Statistical Analysis Plan for the study, since binimetinib was administered in continuous cycles, the pre-dose sample on Cycle 2 Day 1 was assumed to be at steady state and was interpolated as the concentration for 12 hours for binimetinib and AR00426032 on Cycle 1 Day 15 for the noncompartmental analysis. In doing so, the reported Tlast values from the noncompartmental analysis (NCA) are 12 hours for binimetinib and AR00426032. |
| Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed. |
| RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed. |
| Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed. |
| Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed. |
| Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed. |
| MRAUClast of AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/binimetinib at C1D1, and C1D15 was assessed. |
| Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed. |
| MRCmax of AR00426032: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/ binimetinib at C1D1, and C1D15 was assessed. |
| Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose | In this outcome measure, time to reach maximum concentration (Tmax) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. |
| Global Response Rate: SLI Phase and Phase 2 | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | Global response rate was defined as the percentage of participants with a BOR of confirmed CR or confirmed PR by investigator assessment in brain metastasis and extracranial lesions per combined mRECIST v1.1 and RECIST v1.1, respectively. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). |
| Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2 | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | DCR was defined as the percentage of participants with a BOR of CR, PR or stable disease (SD) by Investigator assessment per mRECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started. |
| DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | DCR was defined as the percentage of participants with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum demonstrates an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| DCR for Global Response: SLI Phase and Phase 2 | From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | DCR was defined as the percentage of participants with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to quality for PD. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm. |
| Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2 | From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression. |
| DOR for Global Response: SLI Phase and Phase 2 | From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression. |
| DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression. |
| Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months) | PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase of at least 5 mm. If a participant did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. |
Countries
Argentina, Australia, Belgium, Italy, United States
Participant flow
Recruitment details
Study had 2 parts, Safety lead-in and Phase 2. In Phase 2, participants would be randomized either to the standard-dose or high-dose treatment, only if high dose was determined to be safe in safety lead-in.
Pre-assignment details
Pfizer and the Steering Committee reviewed safety lead-in data and decided not to evaluate high dose combination of encorafenib + binimetinib in Phase 2 of the study.
Participants by arm
| Arm | Count |
|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID Participants diagnosed with BRAFV600-mutant melanoma brain metastasis received combination therapy of encorafenib (300 mg orally, BID) and binimetinib (45 mg orally, BID) in 28-day cycles and continued until disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent anticancer therapy, or death, whichever occurred first. Participants were followed up to 30 days after last dose of study drug. | 10 |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID Participants diagnosed with BRAFV600-mutant melanoma brain metastasis received standard combination therapy of encorafenib (450 mg orally, QD) and binimetinib (45 mg orally, BID) in 28-day cycles and participants who were able to tolerate the encorafenib 450 mg dose further received 600 mg QD after 4 Weeks. Participants were followed up to 30 days after last dose of study drug. | 3 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 2 | Death | 0 | 3 | 0 |
| Safety Lead-in Phase | Death | 7 | 0 | 0 |
| Safety Lead-in Phase | Other | 1 | 0 | 0 |
| Safety Lead-in Phase | Study termination by sponsor | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Total | Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID |
|---|---|---|---|
| Age, Continuous | 45.7 Years STANDARD_DEVIATION 5.86 | 59.2 Years STANDARD_DEVIATION 13.8 | 63.2 Years STANDARD_DEVIATION 12.94 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 10 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 10 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 10 | 3 / 3 |
| other Total, other adverse events | 10 / 10 | 3 / 3 |
| serious Total, serious adverse events | 4 / 10 | 1 / 3 |
Outcome results
Primary
Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2
BMRR was reported in terms of percentage of participants who achieved a confirmed best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurred first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Brain Metastasis Response Rate (BMRR) Based on Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST v1.1): Phase 2 | 66.7 Percentage of participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase
DLT: any adverse event (AE) or laboratory abnormality not explained by underlying disease/disease progression/intercurrent illness/concomitant therapies/resulting in inability to tolerate 75% of planned dose of binimetinib or encorafenib during Cycle 1. Left ventricular ejection fraction (LVEF) \>10%, Grade (G)\>=3 cardiac disorders; G3/4 hypertension vascular disorders; G3/4 rash, hand foot skin reaction, photosensitivity; G3/4 diarrhea, nausea/vomiting Total bilirubin (TBL) G\>=3 (\>3.0\*upper limit of normal \[ULN)\]);AST/ALT\>5-8\*ULN\>5 days,\>8\*ULN,\>3\*ULN concurrent TBL\>2\*ULN;G\>=3 serum creatinine, CK elevation, ECG QTcF prolonged,G3 troponin, electrolyte\>72 hours,G3/4 amylase/lipase.G4 ANC, platelet count\>7 days;G3/4 platelet count, other AE except lymphopenia. G\>=3 retinopathy, other disorder\>21 days; G2 uveitis/eye pain/blurred vision/decreased visual acuity; G4 other disorder; Other hematologic/non hematologic G\>=3 AE. This outcome measure was planned to be analyzed in SLI phase only.
Time frame: Cycle 1 of SLI phase (up to 28 days)
Population: The dose-determining set included all participants enrolled in the high-dose treatment arm in the safety lead-in who completed one 28-day cycle of treatment and received at least 75 percentage (%) of the planned cumulative dose of both study drugs or discontinued treatment because of DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Safety Lead-in (SLI) Phase | 3 Participants |
Primary
Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase
Hepatology laboratory abnormalities included following parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT or AST greater than or equal to (\>=) 3\*upper limit normal (ULN), \>=5\*ULN, \>=10\*ULN, \>=20\*ULN; total bilirubin (TBILI): \>=2\*ULN; ALT \>=3\*ULN and TBILI \>=2\*ULN; AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \>2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \<=2\*ULN or missing. Only those laboratory test parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase | ALT: >=5*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase | ALT: >=3*ULN | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase | AST: >=3*ULN | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase | ALT or AST: >=3*ULN | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: SLI Phase | ALT or AST: >=5*ULN | 1 Participants |
Primary
Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase
An AE is any untoward medical occurrence in clinical investigation participant administered a product or medical device; event need not necessarily to have a causal relationship with treatment or usage. In this outcome measure, number of participants with incidence of dose interruptions, dose modifications and discontinuations due to AEs were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase | Dose interruptions due to AE | 6 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase | Dose modifications due to AE | 4 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to AEs: SLI Phase | Discontinuations due to AE | 1 Participants |
Primary
Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase
In this outcome measure, number of participants with notable abnormal ECG values included: Fridericia's Correction Formula (QTcF) values in millisecond (msec) based on following criteria: 1) Increase from baseline \>30 msec; 2) Increase from baseline \>60 msec; 3) New \>450 msec; 4) New \>480 msec; and 5) New \>500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline \>25% and to a value \>100; 2) Decrease from baseline \>25% and to a value \<50. Only those ECG parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase | QTcF: New >450 msec | 6 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase | QTcF:Increase from baseline >30 msec | 5 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: SLI Phase | QTcF:Increase from baseline >25% and to a value >100 | 1 Participants |
Primary
Number of Participants With Notable Abnormal Vital Signs: SLI Phase
Vital signs included: systolic and diastolic blood pressure (BP),pulse rate,weight and temperature.Systolic and diastolic BP was measured in millimeters of mercury (mmHg) based on criteria:High Systolic BP:\>=160 mmHg and increase \>=20 mmHg from baseline;High Diastolic BP:\>=100 mmHg and increase\>=15 mmHg from baseline;Low Systolic BP:\<=90 mmHg with decrease from baseline of \>=20 mmHg;Low Diastolic BP:\<=50 mmHg with decrease from baseline of \>=15 mmHg;Pulse rate was measured in beats per minute (bpm) based on criteria:High pulse rate \>=120 bpm with increase from baseline of \>=15 bpm;Low pulse rate \<=50 bpm with decrease from baseline of \>=15 bpm;Weight was measured in in kilogram (kg) based on criteria:Increase from baseline of \>=10%,:\>=20% decrease from baseline;Temperature was measured in degree Celsius (C) based on criteria:High body temperature \>=37.5 degree C,Low body temperature \<=36 degree C.Only those vital signs parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | High systolic BP | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | Low diastolic BP | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | High pulse rate | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | Low pulse rate | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | Increased body weight | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | High body temperature | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Vital Signs: SLI Phase | Low body temperature | 3 Participants |
Primary
Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase
Biochemistry laboratory test included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine kinase (CK) increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, and serum amylase increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for biochemistry laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, Number Analyzed signifies participants evaluable for specified rows. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alanine aminotransferase increased: Grade 0 (baseline) to Grade 3 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypermagnesemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alanine aminotransferase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alanine aminotransferase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alanine aminotransferase increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alanine aminotransferase increased: Grade 1 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alkaline phosphatase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 5 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alkaline phosphatase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Alkaline phosphatase increased: Grade 1 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Aspartate aminotransferase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 4 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Aspartate aminotransferase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Aspartate aminotransferase increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Aspartate aminotransferase increased: Grade 1 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Aspartate aminotransferase increased: Grade 1 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Blood bilirubin increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | CK increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 6 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | CK increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | CK increased: Grade 0 (baseline) to Grade 4 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Creatinine increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 9 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Creatinine increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypercalcemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyperglycemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 5 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyperglycemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyperglycemia: Grade 0 (baseline) to Grade 3 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyperglycemia: Baseline to post-baseline | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyperglycemia: Missing (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyperkalemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypermagnesemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 9 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypernatremia: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypoalbuminemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 6 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypoalbuminemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypoalbuminemia: Grade 2 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypocalcemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 8 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypocalcemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypoglycemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypokalemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypomagnesemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyponatremia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyponatremia: Grade 0 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyponatremia: Grade 0 (baseline) to Grade 3 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyponatremia: Grade 1 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hyponatremia: Grade 1 (baseline) to Grade 3 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypophosphatemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 6 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypophosphatemia: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypophosphatemia: Missing (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hypophosphatemia: Missing (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lipase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 7 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lipase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Serum amylase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
Primary
Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase
Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, Number Analyzed signifies participants evaluable for specified rows. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Anemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | INR increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Activated partial thromboplastin time prolonged: Grade 0 (baseline) to Grade 0 (post-baseline) | 5 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Activated partial thromboplastin time prolonged: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Anemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 7 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Anemia: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Hemoglobin increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Leukocytosis: Grade 0 (baseline) to Grade 0 (post-baseline) | 10 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lymphocyte count decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lymphocyte count decreased: Grade 0 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lymphocyte count decreased: Grade 0 (baseline) to Grade 2 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lymphocyte count decreased: Grade 0 (baseline) to Grade 3 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lymphocyte count increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 8 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Lymphocyte count increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Neutrophil count decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 8 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Neutrophil count decreased: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Platelet count decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 7 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | Platelet count decreased: Grade 0 (baseline) to Grade 1 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | White blood cell decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 8 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: SLI Phase | White blood cell decreased: Grade 0 (baseline) to Grade 2 (post-baseline) | 2 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase
AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs: events between first dose of study drug up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy minus 1 day, whichever occurred first. Grades by NCI CTCAE v.4.03: Grade 1= asymptomatic or mild , clinical or diagnostic observations only, intervention not indicated; Grade 2= moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3= severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4= life-threatening consequence, urgent intervention indicated; Grade 5= death related to AE. Number of participants with AEs per maximum grades were reported.
Time frame: Day 1 of dosing up to 30 days after last dose of study drug in SLI Phase, maximum duration up to 10.4 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase | Grade 1 | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase | Grade 2 | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase | Grade 3 | 5 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase | Grade 4 | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI _CTCAE) Version (v) 4.03: SLI Phase | Grade 5 | 0 Participants |
Secondary
Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib | 0.468 ratio | Geometric Coefficient of Variation 46 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Accumulation Ratio Between AUClast,ss and AUClast (RAUC) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 | 7.25 ratio | Geometric Coefficient of Variation 46.7 |
Secondary
Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, accumulation ratio of encorafenib and its metabolite LHY746 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib | 0.490 ratio | Geometric Coefficient of Variation 71.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Accumulation Ratio Between Cmax,ss and Cmax (RCmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 | 5.78 ratio | Geometric Coefficient of Variation 41.7 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of encorafenib and its metabolite LHY746 in nanogram\*hour per milliliter (ng\*hr/mL) at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D1 | 9530 ng*hr/mL | Geometric Coefficient of Variation 50.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D15 | 3930 ng*hr/mL | Geometric Coefficient of Variation 52.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D1 | 1230 ng*hr/mL | Geometric Coefficient of Variation 60.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-Time Curve From Time Zero to 6 Hours (AUC 0-6) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D15 | 8160 ng*hr/mL | Geometric Coefficient of Variation 67.7 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D1 | 9190 ng*hr/mL | Geometric Coefficient of Variation 47.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D15 | 7490 ng*hr/mL | Geometric Coefficient of Variation 52.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D1 | 1180 ng*hr/mL | Geometric Coefficient of Variation 56.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-time Curve From Time Zero to Last Time Point (AUClast) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D15 | 29600 ng*hr/mL | Geometric Coefficient of Variation 73 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib | 7490 ng*hr/mL | Geometric Coefficient of Variation 52.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration-time Curve From Time Zero to Tau (AUCtau) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 | 29600 ng*hr/mL | Geometric Coefficient of Variation 73 |
Secondary
AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, area under the plasma concentration-time curve from zero to 6 hours (AUC 0-6) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D1 | 1410 ng*hr/mL | Geometric Coefficient of Variation 85.5 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D15 | 1050 ng*hr/mL | Geometric Coefficient of Variation 39.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D1 | 159 ng*hr/mL | Geometric Coefficient of Variation 65.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUC0-6 of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D15 | 53.9 ng*hr/mL | Geometric Coefficient of Variation 48.6 |
Secondary
AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, area under the plasma concentration-time curve from zero to the last measurable time point (AUClast) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D1 | 1350 ng*hr/mL | Geometric Coefficient of Variation 79.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D15 | 1440 ng*hr/mL | Geometric Coefficient of Variation 43.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D1 | 156 ng*hr/mL | Geometric Coefficient of Variation 60.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUClast of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D15 | 77.9 ng*hr/mL | Geometric Coefficient of Variation 49.7 |
Secondary
AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, area under the plasma concentration-time curve from time zero to the last measurable time point Tau (AUCtau) of encorafenib and its metabolite LHY746 over a dosing interval (6 hours as appropriate) of C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib | 1440 ng*hr/mL | Geometric Coefficient of Variation 43.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | AUCtau of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 | 77.9 ng*hr/mL | Geometric Coefficient of Variation 49.7 |
Secondary
BMRR Based on mRECIST v1.1: SLI Phase
BMRR: percentage of participants who achieved a confirmed best overall response (BOR) of confirmed CR or PR in brain metastasis per mRECIST v1.1 from date of first dose until disease progression, death due to any cause, or start of subsequent anticancer therapy, whichever occurs first. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: Disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (e.g., percent change from baseline).
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months)
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | BMRR Based on mRECIST v1.1: SLI Phase | 60.0 Percentage of participants |
Secondary
Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, maximum observed plasma concentration (Cmax) after administration of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D1 | 506 ng/mL | Geometric Coefficient of Variation 85.5 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D15 | 359 ng/mL | Geometric Coefficient of Variation 40.5 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D1 | 53.9 ng/mL | Geometric Coefficient of Variation 77.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Cmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D15 | 16.9 ng/mL | Geometric Coefficient of Variation 54 |
Secondary
Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, minimum observed plasma concentration (Cmin) after administration of binimetinib and its metabolite AR00426032 at C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib | 47.7 ng/mL | Geometric Coefficient of Variation 71.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Cmin of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 | 3.04 ng/mL | Geometric Coefficient of Variation 47.8 |
Secondary
Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of binimetinib and its metabolite AR00426032 at C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib | 79.9 ng/mL | Geometric Coefficient of Variation 56.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ctrough of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 | 4.71 ng/mL | Geometric Coefficient of Variation 62.8 |
Secondary
Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, measured concentration at the end of a dosing interval (Ctrough) of encorafenib and its metabolite LHY746 at C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib | 332 ng/mL | Geometric Coefficient of Variation 61 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ctrough of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 | 1520 ng/mL | Geometric Coefficient of Variation 59 |
Secondary
DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2
DCR was defined as the percentage of participants with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum demonstrates an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | 70.0 Percentage of participants |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | DCR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | 100 Percentage of participants |
Secondary
DCR for Global Response: SLI Phase and Phase 2
DCR was defined as the percentage of participants with a BOR of CR, PR or SD by Investigator assessment per RECIST v1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to quality for PD. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm.
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DCR for Global Response: SLI Phase and Phase 2 | 90.0 Percentage of participants |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | DCR for Global Response: SLI Phase and Phase 2 | 100 Percentage of participants |
Secondary
Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2
DCR was defined as the percentage of participants with a BOR of CR, PR or stable disease (SD) by Investigator assessment per mRECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started.
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2 | 100 Percentage of participants |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Disease Control Rate (DCR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2 | 100 Percentage of participants |
Secondary
DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2
DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression.
Time frame: From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable for specified rows. Data has been presented per participant as data was not summarized due to due to limited number of participants with events.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 1 | 2.4 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 2 | 4.3 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 3 | 5.5 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 4 | 2.8 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 5 | 1.8 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 6 | 2.8 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 7 | 7.7 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 8 | 3.9 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | DOR for Extracranial Response Based on RECIST v1.1: SLI Phase and Phase 2 | Participant 9 | 7.3 Months |
Secondary
DOR for Global Response: SLI Phase and Phase 2
DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. Any pathological lymph nodes must be \<10 mm on the short axis. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline). DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression.
Time frame: From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | DOR for Global Response: SLI Phase and Phase 2 | 2.9 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | DOR for Global Response: SLI Phase and Phase 2 | 5.0 Months |
Secondary
Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2
DOR: time from date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. DOR (months) = (date of event or censoring - date of first CR or PR + 1)/30.4375. If a participant with a CR or PR did not have an event at time of analysis cutoff or with an event more than 16 weeks (for first 11 cycles after treatment start date) or 24 weeks (after Cycle 11) after last adequate tumor assessment, participant was censored on date of last adequate tumor assessment that documented no progression.
Time frame: From date of first radiographic response (CR or PR) to earliest documented disease progression or death due to any cause in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2 | 3.3 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Duration of Response (DOR) for Brain Metastasis Response Based on mRECIST v1.1: SLI Phase and Phase 2 | 5.6 Months |
Secondary
Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2
Extracranial response rate was defined as the percentage of participants with a BOR of confirmed CR or confirmed PR in extracranial lesions by investigator assessment per RECIST v1.1. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2 | 60.0 Percentage of participants |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Extracranial Response Rate Based on RECIST v1.1: SLI Phase and Phase 2 | 100 Percentage of participants |
Secondary
Global Response Rate: SLI Phase and Phase 2
Global response rate was defined as the percentage of participants with a BOR of confirmed CR or confirmed PR by investigator assessment in brain metastasis and extracranial lesions per combined mRECIST v1.1 and RECIST v1.1, respectively. BOR: best response recorded from date of first dose of study treatment until progression by investigator assessment at each time point. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum of the diameters (e.g., percent change from baseline).
Time frame: From date of first dose until disease progression, death due to any cause or subsequent therapy initiation, whichever occurred first in SLI Phase (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Global Response Rate: SLI Phase and Phase 2 | 50.0 Percentage of participants |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Global Response Rate: SLI Phase and Phase 2 | 100 Percentage of participants |
Secondary
Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, maximum observed plasma concentration (Cmax) after administration of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D1 | 3210 ng/mL | Geometric Coefficient of Variation 47.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D15 | 1370 ng/mL | Geometric Coefficient of Variation 79.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D1 | 340 ng/mL | Geometric Coefficient of Variation 47.2 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Maximum Observed Plasma Concentration (Cmax) After Drug Administration of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D15 | 1720 ng/mL | Geometric Coefficient of Variation 65.3 |
Secondary
Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, minimum observed plasma concentration (Cmin) after administration of encorafenib and its metabolite LHY746 at C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib | 91.1 ng/mL | Geometric Coefficient of Variation 88.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Minimum Observed Plasma Concentration (Cmin) at the End of a Dosing Interval at Steady State of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 | 829 ng/mL | Geometric Coefficient of Variation 99.3 |
Secondary
MRAUClast of AR00426032: SLI Phase
In this outcome measure, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/binimetinib at C1D1, and C1D15 was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | MRAUClast of AR00426032: SLI Phase | C1D1 | 0.109 ratio | Geometric Coefficient of Variation 54.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | MRAUClast of AR00426032: SLI Phase | C1D15 | 0.0494 ratio | Geometric Coefficient of Variation 63.9 |
Secondary
MRCmax of AR00426032: SLI Phase
In this outcome measure, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for AR00426032/ binimetinib at C1D1, and C1D15 was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | MRCmax of AR00426032: SLI Phase | C1D1 | 0.103 ratio | Geometric Coefficient of Variation 49.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | MRCmax of AR00426032: SLI Phase | C1D15 | 0.0453 ratio | Geometric Coefficient of Variation 53.8 |
Secondary
Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2
In this outcome measure, number of participants with notable abnormal vital signs included: systolic and diastolic BP in mmHg based on following criteria: 1) High Systolic BP: \>=160 mmHg and an increase \>=20 mmHg from baseline; 2) High Diastolic BP: \>=100 mmHg and an increase \>=15 mmHg from baseline; 3) Low Systolic BP: \<=90 mmHg with decrease from baseline of \>=20 mmHg; 4) Low Diastolic BP: \<=50 mmHg with decrease from baseline of \>=15 mmHg; pulse rate in bpm based on following criteria: 1) High pulse rate \>=120 bpm with increase from baseline of \>=15 bpm; 2) Low pulse rate \<=50 bpm with decrease from baseline of \>=15 bpm; weight in kg based on following criteria: 1) Weight: Increase from baseline of \>=10%, 2) Weight: \>=20 % decrease from baseline; temperature in degree C based on following criteria: 1) High body temperature \>=37.5 degree C, 2) Low body temperature \<=36 degree C. Only those vital signs parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2 | Increased body weight | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Clinically Significant Change in Notable Abnormal Vital Signs: Phase 2 | Low body temperature | 2 Participants |
Secondary
Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2
Hepatology laboratory abnormalities included following parameters: ALT, AST, ALT or AST \>=3\*ULN, \>=5\*ULN, \>=10\*ULN, \>=20\*ULN; TBILI: \>=2\*ULN; ALT \>=3\*ULN and TBILI \>=2\*ULN; AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \>2\*ULN; ALT or AST \>=3\*ULN and TBILI \>=2\*ULN and ALP \<=2\*ULN or missing. Only those laboratory test parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT: >=20*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT: >=3*ULN | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT: >=5*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT: >=10*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | AST: >=3*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | AST: >=5*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | AST: >=10*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT or AST: >=3*ULN | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT or AST: >=5*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT or AST: >=10*ULN | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hepatology Laboratory Test Abnormalities: Phase 2 | ALT or AST: >=20*ULN | 1 Participants |
Secondary
Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2
In this outcome measure, number of participants with notable abnormal ECG values included: QTcF values in msec based on following criteria: 1) increase from baseline \>30 msec; 2) increase from baseline \>60 msec; 3) new \>450 msec; 4) new \>480 msec; and 5) new \>500 msec; heart rate values in bpm based on following criteria: 1) Increase from baseline \>25% and to a value \>100; 2) Decrease from baseline \>25% and to a value \<50. Only those vital ECG parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Notable Abnormal Electrocardiogram (ECG) Values: Phase 2 | 1 Participants |
Secondary
Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2
Biochemistry laboratory test included: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, CK increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, and serum amylase increased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for biochemistry laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, Number Analyzed signifies participants evaluable for specified rows. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Aspartate aminotransferase increased: Grade 0 (baseline) to Grade 3 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypernatremia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypoalbuminemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypoalbuminemia: Grade 1 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypocalcemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypocalcemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypoglycemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypokalemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypokalemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypomagnesemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hyponatremia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypophosphatemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Lipase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Lipase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Serum amylase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Serum amylase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Blood bilirubin increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | CK increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | CK increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Creatinine increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Creatinine increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypercalcemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hypermagnesemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hyperkalemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hyperglycemia: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Aspartate aminotransferase increased: Grade 1 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Alanine aminotransferase increased: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Alanine aminotransferase increased: Grade 1 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Alanine aminotransferase increased: Grade 1 (baseline) to Grade 4 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Alkaline phosphatase increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Alkaline phosphatase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Alkaline phosphatase increased: Grade 2 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Biochemistry Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Aspartate aminotransferase increased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
Secondary
Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2
Hematology and coagulation laboratory test included: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory results were categorically summarized according to the NCI-CTCAE criteria v4.03. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Grade 0 was assigned for all non-missing values not graded as 1 or higher per CTCAE criteria. Number of participants with shift from baseline for hematology and coagulation laboratory test were assessed. Only those laboratory test parameters in which at least 1 participant had data were reported.
Time frame: Baseline (Day 1) up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, Number Analyzed signifies participants evaluable for specified rows. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Lymphocyte count decreased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Activated partial thromboplastin time prolonged: Grade 0 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Anemia: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Anemia: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Anemia: Grade 1 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Hemoglobin increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | INR increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Leukocytosis: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Lymphocyte count decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Lymphocyte count increased: Grade 0 (baseline) to Grade 0 (post-baseline) | 3 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Neutrophil count decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Neutrophil count decreased: Grade 0 (baseline) to Grade 2 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Platelet count decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | Platelet count decreased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | White blood cell decreased: Grade 0 (baseline) to Grade 0 (post-baseline) | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Shift From Baseline for Hematology and Coagulation Laboratory Test Abnormalities Based on NCI-CTCAE v4.03: Phase 2 | White blood cell decreased: Grade 0 (baseline) to Grade 1 (post-baseline) | 1 Participants |
Secondary
Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2
AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship.TEAEs were events between 1st dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state or start of subsequent anticancer drug therapy minus 1 day, whichever occurs first.Severity was graded by NCI CTCAE v.4.03.Grade 1:asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2:moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL;Grade 3:severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL;Grade 4:life-threatening consequence, urgent intervention indicated; Grade 5:death related to AE. Only those categories in which at least 1 participant had data were reported.
Time frame: Day 1 of dosing up to 30 days after last dose of study drug in Phase 2, maximum duration up to 8.3 months
Population: The safety set included all participants who received at least 1 dose of any study drug. This outcome measure was planned to be analyzed in phase 2 only.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2 | Grade 2 | 2 Participants |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent AEs of Maximum Severity Grades Based on NCI CTCAE v4.03: Phase 2 | Grade 4 | 1 Participants |
Secondary
Overall Survival: SLI Phase and Phase 2
Overall survival (OS) was defined as the time from date of the first dose of study treatment to the date of death due to any cause. If a death was not observed by the date of the analysis cutoff, OS was censored at the date of last contact. OS (months) = (date of death or censoring - date of first dose +1)/30.4375
Time frame: From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: Data was not collected due to the premature termination of the study and consequent lack of meaningful data, data are not available and no analyses were performed.
Secondary
PFS for Global Tumor Assessment: SLI Phase and Phase 2
PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of the diameters of target lesions, taking as a reference the smallest sum of diameters recorded since the treatment started (i.e., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of at least 5 mm. Global tumor assessment consists of brain metastasis and extracranial lesions. If a participant did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment.
Time frame: From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, 'Number Analyzed' signifies participants evaluable for specified rows. Data has been presented per participant as data was not summarized due to limited number of participants with events.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 1 | 3.5 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 2 | NA Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 3 | 3.6 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 4 | NA Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 5 | 9.4 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 6 | 3.7 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 7 | 3.8 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 8 | 7.3 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 9 | 3.7 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 10 | 1.0 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 11 | 7.4 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 12 | 5.5 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | PFS for Global Tumor Assessment: SLI Phase and Phase 2 | Participant 13 | 6.8 Months |
Secondary
Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, plasma concentrations of binimetinib and its metabolite AR00426032 at C1D1, C1D15, C2D1, and C3D1 at different time points were reported.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D1: 0.5 hrs post dose | 86.6 ng/mL | Geometric Coefficient of Variation 567.4 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D1: 1.5 hrs post dose | 297 ng/mL | Geometric Coefficient of Variation 341.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D1: 3 hrs post dose | 233 ng/mL | Geometric Coefficient of Variation 83.2 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D1: 6 hrs post dose | 151 ng/mL | Geometric Coefficient of Variation 91.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D15: pre-dose | 47.7 ng/mL | Geometric Coefficient of Variation 71.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D15: 0.5 hrs post dose | 151 ng/mL | Geometric Coefficient of Variation 67.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D15: 1.5 hrs post dose | 232 ng/mL | Geometric Coefficient of Variation 121.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D15: 3 hrs post dose | 215 ng/mL | Geometric Coefficient of Variation 55.2 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C1D15: 6 hrs post dose | 79.9 ng/mL | Geometric Coefficient of Variation 56.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C2D1: pre-dose | 42.0 ng/mL | Geometric Coefficient of Variation 47.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib C3D1: pre-dose | 30.0 ng/mL | Geometric Coefficient of Variation 65.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D1: 0.5 hrs post dose | 8.10 ng/mL | Geometric Coefficient of Variation 132.4 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D1: 1.5 hrs post dose | 30.3 ng/mL | Geometric Coefficient of Variation 345.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D1: 3 hrs post dose | 31.7 ng/mL | Geometric Coefficient of Variation 60.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D1: 6 hrs post dose | 21.9 ng/mL | Geometric Coefficient of Variation 36.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D15: pre-dose | 3.13 ng/mL | Geometric Coefficient of Variation 53 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D15: 0.5 hrs post dose | 5.89 ng/mL | Geometric Coefficient of Variation 136.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D15: 1.5 hrs post dose | 10.6 ng/mL | Geometric Coefficient of Variation 56.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D15: 3 hrs post dose | 12.5 ng/mL | Geometric Coefficient of Variation 58 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C1D15: 6 hrs post dose | 4.71 ng/mL | Geometric Coefficient of Variation 62.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C2D1: pre-dose | 2.97 ng/mL | Geometric Coefficient of Variation 29.6 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 C3D1: pre-dose | 1.57 ng/mL | Geometric Coefficient of Variation 42.2 |
Secondary
Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, plasma concentrations (in nanogram per milliliter \[ng/mL\]) of encorafenib and its metabolite LHY746 at Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), Cycle 2 Day 1 (C2D1), and Cycle 3 Day 1 (C3D1) at different time points were reported.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose; Pre-dose on Cycle 2 Day 1, Cycle 3 Day 1
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D1: 0.5 hrs post dose | 65.5 ng/mL | Geometric Coefficient of Variation 328.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D1: 1.5 hrs post dose | 1830 ng/mL | Geometric Coefficient of Variation 325.5 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D1: 3 hrs post dose | 2120 ng/mL | Geometric Coefficient of Variation 36.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D1: 6 hrs post dose | 1170 ng/mL | Geometric Coefficient of Variation 67.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D15: pre-dose | 92.3 ng/mL | Geometric Coefficient of Variation 87.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D15: 0.5 hrs post dose | 182 ng/mL | Geometric Coefficient of Variation 243.5 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D15: 1.5 hrs post dose | 745 ng/mL | Geometric Coefficient of Variation 132.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D15: 3 hrs post dose | 953 ng/mL | Geometric Coefficient of Variation 50 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C1D15: 6 hrs post dose | 332 ng/mL | Geometric Coefficient of Variation 61 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C2D1: pre-dose | 59.7 ng/mL | Geometric Coefficient of Variation 65.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib C3D1: pre-dose | 50.1 ng/mL | Geometric Coefficient of Variation 47.8 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D1: 0.5 hrs post dose | 6.46 ng/mL | Geometric Coefficient of Variation 114.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D1: 1.5 hrs post dose | 123 ng/mL | Geometric Coefficient of Variation 345.5 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D1: 3 hrs post dose | 296 ng/mL | Geometric Coefficient of Variation 46.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D1: 6 hrs post dose | 277 ng/mL | Geometric Coefficient of Variation 62.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D15: pre-dose | 892 ng/mL | Geometric Coefficient of Variation 101.1 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D15: 0.5 hrs post dose | 941 ng/mL | Geometric Coefficient of Variation 88.2 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D15: 1.5 hrs post dose | 1040 ng/mL | Geometric Coefficient of Variation 93.4 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D15: 3 hrs post dose | 1690 ng/mL | Geometric Coefficient of Variation 64.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C1D15: 6 hrs post dose | 1520 ng/mL | Geometric Coefficient of Variation 59 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C2D1: pre-dose | 655 ng/mL | Geometric Coefficient of Variation 91.3 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Plasma Concentrations of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746 C3D1: pre-dose | 256 ng/mL | Geometric Coefficient of Variation 2956 |
Secondary
Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2
PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression (PD) by Investigator assessment, or death due to any cause, whichever occurs first. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase of at least 5 mm. If a participant did not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment.
Time frame: From date of first dose of study treatment to the earliest documented disease progression by investigator assessment, or death due to any cause, whichever occurs first in SLI (approximately up to 10.4 months) and Phase 2 (approximately up to 8.3 months)
Population: The safety set included all participants who received at least 1 dose of any study drug. Here, 'Number Analyzed' signifies participants evaluable for specified rows. Data has been presented per participant as data was not summarized due to due to limited number of participants with events.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 1 | 3.5 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 2 | 3.7 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 3 | 3.6 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 4 | 5.5 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 5 | 9.4 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 6 | 3.7 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 7 | 3.8 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 8 | 7.3 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 9 | 3.7 Months |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 10 | 5.4 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 11 | 7.4 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 12 | 5.5 Months |
| Phase 2, Standard Dose Arm: Encorafenib 450 mg QD + Binimetinib 45 mg BID | Progression Free Survival (PFS) for Brain Metastasis Based on mRECIST v1.1: SLI Phase and Phase 2 | Participant 13 | 6.8 Months |
Secondary
Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase
In this outcome measure, ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase | C1D1 | 0.164 ratio | Geometric Coefficient of Variation 21.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) of LHY746: SLI Phase | C1D15 | 2.64 ratio | Geometric Coefficient of Variation 36 |
Secondary
Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase
In this outcome measure, ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, for LHY746/encorafenib at C1D1, and C1D15 was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase | C1D1 | 0.135 ratio | Geometric Coefficient of Variation 16.7 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) of LHY746: SLI Phase | C1D15 | 1.59 ratio | Geometric Coefficient of Variation 47.8 |
Secondary
RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 AUC0-6 divided by C1D1 AUC0-6 was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib | 0.877 ratio | Geometric Coefficient of Variation 60.4 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | RAUC of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 | 0.359 ratio | Geometric Coefficient of Variation 93 |
Secondary
Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, accumulation ratio of binimetinib and its metabolite AR00426032 calculated as: C1D15 Cmax divided by C1D1 Cmax was assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib | 0.818 ratio | Geometric Coefficient of Variation 95.9 |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Rcmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032 | 0.347 ratio | Geometric Coefficient of Variation 130.9 |
Secondary
Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, time of last PK sample (Tlast) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed. As outlined in the prespecified Statistical Analysis Plan for the study, since encorafenib was administered in continuous cycles, the pre-dose sample on Cycle 2 Day 1 was assumed to be at steady state and was interpolated as the concentration on 24 hours for encorafenib and LHY746 on Cycle 1 Day 15 during the analysis. In doing so, the reported Tlast values from the noncompartmental analysis (NCA) are 24 hours for encorafenib and LHY746.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6, 24 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D1 | 5.78 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D15 | 24.00 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D1 | 5.78 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time of Last PK Sample (Tlast) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D15 | 24.00 hours |
Secondary
Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase
In this outcome measure, time to reach maximum concentration (Tmax) of encorafenib and its metabolite LHY746 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D1 | 1.53 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | Encorafenib: C1D15 | 1.55 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D1 | 4.33 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Time to Reach Maximum Concentration (Tmax) of Encorafenib and Its Metabolite LHY746: SLI Phase | LHY746: C1D15 | 3.00 hours |
Secondary
Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, time of last PK sample (Tlast) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed. As outlined in the prespecified Statistical Analysis Plan for the study, since binimetinib was administered in continuous cycles, the pre-dose sample on Cycle 2 Day 1 was assumed to be at steady state and was interpolated as the concentration for 12 hours for binimetinib and AR00426032 on Cycle 1 Day 15 for the noncompartmental analysis. In doing so, the reported Tlast values from the noncompartmental analysis (NCA) are 12 hours for binimetinib and AR00426032.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hours (hrs) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6, 12 hrs post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D1 | 5.78 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D15 | 12.00 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D1 | 5.78 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tlast of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D15 | 12.00 hours |
Secondary
Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase
In this outcome measure, time to reach maximum concentration (Tmax) of binimetinib and its metabolite AR00426032 at C1D1, and C1D15 were assessed.
Time frame: Cycle 1 Day 1: 0.5, 1.5, 3, 6 hrs (+/- 20 minutes [min]) post-dose; Cycle 1 Day 15: Pre-dose, 0.5, 1.5, 3, 6 hrs (+/- 20 min) post-dose
Population: The PK set included all participants who received at least 1 dose of any study drug and had at least 1 PK blood collection after the first dose of study drug with associated bioanalytical results. Here 'Overall Number of Participants Analyzed' signifies number of participants evaluable for this outcome measure and 'Number Analyzed' signifies participants evaluable at specified time points. This outcome measure was planned to be analyzed in SLI phase only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D1 | 1.50 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | Binimetinib: C1D15 | 1.55 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D1 | 1.53 hours |
| Safety Lead-in Phase: Encorafenib 300 mg BID + Binimetinib 45 mg BID | Tmax of Binimetinib and Its Metabolite AR00426032: SLI Phase | AR00426032: C1D15 | 1.58 hours |