Colorectal Cancer
Conditions
Keywords
Open-label dose escalation, BRAF inhibitor, LGX818, PI3K inhibitor, BYL719, EGFR, cetuximab, metastatic colorectal cancer, KRAS, BRAF, V600
Brief summary
This study will assess the safety and efficacy of LGX818 when combined with cetuximab or combined with cetuximab and BYL719 in patients with BRAF mutant metastatic colorectal cancer
Interventions
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Metastatic colorectal cancer * Progression after at least one prior standard of care regimen or be intolerant to irinotecan-based regimens * Life expectancy ≥ 3 months * ECOG performance status ≤ 2
Exclusion criteria
* Symptomatic or untreated leptomeningeal disease * Symptomatic brain metastasis * Patients with clinically manifested diabetes * Acute or chronic pancreatitis * Clinically significant cardiac disease Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | Cycle 1: Day 1 to Day 28 | DLTs were defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first 28 days of treatment and meets any of the criteria included blood and lymphatic system disorders, investigations (blood, renal, hepatic, metabolic), skin and subcutaneous tissue disorders: rash, HFSR (hand foot skin reaction) and/or photosensitivity, metabolism and nutrition disorders: hyperglycemia, gastrointestinal disorders, cardiac disorders, vascular disorders, general disorders and administration site conditions, tumor lysis syndrome, ophthalmologic and other adverse events: study drug-related fever, alkaline phosphatase elevation. |
| Phase 2: Progression Free Survival (PFS) | From the date of randomization until the first documentation of disease progression or death due to any cause, censored date, whichever occurred first (maximum up to 43 months) | PFS was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. Participants who did not progress per RECIST (Response Evaluation Criteria in Solid Tumors) version (v) 1.1, were not known to have died prior to the data cut-off, or received any further anticancer therapy were censored at the date of last adequate tumor assessment or the anticancer therapy date, whichever was earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
| Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Volume of distribution at steady state is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F, ss) is influenced by the fraction absorbed. |
| Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. |
| Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F, ss) is influenced by the fraction absorbed. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Tmax was defined as the time to reach maximum observed plasma concentration of encorafenib. |
| Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Tmax, ss was defined as the time to reach maximum observed plasma concentration of LGX818 (encorafenib) at steady state. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Tmax was defined as the time to reach maximum observed plasma concentration of alpelisib. |
| Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Tmax, ss was defined as the time to reach maximum observed plasma concentration of BYL719 (alpelisib) at steady state. |
| Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | From screening up to 30 days after the last dose of study treatment (for a maximum duration of 43 months, approximately) | An AE was any untoward medical occurrence attributed to study drug in participants who received study drug. As per NCI-CTCAE v4.0, 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 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 study drug. Treatment-emergent AEs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of participants with any Grade 3 or 4 treatment-emergent AE were reported in this outcome measure. |
| Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | T-last, ss was defined as the time to reach last observed plasma concentration of encorafenib at steady state. |
| Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | T-last was defined as the time to reach last observed plasma concentration of alpelisib. |
| Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | T-last, ss was defined as the time to reach last observed plasma concentration of alpelisib at steady state. |
| Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Ctrough, ss was defined as plasma trough concentration of encorafenib at steady state. |
| Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Ctrough, ss was defined as plasma trough concentration of alpelisib at steady state. |
| Overall Survival (OS) | From the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first (up to 43 months) | OS was defined as the time (in months) from the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. |
| Overall Response Rate (ORR) | From date of randomization or date of start of treatment until date of first documentation of PD or death due to any cause (maximum up to 43 months) | Overall response rate as assessed by the investigator per RECIST v1.1, was defined as percentage of participants with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-nodal target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Only confirmed CR and PR are counted (those confirmed at least 4 weeks). |
| Duration of Response (DOR) | From the first documentation of OR (confirmed CR or PR) to first documentation of PD/death due to any cause or censoring date, whichever occurred first (up to 43 months) | DOR: Time between date of the first documented response (CR or PR) and the date of first documented PD or death due to underlying cancer. If PD or death due to underlying cancer not occurred, then participant was censored at the date of last tumor assessment other than unknown. DOR was calculated for responders (confirmed) only. CR: Disappearance of all target, non-target lesions sustained for \>=4 weeks and any pathological lymph nodes reduced in short axis to \<10mm. PR: \>=30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameter. PD for target lesions: At least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study treatment, with absolute increase of \>=5 mm, or appearance of \>=1 new lesions. PD for non-target lesions: Unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy or appearance of new unequivocal malignant lesion. |
| Time to Response (TTR) | From the date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first (maximum up to 43 months) | TTR as assessed by investigator according to RECIST v1.1, was defined as the time (in months) from date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. |
| Phase 1b: Progression Free Survival (PFS) | From date of start of treatment to the date of event defined as the first documented progression or death due to any cause, censored date, whichever occurred first (maximum up to 43 months) | PFS was defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. Participants who did not progress per RECIST v1.1, were not known to have died prior to the data cut-off, or received any further anticancer therapy were censored at the date of last adequate tumor assessment or the anticancer therapy date, whichever was earlier. |
| Phase 2: Number of Participants With Any Variant in Gene Status at Baseline | Baseline (Day 1) | Gene alterations/expression relevant to the RAF/MEK/ERK (proto-oncogene serine/threonine-protein kinase/ mitogen-activated ERK kinase/ extracellular signal-regulated kinases) and EGFR/PI3K/AKT (epidermal growth factor receptor/ phosphatidylinositol 3-kinase/ protein kinase B) pathways in tumor tissue, baseline molecular status (mutation/amplification/expression) in tumor tissue of potential predictive markers of tumor response or resistance i.e. BRAF (v-raf murine sarcoma viral oncogene homolog B1), HRAS (harvey rat sarcoma protein), KRAS (V-Ki-ras2 kirsten rat sarcoma viral oncogene homolog B1), NRAS (neuroblastoma RAS viral oncogene homolog), PTEN (phosphatase and tensin homolog), PIK3CA (phosphatidylinositol 3-kinase gene), MAP2K1 (mitogen-activated protein kinase 1), MAP2K2 (mitogen-activated protein kinase 2), ARAF, c-MET, RAF1, EGFR was analyzed. |
| Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | T-last was defined as the time to reach last observed plasma concentration of encorafenib. |
| Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
Countries
Australia, Belgium, Canada, France, Germany, Italy, Japan, Netherlands, Norway, South Korea, Spain, United States
Participant flow
Pre-assignment details
This study was conducted in two phases Phase 1b and Phase 2. Phase 1b of the study was dose escalation phase to determine maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of LGX818 in combination with cetuximab (dual combination) and of LGX818 in combination with BYL719 and cetuximab (triple combination). Phase 2 of the study was to determine the clinical efficacy and safety of dual and triple combination in study participants.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab Participants received 100 mg of LGX818 (encorafenib) orally once daily along with cetuximab orally once weekly in each cycle of 28 days continuously, until disease progression (PD), unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 2 |
| Phase 1b: LGX818 200 mg + Cetuximab Participants received 200 mg of LGX818 orally once daily along with cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 7 |
| Phase 1b: LGX818 400 mg + Cetuximab Participants received 400 mg of LGX818 orally once daily along with cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 9 |
| Phase 1b: LGX818 450 mg + Cetuximab Participants received 450 mg of LGX818 orally once daily along with cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 8 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab Participants received 200 mg of LGX818 along with 100 mg of BYL719 (alpelisib) orally once daily and cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 3 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab Participants received 200 mg of LGX818 along with 200 mg of BYL719 orally once daily and cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 8 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab Participants received 200 mg of LGX818 along with 300 mg of BYL719 orally once daily and cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 10 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab Participants received 300 mg of LGX818 along with 200 mg of BYL719 orally once daily and cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 7 |
| Phase 2: LGX818 200 mg + Cetuximab Participants received 200 mg of LGX818 orally once daily along with cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 50 |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab Participants received 200 mg of LGX818 along with 300 mg of BYL719 orally once daily and cetuximab orally once weekly in each cycle of 28 days continuously, until PD, unacceptable toxicity, withdrawal of informed consent or death, whichever occurred first. Participants were followed up to 30 days after last dose of study treatment (up to a maximum duration of 43 months). | 52 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 2 | 0 | 1 | 0 | 1 | 4 | 3 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 3 |
| Overall Study | Lack of Efficacy | 2 | 6 | 5 | 6 | 3 | 7 | 10 | 6 | 39 | 42 |
| Overall Study | Participant/Guardian Decision | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 1b: LGX818 100 mg + Cetuximab | Phase 1b: LGX818 200 mg + Cetuximab | Phase 1b: LGX818 400 mg + Cetuximab | Phase 1b: LGX818 450 mg + Cetuximab | Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Phase 2: LGX818 200 mg + Cetuximab | Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized <65 years | 1 Participants | 4 Participants | 7 Participants | 5 Participants | 2 Participants | 4 Participants | 8 Participants | 6 Participants | 32 Participants | 38 Participants | 107 Participants |
| Age, Customized >=65 years | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 18 Participants | 14 Participants | 49 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 6 Participants | 4 Participants | 1 Participants | 5 Participants | 7 Participants | 5 Participants | 36 Participants | 27 Participants | 96 Participants |
| Sex: Female, Male Male | 0 Participants | 4 Participants | 3 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 14 Participants | 25 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 7 / 7 | 9 / 9 | 8 / 8 | 3 / 3 | 8 / 8 | 10 / 10 | 7 / 7 | 50 / 50 | 52 / 52 |
| serious Total, serious adverse events | 2 / 2 | 5 / 7 | 6 / 9 | 6 / 8 | 2 / 3 | 5 / 8 | 6 / 10 | 4 / 7 | 25 / 50 | 33 / 52 |
Outcome results
Primary
Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1
DLTs were defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first 28 days of treatment and meets any of the criteria included blood and lymphatic system disorders, investigations (blood, renal, hepatic, metabolic), skin and subcutaneous tissue disorders: rash, HFSR (hand foot skin reaction) and/or photosensitivity, metabolism and nutrition disorders: hyperglycemia, gastrointestinal disorders, cardiac disorders, vascular disorders, general disorders and administration site conditions, tumor lysis syndrome, ophthalmologic and other adverse events: study drug-related fever, alkaline phosphatase elevation.
Time frame: Cycle 1: Day 1 to Day 28
Population: The dose-determining set consisted of all participants from the phase 1b safety set who either met the following minimum exposure criterion and had scheduled safety evaluations or discontinued earlier due to DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 0 Participants |
| Phase 1b: LGX818 200 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 1 Participants |
| Phase 1b: LGX818 400 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 1 Participants |
| Phase 1b: LGX818 450 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 1 Participants |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 0 Participants |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 0 Participants |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 1 Participants |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Phase 1b: Number of Participants With Incidence of Dose Limiting Toxicities (DLTs): Cycle 1 | 1 Participants |
Primary
Phase 2: Progression Free Survival (PFS)
PFS was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. Participants who did not progress per RECIST (Response Evaluation Criteria in Solid Tumors) version (v) 1.1, were not known to have died prior to the data cut-off, or received any further anticancer therapy were censored at the date of last adequate tumor assessment or the anticancer therapy date, whichever was earlier.
Time frame: From the date of randomization until the first documentation of disease progression or death due to any cause, censored date, whichever occurred first (maximum up to 43 months)
Population: The full analysis set 2 (FAS2) comprised of all participants to whom study treatment was assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Phase 2: Progression Free Survival (PFS) | 4.2 months |
| Phase 1b: LGX818 200 mg + Cetuximab | Phase 2: Progression Free Survival (PFS) | 4.9 months |
Secondary
Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib)
Volume of distribution at steady state was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F, ss) is influenced by the fraction absorbed.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 138 liter | Standard Deviation 20.7 |
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 110 liter | Standard Deviation 40.7 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 97.0 liter | Standard Deviation 20.6 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 75.4 liter | Standard Deviation 11.2 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 105 liter | Standard Deviation 30.2 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 104 liter | Standard Deviation 10.7 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 144 liter | Standard Deviation 44.5 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 82.5 liter | Standard Deviation 18.8 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 149 liter | Standard Deviation 100 |
Secondary
Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib)
Volume of distribution at steady state is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F, ss) is influenced by the fraction absorbed.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 66.8 liter | Standard Deviation 13.7 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 131 liter | Standard Deviation 45.8 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 110 liter | Standard Deviation 41.1 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 142 liter | Standard Deviation 84.5 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 78.4 liter | Standard Deviation 13 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 137 liter | Standard Deviation 32.9 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 98.2 liter | Standard Deviation 84.5 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 91.6 liter | Standard Deviation 41.4 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 78.6 liter | Standard Deviation 26.2 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 102 liter | Standard Deviation 39.9 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 88.8 liter | Standard Deviation 53.6 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 187 liter | Standard Deviation 89.5 |
| Phase 2: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 117 liter | Standard Deviation 37.6 |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Terminal Volume of Distribution at Steady State (Vz/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 105 liter | Standard Deviation 42.2 |
Secondary
Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib)
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | 112 liter | Standard Deviation 22 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | 104 liter | Standard Deviation 31 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | 105 liter | Standard Deviation 34.3 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | 106 liter | Standard Deviation 78.6 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of BYL719 (Alpelisib) | 123 liter | Standard Deviation 50.7 |
Secondary
Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 104 liter | Standard Deviation 28.3 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 60.3 liter | Standard Deviation 25.8 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 62.8 liter | Standard Deviation 31.8 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 57.2 liter | Standard Deviation 29.6 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 49.2 liter | Standard Deviation 12.4 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 75.7 liter | Standard Deviation 31.6 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 64.6 liter | Standard Deviation 20.6 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 60.7 liter | Standard Deviation 44 |
| Phase 2: LGX818 200 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 63.5 liter | Standard Deviation 29.9 |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Terminal Volume of Distribution (Vz/F) of LGX818 (Encorafenib) | 80.9 liter | Standard Deviation 93.9 |
Secondary
Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib)
Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 16.5 liter per hour | Standard Deviation 5.96 |
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 18.3 liter per hour | Standard Deviation 0.794 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 10.3 liter per hour | Standard Deviation 1.23 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 13.2 liter per hour | Standard Deviation 2.29 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 13.7 liter per hour | Standard Deviation 7.2 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 12.5 liter per hour | Standard Deviation 1.6 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 19.0 liter per hour | Standard Deviation 6.51 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 11.6 liter per hour | Standard Deviation 6.05 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 17.9 liter per hour | Standard Deviation 10.5 |
Secondary
Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib)
Clearance of a drug at steady state is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least one blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 13.9 liter per hour | Standard Deviation 4.72 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 31.1 liter per hour | Standard Deviation 11.9 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 31.6 liter per hour | Standard Deviation 2.19 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 30.5 liter per hour | Standard Deviation 12.3 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 17.0 liter per hour | Standard Deviation 3.42 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 32.6 liter per hour | Standard Deviation 6.88 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 20.2 liter per hour | Standard Deviation 7.91 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 24.4 liter per hour | Standard Deviation 18.3 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 15.4 liter per hour | Standard Deviation 4.25 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 22.7 liter per hour | Standard Deviation 5.68 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 22.4 liter per hour | Standard Deviation 17.7 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 38.4 liter per hour | Standard Deviation 16.4 |
| Phase 2: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 28.2 liter per hour | Standard Deviation 8.97 |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Total Plasma Clearance at Steady State (CL/F, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.3 liter per hour | Standard Deviation 11.6 |
Secondary
Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib)
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | 12.7 liter per hour | Standard Deviation 2.03 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | 12.1 liter per hour | Standard Deviation 3.96 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | 11.6 liter per hour | Standard Deviation 1.85 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | 11.7 liter per hour | Standard Deviation 5.38 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of BYL719 (Alpelisib) | 15.6 liter per hour | Standard Deviation 9.61 |
Secondary
Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib)
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least one blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 16.8 liter per hour | Standard Deviation 3.6 |
| Phase 1b: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 11.7 liter per hour | Standard Deviation 6.1 |
| Phase 1b: LGX818 400 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 12.1 liter per hour | Standard Deviation 5.95 |
| Phase 1b: LGX818 450 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 12.3 liter per hour | Standard Deviation 4.96 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 7.69 liter per hour | Standard Deviation 3.13 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 14.2 liter per hour | Standard Deviation 5.75 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 14.1 liter per hour | Standard Deviation 3.65 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 17.8 liter per hour | Standard Deviation 17.4 |
| Phase 2: LGX818 200 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 13.1 liter per hour | Standard Deviation 5.07 |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Apparent Total Plasma Clearance (CL/F) of LGX818 (Encorafenib) | 10.9 liter per hour | Standard Deviation 5.7 |
Secondary
Duration of Response (DOR)
DOR: Time between date of the first documented response (CR or PR) and the date of first documented PD or death due to underlying cancer. If PD or death due to underlying cancer not occurred, then participant was censored at the date of last tumor assessment other than unknown. DOR was calculated for responders (confirmed) only. CR: Disappearance of all target, non-target lesions sustained for \>=4 weeks and any pathological lymph nodes reduced in short axis to \<10mm. PR: \>=30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameter. PD for target lesions: At least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study treatment, with absolute increase of \>=5 mm, or appearance of \>=1 new lesions. PD for non-target lesions: Unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy or appearance of new unequivocal malignant lesion.
Time frame: From the first documentation of OR (confirmed CR or PR) to first documentation of PD/death due to any cause or censoring date, whichever occurred first (up to 43 months)
Population: The FAS 1 comprised all participants who received at least 1 full or partial dose of their assigned combination of study drugs during Phase 1b. The FAS2 comprised all randomized participants in Phase 2. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Duration of Response (DOR) | 10.6 months |
| Phase 1b: LGX818 200 mg + Cetuximab | Duration of Response (DOR) | 2.3 months |
| Phase 1b: LGX818 400 mg + Cetuximab | Duration of Response (DOR) | 21.7 months |
| Phase 1b: LGX818 450 mg + Cetuximab | Duration of Response (DOR) | 8.1 months |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Duration of Response (DOR) | 3.9 months |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Duration of Response (DOR) | 3.6 months |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Duration of Response (DOR) | 3.3 months |
| Phase 2: LGX818 200 mg + Cetuximab | Duration of Response (DOR) | 5.6 months |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Duration of Response (DOR) | 5.3 months |
Secondary
Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0
An AE was any untoward medical occurrence attributed to study drug in participants who received study drug. As per NCI-CTCAE v4.0, 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 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 study drug. Treatment-emergent AEs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of participants with any Grade 3 or 4 treatment-emergent AE were reported in this outcome measure.
Time frame: From screening up to 30 days after the last dose of study treatment (for a maximum duration of 43 months, approximately)
Population: The safety set included all participants from the full analysis set who received at least 1 dose of LGX818 (encorafenib), BYL719 (alpelisib) or cetuximab and had at least 1 valid post baseline safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 2 Participants |
| Phase 1b: LGX818 200 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 4 Participants |
| Phase 1b: LGX818 400 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 6 Participants |
| Phase 1b: LGX818 450 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 7 Participants |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 3 Participants |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 5 Participants |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 7 Participants |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 6 Participants |
| Phase 2: LGX818 200 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 33 Participants |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Number of Participants With Treatment - Emergent Adverse Events of Grade 3 or 4 Severity Based on National Cancer Institute of Common Terminology Criteria (NCI-CTCAE), Version 4.0 | 43 Participants |
Secondary
Overall Response Rate (ORR)
Overall response rate as assessed by the investigator per RECIST v1.1, was defined as percentage of participants with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-nodal target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Only confirmed CR and PR are counted (those confirmed at least 4 weeks).
Time frame: From date of randomization or date of start of treatment until date of first documentation of PD or death due to any cause (maximum up to 43 months)
Population: The FAS 1 comprised all participants who received at least 1 full or partial dose of their assigned combination of study drugs during Phase 1b. The FAS2 comprised all randomized participants in Phase 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Overall Response Rate (ORR) | 50.0 percentage of participants |
| Phase 1b: LGX818 200 mg + Cetuximab | Overall Response Rate (ORR) | 14.3 percentage of participants |
| Phase 1b: LGX818 400 mg + Cetuximab | Overall Response Rate (ORR) | 11.1 percentage of participants |
| Phase 1b: LGX818 450 mg + Cetuximab | Overall Response Rate (ORR) | 25.0 percentage of participants |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Overall Response Rate (ORR) | 33.3 percentage of participants |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Overall Response Rate (ORR) | 25.0 percentage of participants |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Overall Response Rate (ORR) | 20.0 percentage of participants |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Overall Response Rate (ORR) | 0 percentage of participants |
| Phase 2: LGX818 200 mg + Cetuximab | Overall Response Rate (ORR) | 24.0 percentage of participants |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Overall Response Rate (ORR) | 26.9 percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time (in months) from the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Time frame: From the date of randomization or date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first (up to 43 months)
Population: The FAS1 comprised all participants who received at least 1 full or partial dose of their assigned combination of study drugs during Phase 1b. The FAS2 comprised all randomized participants in Phase 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Overall Survival (OS) | 15.0 months |
| Phase 1b: LGX818 200 mg + Cetuximab | Overall Survival (OS) | 5.4 months |
| Phase 1b: LGX818 400 mg + Cetuximab | Overall Survival (OS) | NA months |
| Phase 1b: LGX818 450 mg + Cetuximab | Overall Survival (OS) | 16.6 months |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Overall Survival (OS) | 6.6 months |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Overall Survival (OS) | 8.7 months |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Overall Survival (OS) | 9.8 months |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Overall Survival (OS) | NA months |
| Phase 2: LGX818 200 mg + Cetuximab | Overall Survival (OS) | 9.3 months |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Overall Survival (OS) | 8.5 months |
Secondary
Phase 1b: Progression Free Survival (PFS)
PFS was defined as the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. Participants who did not progress per RECIST v1.1, were not known to have died prior to the data cut-off, or received any further anticancer therapy were censored at the date of last adequate tumor assessment or the anticancer therapy date, whichever was earlier.
Time frame: From date of start of treatment to the date of event defined as the first documented progression or death due to any cause, censored date, whichever occurred first (maximum up to 43 months)
Population: The FAS 1 comprised all participants who received at least 1 full or partial dose of their assigned combination of study drugs during Phase 1b.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 12.0 months |
| Phase 1b: LGX818 200 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 3.7 months |
| Phase 1b: LGX818 400 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 2.8 months |
| Phase 1b: LGX818 450 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 12.0 months |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 5.4 months |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 4.3 months |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 4.1 months |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Phase 1b: Progression Free Survival (PFS) | 4.2 months |
Secondary
Phase 2: Number of Participants With Any Variant in Gene Status at Baseline
Gene alterations/expression relevant to the RAF/MEK/ERK (proto-oncogene serine/threonine-protein kinase/ mitogen-activated ERK kinase/ extracellular signal-regulated kinases) and EGFR/PI3K/AKT (epidermal growth factor receptor/ phosphatidylinositol 3-kinase/ protein kinase B) pathways in tumor tissue, baseline molecular status (mutation/amplification/expression) in tumor tissue of potential predictive markers of tumor response or resistance i.e. BRAF (v-raf murine sarcoma viral oncogene homolog B1), HRAS (harvey rat sarcoma protein), KRAS (V-Ki-ras2 kirsten rat sarcoma viral oncogene homolog B1), NRAS (neuroblastoma RAS viral oncogene homolog), PTEN (phosphatase and tensin homolog), PIK3CA (phosphatidylinositol 3-kinase gene), MAP2K1 (mitogen-activated protein kinase 1), MAP2K2 (mitogen-activated protein kinase 2), ARAF, c-MET, RAF1, EGFR was analyzed.
Time frame: Baseline (Day 1)
Population: The FAS2 comprised all randomized participants in Phase 2.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Phase 2: Number of Participants With Any Variant in Gene Status at Baseline | 30 Participants |
| Phase 1b: LGX818 200 mg + Cetuximab | Phase 2: Number of Participants With Any Variant in Gene Status at Baseline | 34 Participants |
Secondary
Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib)
Ctrough, ss was defined as plasma trough concentration of alpelisib at steady state.
Time frame: Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | 36.7 nanogram per milliliter | Standard Deviation 21 |
| Phase 1b: LGX818 200 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | 108 nanogram per milliliter | Standard Deviation 41.1 |
| Phase 1b: LGX818 400 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | 283 nanogram per milliliter | Standard Deviation 156 |
| Phase 1b: LGX818 450 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | 66.0 nanogram per milliliter | — |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of BYL719 (Alpelisib) | 141 nanogram per milliliter | Standard Deviation 76.5 |
Secondary
Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib)
Ctrough, ss was defined as plasma trough concentration of encorafenib at steady state.
Time frame: Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 9.87 nanogram per milliliter | Standard Deviation 6.69 |
| Phase 1b: LGX818 200 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 20.5 nanogram per milliliter | Standard Deviation 28 |
| Phase 1b: LGX818 400 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 15.7 nanogram per milliliter | Standard Deviation 22 |
| Phase 1b: LGX818 450 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 20.6 nanogram per milliliter | Standard Deviation 18.4 |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 7.69 nanogram per milliliter | Standard Deviation 1.76 |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 10.4 nanogram per milliliter | Standard Deviation 5.05 |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 26.5 nanogram per milliliter | Standard Deviation 31.4 |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 29.2 nanogram per milliliter | — |
| Phase 2: LGX818 200 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 9.24 nanogram per milliliter | Standard Deviation 5.19 |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Plasma Trough Concentration at Steady State (Ctrough, ss) of LGX818 (Encorafenib) | 15.0 nanogram per milliliter | Standard Deviation 17.8 |
Secondary
Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib)
T-last, ss was defined as the time to reach last observed plasma concentration of alpelisib at steady state.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 23.78 hour |
| Phase 1b: LGX818 100 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 23.97 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 23.08 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 23.36 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 23.87 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 23.94 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 23.47 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 23.87 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 23.77 hour |
Secondary
Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib)
T-last, ss was defined as the time to reach last observed plasma concentration of encorafenib at steady state.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.89 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 22.13 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 14.05 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.45 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 23.78 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.97 hour |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.08 hour |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 23.36 hour |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 23.92 hour |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.94 hour |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 23.87 hour |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.42 hour |
| Phase 2: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.80 hour |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time of Last Observed Plasma Concentration at Steady State (T-last, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 23.42 hour |
Secondary
Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib)
T-last was defined as the time to reach last observed plasma concentration of alpelisib.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | 23.00 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | 23.06 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | 22.76 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | 23.87 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of BYL719 (Alpelisib) | 23.17 hour |
Secondary
Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib)
T-last was defined as the time to reach last observed plasma concentration of encorafenib.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.98 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.69 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 24.03 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.58 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.00 hour |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.06 hour |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 22.02 hour |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.87 hour |
| Phase 2: LGX818 200 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.85 hour |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time of Last Observed Plasma Concentration (T-last) of LGX818 (Encorafenib) | 23.50 hour |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib)
Tmax was defined as the time to reach maximum observed plasma concentration of alpelisib.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | 1.98 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | 3.97 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | 2.00 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | 2.10 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of BYL719 (Alpelisib) | 2.05 hour |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib)
Tmax was defined as the time to reach maximum observed plasma concentration of encorafenib.
Time frame: Cycle 1 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.00 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 1.99 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.03 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.17 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 1.00 hour |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.02 hour |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.00 hour |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 3.87 hour |
| Phase 2: LGX818 200 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.00 hour |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Reach Maximum Observed Plasma Concentration (Tmax) of LGX818 (Encorafenib) | 2.03 hour |
Secondary
Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib)
Tmax, ss was defined as the time to reach maximum observed plasma concentration of BYL719 (alpelisib) at steady state.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 1.97 hour |
| Phase 1b: LGX818 100 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 2.02 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 4.00 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 3.99 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 2.15 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 3.93 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 4.03 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 1 Day 8 | 4.07 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of BYL719 (Alpelisib) | Cycle 2 Day 1 | 2.02 hour |
Secondary
Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib)
Tmax, ss was defined as the time to reach maximum observed plasma concentration of LGX818 (encorafenib) at steady state.
Time frame: Cycle 1 Day 8, Cycle 2 Day 1: Pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 +/- 2 hours post-dose
Population: The PK analysis set consisted of all participants who had at least 1 blood sample providing evaluable PK data, received at least 1 dose of study drug, and experienced no major protocol deviations with relevant impact on the PK data. Here 'number analyzed' signifies number of participants evaluable for each specified category and 'Overall Number of Participants Analyzed' signifies number of participants with at least one PK sample analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 1.51 hour |
| Phase 1b: LGX818 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 2.00 hour |
| Phase 1b: LGX818 400 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 1.98 hour |
| Phase 1b: LGX818 450 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 1.98 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 0.98 hour |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 2.00 hour |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 2.02 hour |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 1.98 hour |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 2.00 hour |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 3.00 hour |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 1 Day 8 | 3.92 hour |
| Phase 1b: LGX818 300 mg + BYL719 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 2.27 hour |
| Phase 2: LGX818 200 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 1.15 hour |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Reach Maximum Plasma Concentration at Steady State (Tmax, ss) of LGX818 (Encorafenib) | Cycle 2 Day 1 | 2.00 hour |
Secondary
Time to Response (TTR)
TTR as assessed by investigator according to RECIST v1.1, was defined as the time (in months) from date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first. CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to \<10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival.
Time frame: From the date of randomization or date of start of treatment until first documented response (CR or PR) or data censoring date, whichever occurred first (maximum up to 43 months)
Population: The FAS 1 comprised all participants who received at least 1 full or partial dose of their assigned combination of study drugs during Phase 1b. The FAS2 comprised all randomized participants in Phase 2. Here 'Overall Number of Participants Analyzed' signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: LGX818 100 mg + Cetuximab | Time to Response (TTR) | 2.8 months |
| Phase 1b: LGX818 200 mg + Cetuximab | Time to Response (TTR) | 1.4 months |
| Phase 1b: LGX818 400 mg + Cetuximab | Time to Response (TTR) | 3.9 months |
| Phase 1b: LGX818 450 mg + Cetuximab | Time to Response (TTR) | 4.0 months |
| Phase 1b: LGX818 200 mg + BYL719 100 mg + Cetuximab | Time to Response (TTR) | 1.5 months |
| Phase 1b: LGX818 200 mg + BYL719 200 mg + Cetuximab | Time to Response (TTR) | 3.5 months |
| Phase 1b: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Response (TTR) | 2.0 months |
| Phase 2: LGX818 200 mg + Cetuximab | Time to Response (TTR) | 1.7 months |
| Phase 2: LGX818 200 mg + BYL719 300 mg + Cetuximab | Time to Response (TTR) | 1.5 months |