LGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off.

LGX818

MEK162

LEE011

Pfizer Pfizer CT.gov Call Center

This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.

A Phase Ib/II Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF Dependent Advanced Solid Tumors

A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors

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

DLT was defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the study medication, as clinically relevant, as unrelated to disease, disease progression, inter-current illness, or concomitant medications, which occurred (less than equal to) \<=28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011 (cycle 1) and met the defined criteria for the study.

DCR was defined as percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD). As per Response Evaluation Criteria in Solid tumors Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis less than (\<)10 millimeter \[mm\]). PR was defined as more than equal to (\>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD).

ORR was defined as the percentage of participants with a best overall response of CR or PR. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis \<10 mm. PR was defined as \>= 30% decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters.

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those events with onset dates occurring during the on-treatment period (the time from the Day 1 up to 30 days after last dose). AEs were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 indicates Mild AE, Grade 2 indicates Moderate AE, Grade 3 indicates severe AE, and grade 4 indicates life-threatening consequences; urgent intervention indicated. Grade 5 indicates death related to AE.

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those events with onset dates occurring during the on-treatment period (the time from the Day 1 up to 30 days after last dose). AEs were graded according to CTCAE version 4.03 as Grade 1 indicates Mild AE, Grade 2 indicates Moderate AE, Grade 3 indicates severe AE, and grade 4 indicates life-threatening consequences; urgent intervention indicated. Grade 5 indicates death related to AE.

AUCinf was reported in unit of measure as hour\*nanogram per millilitre (h\*ng/mL).

Accumulation ratio was calculated as AUCtau,ss/AUCtau.

ORR was defined as the percentage of participants with a best overall response of CR or PR. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis \<10 mm. PR was defined as \>= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters.

PFS was defined as the time from the start of study treatment to the date of the event defined as the first documented progression or death due to any cause. If a participant did not have an event, PFS was censored at the date of last adequate tumor assessment. Per RECIST 1.1, PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm\^2. Unequivocal progression of existing non-target lesions. Kaplan-Meier method was used for analysis.

TTR was defined as the time from the first dose of study treatment to the first documentation of objective tumor response documented in participants with confirmed objective response (CR or PR). As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis \<10 mm. PR was defined as \>= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. Kaplan-Meier method was used for analysis.

DOR was defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to underlying cancer, whichever occurred first in participants with confirmed objective response (CR or PR). As per RECIST v1.1, CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must have a reduction in short axis \<10 mm. PR was defined as \>= 30 % decrease under baseline of sum of diameters of all target lesions taking as reference the baseline sum of diameters. Kaplan-Meier method was used for analysis.

OS was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last contact. Analysis was performed using Kaplan-Meier method.

Molecular alterations of tumor tissues was determined using the following potential predictive markers: Biomarkers like V-raf murine sarcoma viral oncogene homolog B1 (BRAF),V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), Phosphatase and tensin homolog (PTEN), Phosphatidylinositol 3' kinase catalytic alphapolypeptide (PIK3CA), Epidermal growth factor receptor (EGFR).

Molecular alterations of tumor tissues was determined using the following potential predictive markers: BRAF, HRAS, KRAS, Neuroblastoma RAS viral oncogene homolog (NRAS), PTEN, PIK3CA, Mitogen-activated protein kinase 1 (MAP2K1), Mitogen-activated protein kinase 2 (MAP2K2), EGFR.

Pfizer

Same event may appear as both non-SAE and SAE, but what is presented are distinct events. An event may be categorized as serious in 1 participant and non-serious in other participant, or a participant may have experienced both SAE and non-SAE. Safety analysis set was evaluated.

Participants received Encorafenib 50 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 50 mg + Binimetinib 45 mg

Participants received Encorafenib 100 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 100 mg+ Binimetinib 45 mg

Participants received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 200 mg + Binimetinib 45 mg

Participants received Encorafenib 400 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 400 mg + Binimetinib 45 mg

Participants received Encorafenib 450 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 450 mg+ Binimetinib 45 mg

Participants received Encorafenib 600 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 600 mg + Binimetinib 45 mg

Participants received Encorafenib 800 mg QD and Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks.

Phase 1b: Encorafenib 800 mg + Binimetinib 45 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 100 mg QD orally for 3 weeks on, 1 week off schedule.

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg+ Ribociclib 100 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 200 mg QD orally for 3 weeks on, 1 week off schedule.

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg+ Ribociclib 200 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 400 mg QD orally for 3 weeks on, 1 week off schedule.

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg+ Ribociclib 400 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 600 mg QD orally for 3 weeks on, 1 week off schedule.

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg + Ribociclib 600 mg

Participants received Encorafenib at MTD (600 mg QD, permitted dose reduction to 450 mg QD) and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Phase 2: Arm 1 (mCRC): Encorafenib + Binimetinib

Participants received Encorafenib at MTD (600 mg QD, permitted dose reduction to 450 mg QD) and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks.

Phase 2: Arm 2 (Prior BRAFi Melanoma): Encorafenib + Binimetinib

Phase 2: Arm 3 (BRAFi-naïve Melanoma): Encorafenib + Binimetinib

Participants received Encorafenib 200 mg QD (MTD), Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 600 mg QD orally for 3 weeks on, 1 week off schedule.

Phase 2: Arm A (BRAFi-naïve Melanoma): Encorafenib + Binimetinib + Ribociclib

Total

Age, Categorical

Sex: Female, Male

Race

Race/Ethnicity, Customized

Ethnicity

Safety set included all participants who received at least one dose of Encorafenib or Binimetinib or Ribociclib and had at least one valid post-baseline safety assessment.

Pfizer ClinicalTrials.gov Call Center

Phase 1b: Encorafenib 100 mg + Binimetinib 45 mg

Phase 1b: Encorafenib 450 mg + Binimetinib 45 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 100 mg QD orally for 3 weeks on,1 week off schedule.

Phase 1b: Encorafenib 200 mg + Binimetinib 45 mg+ Ribociclib 100 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 200 mg QD orally for 3 weeks on,1 week off schedule.

Phase 1b: Encorafenib 200 mg + Binimetinib 45 mg + Ribociclib 200 mg

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 400 mg QD orally for 3 weeks on,1 week off schedule.

Participants received Encorafenib 200 mg QD, Binimetinib 45 mg BID orally on a schedule of continuous 4 weeks and Ribociclib 600 mg QD orally for 3 weeks on,1 week off schedule.

Phase 1b: Encorafenib 200 mg + Binimetinib 45 mg+ Ribociclib 600 mg

Dose Determining Set (DDS) included all Phase 1b participants from the safety set who either completed a minimum exposure requirement and had sufficient safety evaluations or discontinued prematurely due to a DLT. All participants reported under "Number of Participants Analyzed" contributed data to this outcome measure.

Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b

Full Analysis Set (FAS) included all participants who received at least one dose of LGX818 or MEK162 or LEE011.

Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Participants)

FAS included all participants who received at least one dose of LGX818 or MEK162 or LEE011.

Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A

Overall Grades

Grade 3/4

Phase 1b: Encorafenib 800 mg+ Binimetinib 45 mg

Phase 1b: Encorafenib 200 mg + Binimetinib 45 mg+ Ribociclib 400 mg

Safety set included all participants who received at least one dose of LGX818 or MEK162 or LEE011 and had at least one valid post-baseline safety assessment.

Number of Participants With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b

Number of Participants With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2

Encorafenib

Binimetinib

Ribociclib

Metabolite of Binimetinib

Metabolite of Ribociclib

Phase 1b: Encorafenib 50 mg+ Binimetinib 45 mg

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg

Phase 1b: Encorafenib 400 mg+ Binimetinib 45 mg

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg + Ribociclib 100 mg

Phase 1b: Encorafenib 200 mg + Binimetinib 45 mg+ Ribociclib 200 mg

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg+ Ribociclib 600 mg

FAS evaluated. All participants reported under "Number of Participants Analyzed" contributed data to the table; however, may not have evaluable data for every row. Here, "Number Analyzed" signifies number of participants evaluable for specified rows.

Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Phase 1b: Encorafenib 600 mg+ Binimetinib 45 mg

Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Phase 1b: Encorafenib 200 mg+ Binimetinib 45 mg + Ribociclib 400 mg

Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b

Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b

Objective Response Rate (ORR): Phase 1b

Progression Free Survival (PFS): Phase 2

FAS evaluated.Here "Number of Participants Analyzed" signifies the number of participants who were confirmed responders and were evaluable for this outcome measure.

Time to Response (TTR): Phase 2

Duration of Response (DOR): Phase 2

Overall Survival (OS): Phase 2

BRAF

KRAS

PTEN

PIK3CA

EGFR

Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b

HRAS

NRAS

MAP2K1

MAP2K2

ARAF

Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 2

Participants received Encorafenib 50 milligram (mg) once daily (QD) and Binimetinib 45 mg twice a daily (BID) orally 4 weeks till sponsor/investigator determined the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 100 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 400 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 450 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 600 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 800 mg QD and Binimetinib 45 mg BID orally for 4 weeks till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 100 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 200 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 400 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 200 mg QD and Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 600 mg BID orally for 3 weeks on, 1 week off schedule, till sponsor/investigator determined MTD and/or RP2D, until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Participants received Encorafenib 200 mg QD (MTD), Binimetinib 45 mg BID orally on a continuous schedule of 4 weeks, and Ribociclib 600 mg QD orally for 3 weeks on, 1 week off schedule until disease progression, unacceptable toxicity or withdrawal of informed consent, whichever occurred first.

Spots Global Cancer Trial Database for solid tumors harboring a braf v600 mutation