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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01543698




Registration number
NCT01543698
Ethics application status
Date submitted
1/02/2012
Date registered
5/03/2012

Titles & IDs
Public title
A Phase Ib/II Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF Dependent Advanced Solid Tumors
Scientific title
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
Secondary ID [1] 0 0
C4221005
Secondary ID [2] 0 0
CMEK162X2110
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumors Harboring a BRAF V600 Mutation 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Experimental: dual combination - LGX818 QD and MEK162 BID

Experimental: triple combination - LGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off.
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Phase 1b: Cycle 1 (28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011)
Primary outcome [2] 0 0
Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Participants)
Assessment method [2] 0 0
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).
Timepoint [2] 0 0
Phase 2: Week 16
Primary outcome [3] 0 0
Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A
Assessment method [3] 0 0
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.
Timepoint [3] 0 0
Phase 2: From Day 1 of dosing till complete response or partial response achieved (maximum exposure of treatment for Phase 2 was 111.5 months]
Secondary outcome [1] 0 0
Number of Participants With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Phase 1b: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 1b was 118.3 months)
Secondary outcome [2] 0 0
Number of Participants With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
Phase 2: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 2 was 111.5 months)
Secondary outcome [3] 0 0
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
Assessment method [3] 0 0
AUCinf was reported in unit of measure as hour\*nanogram per millilitre (h\*ng/mL).
Timepoint [3] 0 0
Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hours (hr) post dose on Day 1 of Cycle 1
Secondary outcome [4] 0 0
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
Assessment method [4] 0 0
Timepoint [4] 0 0
Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
Secondary outcome [5] 0 0
AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [5] 0 0
Timepoint [5] 0 0
Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
Secondary outcome [6] 0 0
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
Assessment method [6] 0 0
Timepoint [6] 0 0
Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
Secondary outcome [7] 0 0
AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [7] 0 0
Timepoint [7] 0 0
Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
Secondary outcome [8] 0 0
Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [8] 0 0
Timepoint [8] 0 0
Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
Secondary outcome [9] 0 0
Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [9] 0 0
Timepoint [9] 0 0
Phase 1b: Pre dose,0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
Secondary outcome [10] 0 0
Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [10] 0 0
Timepoint [10] 0 0
Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
Secondary outcome [11] 0 0
t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [11] 0 0
Timepoint [11] 0 0
Phase 1b: Pre dose,0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
Secondary outcome [12] 0 0
Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b
Assessment method [12] 0 0
Accumulation ratio was calculated as AUCtau,ss/AUCtau.
Timepoint [12] 0 0
Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 and 15 of Cycle 1
Secondary outcome [13] 0 0
Objective Response Rate (ORR): Phase 1b
Assessment method [13] 0 0
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.
Timepoint [13] 0 0
Phase 1b: From Day 1 of dosing till complete response or partial response achieved (maximum exposure of treatment in Phase 1b was 118.3 months)
Secondary outcome [14] 0 0
Progression Free Survival (PFS): Phase 2
Assessment method [14] 0 0
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.
Timepoint [14] 0 0
Phase 2: From start of study drug until documented PD or death due to any cause or censoring date (maximum exposure of treatment in Phase 2 was 111.5 months)
Secondary outcome [15] 0 0
Time to Response (TTR): Phase 2
Assessment method [15] 0 0
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.
Timepoint [15] 0 0
Phase 2: From date of start of treatment until date of first documentation of objective tumor response (maximum exposure of treatment in Phase 2 was 111.5 months)
Secondary outcome [16] 0 0
Duration of Response (DOR): Phase 2
Assessment method [16] 0 0
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.
Timepoint [16] 0 0
Phase 2: From date of first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to underlying cancer, whichever occurred first (maximum exposure of treatment in Phase 2 was 111.5 months)
Secondary outcome [17] 0 0
Overall Survival (OS): Phase 2
Assessment method [17] 0 0
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.
Timepoint [17] 0 0
Phase 2: From date of start of study treatment until date of death or censoring date (maximum exposure of treatment in Phase 2 was 111.5 months)
Secondary outcome [18] 0 0
Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b
Assessment method [18] 0 0
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).
Timepoint [18] 0 0
Phase 1b: Baseline
Secondary outcome [19] 0 0
Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 2
Assessment method [19] 0 0
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.
Timepoint [19] 0 0
Phase 2: Baseline

Eligibility
Key inclusion criteria
Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available

* Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation
* Evidence of measurable disease as determined by RECIST v1.1
* World Health Organization (WHO) Performance Status = 2
* Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors

* Symptomatic or untreated leptomeningeal disease
* Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing anti-epileptic drugs
* Known acute or chronic pancreatitis
* History or current evidence of retinal disease, retinal vein occlusion or ophthalmopathy
* Clinically significant cardiac disease
* Patients with abnormal laboratory values at Screening/baseline
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/MEK162
* Previous or concurrent malignancy
* Pregnant or nursing (lactating) women
* For addition of LEE011 in the triple combination, congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade = 3, brain metastases at baseline, abnormal coagulation results PT/INR >1.5 x ULN or aPTT >1.5 x ULN.

Other protocol-defined inclusion/exclusion criteria may apply

Study design
Purpose of the study
Other
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/05/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
9/03/2023
Sample size
Target
Accrual to date
Final
189
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Chris O'Brien Lifehouse Hospital - Camperdown
Recruitment hospital [2] 0 0
Melanoma Institute Australia - North Sydney
Recruitment hospital [3] 0 0
Westmead Hospital-Redbank Rd - Northmead
Recruitment hospital [4] 0 0
Westmead Hospital-Redbank Rd - Westmead
Recruitment hospital [5] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
02050 - Camperdown
Recruitment postcode(s) [2] 0 0
2060 - North Sydney
Recruitment postcode(s) [3] 0 0
2152 - Northmead
Recruitment postcode(s) [4] 0 0
2145 - Westmead
Recruitment postcode(s) [5] 0 0
2065 - North Sydney
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Florida
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
Texas
Country [5] 0 0
Belgium
State/province [5] 0 0
Vlaams Brabant
Country [6] 0 0
Canada
State/province [6] 0 0
Quebec
Country [7] 0 0
France
State/province [7] 0 0
Paris
Country [8] 0 0
Italy
State/province [8] 0 0
Campania
Country [9] 0 0
Italy
State/province [9] 0 0
Milan
Country [10] 0 0
Italy
State/province [10] 0 0
Napoli
Country [11] 0 0
Singapore
State/province [11] 0 0
Singapore
Country [12] 0 0
Spain
State/province [12] 0 0
Barcelona
Country [13] 0 0
Spain
State/province [13] 0 0
Madrid
Country [14] 0 0
Switzerland
State/province [14] 0 0
Zurich
Country [15] 0 0
Switzerland
State/province [15] 0 0
St.Gallen

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Pfizer
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Pfizer Pfizer CT.gov Call Center
Address 0 0
Pfizer
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT01543698