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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01543698




Registration number
NCT01543698
Ethics application status
Date submitted
1/02/2012
Date registered
5/03/2012
Date last updated
13/03/2024

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
Treatment: Drugs - LGX818
Treatment: Drugs - MEK162
Treatment: Drugs - LEE011

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.


Treatment: Drugs: LGX818


Treatment: Drugs: MEK162


Treatment: Drugs: LEE011
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b
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)
Timepoint [2] 0 0
Phase 2: Week 16
Primary outcome [3] 0 0
Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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/Phase 2
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
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01543698
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
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/ct2/show/NCT01543698