Clinical trial NCT01543698: A Phase Ib/II Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF Dependent Advanced Solid Tumors
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Solid Tumors Harboring a BRAF V600 Mutation
Keywords: Advanced solid tumor,
BRAF V600 mutation
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2012-03-05
Enrollment: 189
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: 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

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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b
timeFrame: Phase 1b: Cycle 1 (28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011)
measure: Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Participants)
timeFrame: Phase 2: Week 16
measure: Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A
timeFrame: 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 outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b
timeFrame: Phase 1b: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 1b was 118.3 months)
measure: Number of Participants With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2
timeFrame: Phase 2: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 2 was 111.5 months)
measure: 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
timeFrame: 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
measure: 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
timeFrame: Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
measure: AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
measure: 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
timeFrame: Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
measure: AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
measure: Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
measure: Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: Phase 1b: Pre dose,0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
measure: Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1
measure: t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: Phase 1b: Pre dose,0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1
measure: Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b
timeFrame: 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
measure: Objective Response Rate (ORR): Phase 1b
timeFrame: 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)
measure: Progression Free Survival (PFS): Phase 2
timeFrame: 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)
measure: Time to Response (TTR): Phase 2
timeFrame: 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)
measure: Duration of Response (DOR): Phase 2
timeFrame: 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)
measure: Overall Survival (OS): Phase 2
timeFrame: 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)
measure: Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b
timeFrame: Phase 1b: Baseline
measure: Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 2
timeFrame: Phase 2: Baseline
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute, Inc.
state: Florida
city: Tampa
country: United States
facility: Moffitt McKinley Outpatient Center
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Ophthalmic Consultants of Boston Inc (OCB)
state: Massachusetts
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse Hospital
state: New South Wales
city: North Sydney
country: Australia
facility: Melanoma Institute Australia
state: New South Wales
city: Northmead
country: Australia
facility: Westmead Hospital-Redbank Rd
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital-Redbank Rd
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: North Sydney
country: Australia
facility: Melanoma Institute Australia
city: Leuven
country: Belgium
facility: UZ Leuven- Gasthuisberg Campus
state: Vlaams Brabant
city: Montreal
country: Canada
facility: Sir Mortimer B. Davis-Jewish General Hospital
state: Quebec
city: Paris
country: France
facility: Hôpital Saint louis
city: Paris
country: France
facility: Service de radiologie - Hopital Saint Louis
city: Naples
country: Italy
facility: IRCCS Fondazione Pascale
state: Campania
city: Napoli
country: Italy
facility: Azienda Ospedaliera Monaldi
state: Campania
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
state: Campania
city: Milan
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda
city: Napoli
country: Italy
facility: Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón - PPDS
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro ? CIOCC
city: Zurich-Airport
country: Switzerland
facility: University Hospital Zürich, Dermatology
state: Zurich
city: St.Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
Study officials:
affiliation: Pfizer
name: Pfizer Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Sullivan RJ, Weber J, Patel S, Dummer R, Carlino MS, Tan DSW, Lebbe C, Siena S, Elez E, Wollenberg L, Pickard MD, Sandor V, Ascierto PA. A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. Clin Cancer Res. 2020 Oct 1;26(19):5102-5112. doi: 10.1158/1078-0432.CCR-19-3550. Epub 2020 Jul 15.