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

NCT01543698 | Completed Phase 1 Results

• 3 other identifiers: CMEK162X2110C42210052011-005875-17
• Study Type: interventional
• Target: 189
• Locations: 9 countries
• Sites: 26

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.

Conditions

Solid Tumors Harboring a BRAF V600 Mutation

Keywords

Advanced solid tumor,; BRAF V600 mutation

Outcome Measures

Primary Outcomes (3)

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

  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.

  Phase 1b: Cycle 1 (28 days following the first dose of LGX818 and MEK162 or LGX818 and MEK162 and LEE011)

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

  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).

  Phase 2: Week 16

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

  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.

  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 (19)

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

  Phase 1b: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 1b was 118.3 months)

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

  Phase 2: Day 1 up to 30 days after last dose (maximum treatment exposure for Phase 2 was 111.5 months)

• 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: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hours (hr) post dose on Day 1 of Cycle 1

• 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

  Phase 1b: Pre dose, 0.5,1.5,2.5,4,6,8 and 24 hr post dose on Day 1 of Cycle 1

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

  Phase 1b: Pre dose,0.5,1.5, 2.5,4,6,8 and 24 hr post dose on Day 15 of Cycle 1

Study Arms (2)

dual combination

EXPERIMENTAL

LGX818 QD and MEK162 BID

Drug: LGX818; Drug: MEK162

triple combination

EXPERIMENTAL

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

Drug: LGX818; Drug: MEK162; Drug: LEE011

Interventions

LGX818 DRUG

dual combination; triple combination

MEK162 DRUG

dual combination; triple combination

LEE011 DRUG

triple combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (26)

H. Lee Moffitt Cancer Center & Research Institute, Inc.

Tampa, Florida, 33612, United States

Location

Moffitt McKinley Outpatient Center

Tampa, Florida, 33612, United States

Location

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Ophthalmic Consultants of Boston Inc (OCB)

Boston, Massachusetts, 02114, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Chris O'Brien Lifehouse Hospital

Camperdown, New South Wales, 02050, Australia

Location

Melanoma Institute Australia

North Sydney, New South Wales, 2060, Australia

Location

Westmead Hospital-Redbank Rd

Northmead, New South Wales, 2152, Australia

Location

Westmead Hospital-Redbank Rd

Westmead, New South Wales, 2145, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Melanoma Institute Australia

North Sydney, 2065, Australia

Location

UZ Leuven- Gasthuisberg Campus

Leuven, Vlaams Brabant, 3000, Belgium

Location

Sir Mortimer B. Davis-Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Hôpital Saint louis

Paris, 75010, France

Location

Service de radiologie - Hopital Saint Louis

Paris, 75475, France

Location

IRCCS Fondazione Pascale

Naples, Campania, 80131, Italy

Location

Azienda Ospedaliera Monaldi

Napoli, Campania, 80131, Italy

Location

Azienda Ospedaliera Universitaria Federico II

Napoli, Campania, 80131, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda

Milan, 20162, Italy

Location

Istituto Nazionale per lo studio e la cura dei tumori Fondazione Giovanni Pascale

Napoli, 80131, Italy

Location

National Cancer Centre Singapore

Singapore, 169610, Singapore

Location

Hospital Universitario Vall d'Hebrón - PPDS

Barcelona, 08035, Spain

Location

Hospital Universitario HM Sanchinarro ? CIOCC

Madrid, 28050, Spain

Location

University Hospital Zürich, Dermatology

Zurich-Airport, Canton of Zurich, 8058, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 32669376 DERIVED

MeSH Terms

Interventions

encorafenib; binimetinib; ribociclib

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2012
• First Posted: March 5, 2012
• Study Start: May 28, 2012
• Primary Completion: March 9, 2023
• Study Completion: March 9, 2023
• Last Updated: March 13, 2024
• Results First Posted: March 13, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

CH (2); CA (1); US (6); BE (1); AU (6); FR (2); ES (2); IT (5); SG (1)