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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01543698
First received: February 1, 2012
Last updated: June 17, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Solid Tumors Harboring a BRAF V600 Mutation
Drug: LGX818
Drug: MEK162
Drug: LEE011
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Phase Ib: Estimation of Maximum Tolerated Dose (MTD) by measuring incidence of dose limiting toxicities (DLT) [ Time Frame: up to 8 months ] [ Designated as safety issue: Yes ]
    To estimate the MTD(s) and/or recommended phase 2 dose(s) (RP2D(s)) of oral LGX818 in combination with oral MEK162, and of oral LGX818 in combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors by measuring the incidence of DLTs as defined by the protocol.

  • Phase II: Clinical efficacy [ Time Frame: up to 14 months ] [ Designated as safety issue: No ]
    Assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818 and MEK162 and LEE011 triple combination in the Phase II populations by evaluating the disease control rate (DCR) and objective response rate (ORR) as per RECIST 1.1


Secondary Outcome Measures:
  • Safety and tolerability of LGX818 and MEK162 dual combination, and LGX818 and MEK162 and LEE011 triple combination by evaluating the incidence and severity of adverse events (AE). [ Time Frame: up to 17 months ] [ Designated as safety issue: Yes ]
    To characterize the safety and tolerability of LGX818 and MEK162 in combination, and LGX818 and MEK162 and LEE011 in combination by evaluating the incidence and severity (as per CTCAE grading) of AEs in all patients enrolled in the study.

  • Determination of single and multiple dose of Pharmacokinetics (PK) profile by measuring plasma concentrations versus time after study drug combination dosing (Phase Ib) [ Time Frame: up to 8 months ] [ Designated as safety issue: Yes ]
    To determine the single and multiple dose PK profile of the LGX818 and MEK162 combination and LGX818 and MEK162 and LEE011 combination, by measuring plasma concentrations of MEK162 and LGX818 and LEE011 resp. at different timepoints prior and post study drug combination dosing on several days within cycle 1 and subsequent cycles.

  • Preliminary clinical anti-tumor activity by evaluating the objective response rate (Phase Ib) [ Time Frame: up to 8 months ] [ Designated as safety issue: No ]
    To assess preliminary anti-tumor activity of the LGX818 and MEK162 combination, and the LGX818 and MEK162 and LEE011 combination by evaluating the ORR as per RECIST 1.1. Safety Issue?: (FDAAA) No

  • Further clinical efficacy (phase II) [ Time Frame: up to 14 months ] [ Designated as safety issue: No ]
    To further assess clinical efficacy of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination in the Phase II populations by measuring progression free survival (PFS) as per RECIST 1.1


Estimated Enrollment: 179
Study Start Date: March 2011
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: dual combination
LGX818 QD and MEK162 BID
Drug: LGX818 Drug: MEK162
Experimental: triple combination
LGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off.
Drug: LGX818 Drug: MEK162 Drug: LEE011

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01543698

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute Moffitt SC 2 Active, not recruiting
Tampa, Florida, United States, 33612
United States, Maryland
The Sidney Kimmel Cancer Center at Johns Hopkins Hospital Johns Hopkins Active, not recruiting
Baltimore, Maryland, United States, 21287-0013
United States, Massachusetts
Massachusetts General Hospital Mass General 2 Active, not recruiting
Boston, Massachusetts, United States, 02114
United States, Texas
University of Texas/MD Anderson Cancer Center MD Univ TX Active, not recruiting
Houston, Texas, United States, 77030-4009
Australia, New South Wales
Novartis Investigative Site Completed
Camperdown, New South Wales, Australia, 2050
Novartis Investigative Site Recruiting
North Sydney, New South Wales, Australia, 2060
Novartis Investigative Site Recruiting
Westmead, New South Wales, Australia, 2145
Belgium
Novartis Investigative Site Not yet recruiting
Leuven, Belgium, 3000
Canada, Quebec
Novartis Investigative Site Recruiting
Montreal, Quebec, Canada, H3T 1E2
France
Novartis Investigative Site Recruiting
Paris, France, 75475
Italy
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20162
Novartis Investigative Site Recruiting
Napoli, Italy, 80131
Singapore
Novartis Investigative Site Active, not recruiting
Singapore, Singapore, 169610
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Madrid, Spain, 28050
Switzerland
Novartis Investigative Site Not yet recruiting
St. Gallen, Switzerland, 9007
Novartis Investigative Site Recruiting
Zuerich, Switzerland, 8091
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01543698     History of Changes
Other Study ID Numbers: CMEK162X2110, 2011-005875-17
Study First Received: February 1, 2012
Last Updated: June 17, 2014
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Health Canada
Singapore: Health Sciences Authority
Spain: Agencia Espaniola de Medicamentos y Productos Sanitarios
Switzerland: Swiss Agency for Therapeutic Products (Swissmedic)
Italy:National Institute of Health (Istituto Superiore di Sanita)
France: AFSSAPS - Agence française de sécurité sanitaire des produits de santé
Belgium: Federal Agency for Medicines and Health Products, FAMHP

Keywords provided by Novartis:
Advanced solid tumor,
BRAF V600 mutation

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on November 27, 2014