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

NCT01543698

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: CMEK162X2110
  • SECONDARY ID: 2011-005875-17
  • NCT ID: NCT01543698

Conditions

  • Solid Tumors Harboring a BRAF V600 Mutation

Interventions

DrugSynonymsArms
LGX818dual combination
MEK162dual combination
LEE011triple combination

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.

Trial Arms

NameTypeDescriptionInterventions
dual combinationExperimentalLGX818 QD and MEK162 BID
  • LGX818
  • MEK162
triple combinationExperimentalLGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off.
  • LGX818
  • MEK162
  • LEE011

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase Ib: Estimation of Maximum Tolerated Dose (MTD) by measuring incidence of dose limiting toxicities (DLT)
Time Frame:up to 8 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Preliminary clinical anti-tumor activity by evaluating the objective response rate (Phase Ib)
Time Frame:up to 8 months
Safety Issue:
Description: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
Measure:Further clinical efficacy (phase II)
Time Frame:up to 14 months
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Array BioPharma

Trial Keywords

  • Advanced solid tumor,
  • BRAF V600 mutation

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