Clinical Trials /

LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma

NCT02159066

Description:

The primary purpose of this study is to assess the anti-tumor activity of LGX818/MEK162 in combination with targeted agents after progression on LGX818/MEK162 combination therapy, as well as the safety and tolerability of the novel triple combinations.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">LGX818</span> and MEK162 in Combination With a Third Agent (<span class="go-doc-concept go-doc-intervention">BKM120</span>, LEE011, <span class="go-doc-concept go-doc-intervention">BGJ398</span> or INC280) in Advanced <span class="go-doc-concept go-doc-biomarker">BRAF</span> <span class="go-doc-concept go-doc-disease">Melanoma</span>

Title

  • Brief Title: LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma
  • Official Title: A Phase II, Multi-center, Open-label Study of Sequential LGX818/MEK162 Combination Followed by a Rational Combination With Targeted Agents After Progression, to Overcome Resistance in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma
  • Clinical Trial IDs

    NCT ID: NCT02159066

    ORG ID: CLGX818X2109

    Trial Conditions

    Melanoma

    Trial Interventions

    Drug Synonyms Arms
    LGX818 LGX818 + MEK162
    MEK162 LGX818 + MEK162
    LEE011 LGX818 + MEK162 + LEE011
    BGJ398 LGX818 + MEK162 + BGJ398
    BKM120 LGX818 + MEK162 + BKM120
    INC280 LGX818 + MEK162 + INC280

    Trial Purpose

    The primary purpose of this study is to assess the anti-tumor activity of LGX818/MEK162 in
    combination with targeted agents after progression on LGX818/MEK162 combination therapy, as
    well as the safety and tolerability of the novel triple combinations.

    Detailed Description

    This study consists of two parts: in Part I/Run-In, patients nave to selective BRAF and MEK
    inhibitors will be treated with the LGX818/MEK162 combination until disease progression (as
    defined per RECIST v1.1). Based on the genetic analysis of a tumor biopsy obtained at that
    time, patients will enter Part II of the study for tailored combination treatment in one of
    four arms of LGX818/MEK162 + either BKM120, BGJ398, INC280 or LEE011 Patients with BRAF
    mutant melanoma treated by LGX818/MEK162 combination in other studies can be enrolled
    directly in Part II of CLGX818X2109 after relapse.

    Dose-escalations in the combination arms for which no MTD has been established will be based
    on the recommendations of a Bayesian logistic regression model guided by an escalation with
    overdose control criterion

    Trial Arms

    Name Type Description Interventions
    LGX818 + MEK162 Experimental LGX818, MEK162
    LGX818 + MEK162 + LEE011 Experimental LEE011
    LGX818 + MEK162 + BGJ398 Experimental BGJ398
    LGX818 + MEK162 + BKM120 Experimental BKM120
    LGX818 + MEK162 + INC280 Experimental INC280

    Eligibility Criteria

    INCLUSION CRITERIA:

    - Age 18 years

    - Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma
    (stage IIIC to IV per American Joint Committee on Cancer [AJCC])

    - Documented evidence of BRAF V600 mutation.

    - Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at
    the time of progression, if not medically contraindicated.

    - Evidence of measurable disease, as determined by RECIST v1.1.

    INCLUSION CRITERIA for triple combinations:

    Progressive disease following prior treatment with LGX818/MEK162 combination. PRINCIPAL
    EXCLUSION CRITERIA Symptomatic or untreated leptomeningeal disease.

    - Symptomatic brain metastases. Patients previously treated or untreated for brain
    metastases that are asymptomatic in the absence of corticosteroid therapy or on a
    stable dose of steroids for four weeks are allowed to enroll. Brain metastases must
    be stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at
    screening demonstrating no current evidence of progressive brain metastases).
    Patients are not permitted to receive enzyme inducing anti-epileptic drugs.

    - Patients who have developed brain metastases during Part I of the study may continue
    to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must
    be either asymptomatic or treated and stable for at least 4 weeks and on a stable or
    tapering dose of steroids for at least 2 weeks. Patients with brain metastasis are
    not eligible for the combination with LEE011.

    - Known acute or chronic pancreatitis.

    - History or current evidence of retinal vein occlusion (RVO) or current risk factors
    for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
    or hypercoagulability syndromes);

    - Clinically significant cardiac disease including any of the following:

    - CHF requiring treatment (NYH grade 2),

    - LVEF < 50% as determined by MUGA scan or ECHO

    - History or presence of clinically significant ventricular arrhythmias or atrial
    fibrillation

    - Clinically significant resting bradycardia

    - Unstable angina pectoris 3 months prior to starting study drug

    - Acute Myocardial Infarction (AMI) 3 months prior to starting study drug,

    - QTcF > 480 msec. Patients with any of the following laboratory values at

    Screening/baseline:

    - Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]

    - Platelets < 100,000/mm3 [100 x 109/L]

    - Hemoglobin < 9.0 g/dL

    - Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower
    limit of normal)

    - Serum total bilirubin >1.5 x ULN

    - AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present

    Additional exclusion criteria for the triple combinations:

    LGX818/MEK162/BKM120:

    - Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %.

    - Patient has any of the following mood disorders as judged by the

    Investigator or a Psychiatrist:

    - Patient has a score 12 on the PHQ-9 questionnaire

    - Patient has CTCAE grade 3 anxiety

    LGX818/MEK162/BGJ398:

    - History and/or current evidence of significant ectopic mineralization/ calcification
    with the exception of calcified lymph nodes and asymptomatic vascular calcification.

    - Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/
    band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits
    etc., confirmed by ophthalmologic examination

    LGX818/MEK162/LEE011:

    - Patients with uncontrolled hypertension (please refer to WHO-ISHguidelines) are
    excluded from study.

    - QTcF >450 ms for males and >470 ms for females Congenital long QT syndrome or family
    history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade 3 and
    magnesium levels below the clinically relevant lower limits at study entry

    - Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI
    at screening

    - PT/INR or aPTT > 1.5xULN

    Other protocol-defined inclusion/exclusion criteria may apply.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Overall Response Rate (ORR) (Part II)

    Secondary Outcome Measures

    Incidence of adverse events

    Incidence rate of Dose Limiting Toxicities (DLTs)

    Plasma Pharmacokinetics (PK) parameters of LGX818 + MEK162 and triple combination partners

    Overall Response Rate (ORR) (Part II)

    Progression Free Survival (PFS)(Part I and II)

    Duration Of Response (DOR) (Part I and II)

    Overall Survival (OS) (Part II)

    Molecular status

    Time to Response (TTR) (Part I and II)

    Disease Control Rate (DCR) (Part I and II)

    Severity of adverse events

    Trial Keywords

    Melanoma