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LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma (LOGIC-2)

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ClinicalTrials.gov Identifier: NCT02159066
Recruitment Status : Active, not recruiting
First Posted : June 9, 2014
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
Array BioPharma

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: LGX818 Drug: MEK162 Drug: LEE011 Drug: BGJ398 Drug: BKM120 Drug: INC280 Phase 2

Detailed Description:

This study consists of two parts: in Part I/Run-In, patients naïve 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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : July 2014
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: LGX818 + MEK162 Drug: LGX818
Combination of LGX818 and MEK162 (Part I)

Drug: MEK162
Combination of LGX818 and MEK162 (Part I)

Experimental: LGX818 + MEK162 + LEE011 Drug: LEE011
Combination of LGX818 + MEK162 + LEE011 (Part II)

Experimental: LGX818 + MEK162 + BGJ398 Drug: BGJ398
Combination of LGX818 + MEK162 + BGJ398 (Part II)

Experimental: LGX818 + MEK162 + BKM120 Drug: BKM120
Combination of LGX818 + MEK162 + BKM120 (Part II)

Experimental: LGX818 + MEK162 + INC280 Drug: INC280
Combination of LGX818 + MEK162 + INC280 (Part II)




Primary Outcome Measures :
  1. Overall Response Rate (ORR) (Part II) [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 2 years ]
  2. Incidence rate of Dose Limiting Toxicities (DLTs) [ Time Frame: 2 years ]
    in Cycle 1 of Combination Part (Part II); cycle 1 = 21 days or 28 days

  3. Plasma Pharmacokinetics (PK) parameters of LGX818 + MEK162 and triple combination partners [ Time Frame: 2 years ]
    AUCtau, ss; Cmax; Cmax, ss; Tmax; Tmax, ss; Ctrough; Clast, ss; T1/2, ss; CL,ss/F; Vz,ss/F

  4. Overall Response Rate (ORR) (Part II) [ Time Frame: 2 years ]
  5. Progression Free Survival (PFS)(Part I and II) [ Time Frame: 2 years ]
  6. Duration Of Response (DOR) (Part I and II) [ Time Frame: 2 years ]
  7. Overall Survival (OS) (Part II) [ Time Frame: 2 years ]
  8. Molecular status [ Time Frame: baseline, at progression with LGX818 + MEK162 combination treatment up to 2 years ]
    Molecular Status includes mutation, amplification, expression of markers relevant to the RAF/MEK/ERK and PI3K/AKT pathways

  9. Time to Response (TTR) (Part I and II) [ Time Frame: 2 years ]
  10. Disease Control Rate (DCR) (Part I and II) [ Time Frame: 2 years ]
  11. Severity of adverse events [ Time Frame: 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02159066


Locations
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United States, Arizona
Mayo Clinic - Arizona onc Dept
Scottsdale, Arizona, United States
United States, California
University of California at Los Angeles Onc Dept
Los Angeles, California, United States, 90095
United States, Massachusetts
Massachusetts General Hospital Dept of Onc.
Boston, Massachusetts, United States, 02115
United States, New York
Memorial Sloan Kettering Cancer Center Dept Oncology
New York, New York, United States, 90033
United States, Oregon
Oregon Health & Science University Onc. Dept
Portland, Oregon, United States, 97239
United States, Tennessee
Sarah Cannon Research Institute Onc. Dept
Nashville, Tennessee, United States, 37203
Australia, Victoria
Array BioPharma Investigative Site
East Melbourne, Victoria, Australia, 3002
Canada, Ontario
Array BioPharma Investigative Site
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Array BioPharma Investigative Site
Montreal, Quebec, Canada, H3T 1E2
Germany
Array BioPharma Investigative Site
Heidelberg, Germany, 69120
Array BioPharma Investigative Site
Köln, Germany, 50937
Array BioPharma Investigative Site
Muenchen, Germany, 80336
Array BioPharma Investigative Site
Würzburg, Germany, 97080
Italy
Array BioPharma Investigative Site
Napoli, Italy, 80131
Netherlands
Array BioPharma Investigative Site
Amsterdam, Netherlands, 1066 CX
Spain
Array BioPharma Investigative Site
Barcelona, Catalunya, Spain, 08035
Switzerland
Array BioPharma Investigative Site
Zuerich, Switzerland, 8091
United Kingdom
Array BioPharma Investigative Site
Oxford, United Kingdom, OX3 7LJ
Sponsors and Collaborators
Array BioPharma
Investigators
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Study Director: Array BioPharma 303-381-6604

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Responsible Party: Array BioPharma
ClinicalTrials.gov Identifier: NCT02159066     History of Changes
Other Study ID Numbers: CLGX818X2109
First Posted: June 9, 2014    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019

Keywords provided by Array BioPharma:
Melanoma

Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas