LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma

Melanoma Clinical Trial

— LOGIC  

Official title:

Phase II, Multi-center, Open-label Study of Single-agent LGX818 Followed by a Rational Combination With Agents After Progression on LGX818, in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01820364
• Other study ID #: CLGX818X2102
• Secondary ID: 2012-004798-17
• Status: Completed
• Phase: Phase 2
• First received: March 25, 2013
• Last updated: February 11, 2016
• Start date: November 2013
• Est. completion date: March 2015

Study information

• Verified date: February 2016
• Source: Array BioPharma
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The primary purpose of the Phase II CLGX818X2102 study is to assess the anti-tumor activity of LGX818 in combination with selected agents.

Description:

This is a phase II two part multi-center, open-label study. Part I: LGX818 single agent treatment until progression Part II: Combination treatments of LGX818 + MEK162, or BKM120, or BGJ398, or INC280, or LEE01 to assess the clinical efficacy, to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic BRAF mutant melanoma after relapse on LGX818, and to determine the maximum tolerated dose of the combinations (when not established previously). These drug combinations are selected and assigned to patients based on documentation of molecular resistance mechanism.

Patients with BRAF mutant melanoma treated by LGX818 single agent in other studies can be enrolled directly in Part II of CLGX818X2102 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• locally advanced or metastatic melanoma

• confirmed BRAF V600 mutation

• patients naïve to a selective BRAF inhibitor

• fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse

• life expectancy = 3 months

• World Health Organization (WHO) Performance Status = 2.

Exclusion Criteria:

• Previous treatment with RAF-inhibitor

• Symptomatic or untreated leptomeningeal disease

• Symptomatic brain metastases.

• Known acute or chronic pancreatitis

• Clinically significant cardiac disease

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

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral interventional drug

• Previous or concurrent malignancy.

• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation

Specific exclusion criteria for each treatment arm:

LGX818/MEK162:

History or current evidence of retinal disease History of Gilbert's syndrome.

LGX818/BKM120:

Patients with diabetes mellitus requiring insulin treatment Patient has mood disorders

LGX818/BGJ398:

History and/or current evidence of ectopic mineralization/ calcification Current evidence of corneal disorder/ keratopathy Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis.

History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade = 3 and/or magnesium levels below the clinically relevant lower limits before study entry.

Ionized (i) calcium (Ca) > ULN Serum inorganic phosphorus (Pi) > ULN

LGX818/LEE011 History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade = 3 and/or magnesium levels below the clinically relevant lower limits before study entry.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• LGX818
BRAF inhibitor. LGX818 was administered QD orally on a daily schedule (21-day cycles) as a flat-fixed dose and not by body weight or body surface area. LGX818 100 mg capsules and 50 mg capsules.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	East Melbourne	Victoria
Canada	Novartis Investigative Site	Edmonton	Alberta
Germany	Novartis Investigative Site	Heidelberg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Switzerland	Novartis Investigative Site	Zuerich
United States	Sarah Cannon Research Institute Onc Dept	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Array BioPharma

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Germany,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate		3 years	No
Secondary	Incidence and severity of adverse events		3 years	Yes
Secondary	Incidence rate of Dose Limiting Toxicities (DLTs) in Cycle 1 of Combination Part (Part II)		3 years	Yes
Secondary	Plasma concentration and derived PK parameters of LGX818 and combination partners		3years	Yes
Secondary	Overall Response Rate (ORR) (Part I)		3 years	No
Secondary	Progression Free Survival (PFS)(Part I and II)		3 years	No
Secondary	Duration Of Response (DOR) (Part II)		3 years	No
Secondary	Overall Survival (OS) (Part II)		3 years	No
Secondary	Molecular status (mutation/amplification/expression) of markers relevant to the RAF/MEK/ERK and PI3K/AKT pathways		baseline, at progression with LGX818 single agent treatment up to 3 years	No