Clinical trial NCT01820364: LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Melanoma
Keywords: open-label study
BRAF inhibitor
LGX818
MEK1620
MAPK1/2 inhibitor
Pi3K inhibitor
FGFR
c-Met
CDK4/6
metastatic melanoma
BRAF
V600
Lead sponsor: Array BioPharma
Sponsor class: INDUSTRY
First posted: 2013-03-28
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed 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.

After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014.

This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

Eligibility criteria: 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.

Primary outcomes:
measure: Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
timeFrame: Baseline through study completion (approximately 2 years)
Secondary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLTs) (Part II)
timeFrame: Baseline through study completion (approximately 2 years)
measure: Plasma Concentration and Derived Pharmacokinetic Parameters
timeFrame: Baseline through study completion (approximately 2 years)
measure: Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)
timeFrame: Baseline through completion of Part I of the study (approximately 2 years)
measure: Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)
timeFrame: Entry to Part II of the study through study completion (approximately 22 days)
measure: Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways
timeFrame: Baseline and at progression with LGX818 single agent treatment
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Onc Dept
state: Tennessee
city: East Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
Study officials:
affiliation: 303-381-6604
name: Array BioPharma
role: STUDY_DIRECTOR
References: