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

Primary Purpose

Melanoma

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
LGX818
Sponsored by
Array BioPharma
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma focused on measuring open-label study, BRAF inhibitor, LGX818, MEK1620, MAPK1/2 inhibitor, Pi3K inhibitor, FGFR, c-Met, CDK4/6, metastatic melanoma, BRAF, V600

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Sarah Cannon Research Institute Onc Dept
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

LGX818 single agent

Arm Description

Patients had to have written documentation of a BRAFV600 mutation, which was to have been obtained locally on a fresh tumor biopsy (preferred) or on the most recent archival tumor sample available.

Outcomes

Primary Outcome Measures

Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Secondary Outcome Measures

Incidence of Dose Limiting Toxicities (DLTs) (Part II)
Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Plasma Concentration and Derived Pharmacokinetic Parameters
Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.
Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways
Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.

Full Information

First Posted
March 25, 2013
Last Updated
November 10, 2016
Sponsor
Array BioPharma
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1. Study Identification

Unique Protocol Identification Number
NCT01820364
Brief Title
LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2016
Overall Recruitment Status
Terminated
Why Stopped
Study was withdrawn due to scientific and business considerations.
Study Start Date
November 2013 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Array BioPharma

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
open-label study, BRAF inhibitor, LGX818, MEK1620, MAPK1/2 inhibitor, Pi3K inhibitor, FGFR, c-Met, CDK4/6, metastatic melanoma, BRAF, V600

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LGX818 single agent
Arm Type
Experimental
Arm Description
Patients had to have written documentation of a BRAFV600 mutation, which was to have been obtained locally on a fresh tumor biopsy (preferred) or on the most recent archival tumor sample available.
Intervention Type
Drug
Intervention Name(s)
LGX818
Other Intervention Name(s)
encorafenib
Intervention Description
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.
Primary Outcome Measure Information:
Title
Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
Description
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame
Baseline through study completion (approximately 2 years)
Secondary Outcome Measure Information:
Title
Incidence of Dose Limiting Toxicities (DLTs) (Part II)
Description
Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time Frame
Baseline through study completion (approximately 2 years)
Title
Plasma Concentration and Derived Pharmacokinetic Parameters
Description
Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time Frame
Baseline through study completion (approximately 2 years)
Title
Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)
Description
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame
Baseline through completion of Part I of the study (approximately 2 years)
Title
Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)
Description
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.
Time Frame
Entry to Part II of the study through study completion (approximately 22 days)
Title
Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways
Description
Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time Frame
Baseline and at progression with LGX818 single agent treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Array BioPharma
Organizational Affiliation
303-381-6604
Official's Role
Study Director
Facility Information:
Facility Name
Sarah Cannon Research Institute Onc Dept
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Novartis Investigative Site
City
East Melbourne
State/Province
Victoria
ZIP/Postal Code
3002
Country
Australia
Facility Name
Novartis Investigative Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada
Facility Name
Novartis Investigative Site
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Zuerich
ZIP/Postal Code
8091
Country
Switzerland

12. IPD Sharing Statement

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

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