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

• ClinicalTrials.gov Identifier: NCT01820364
• Recruitment Status: Terminated
• First Posted: March 28, 2013
• Results First Posted: January 9, 2017
• Last Update Posted: January 9, 2017
• Sponsor: Array BioPharma
• Information provided by (Responsible Party): Array BioPharma

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.

Condition or disease	Intervention/treatment	Phase
Melanoma	Drug: LGX818	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: November 2013
• Actual Primary Completion Date: March 2015
• Actual Study Completion Date: March 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: LGX818 single agent; 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.	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.; Other Name: encorafenib

Outcome Measures

Primary Outcome Measures :

1. Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) [ Time Frame: Baseline through study completion (approximately 2 years) ]

   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 :

1. Incidence of Dose Limiting Toxicities (DLTs) (Part II) [ Time Frame: Baseline through study completion (approximately 2 years) ]
   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.
2. Plasma Concentration and Derived Pharmacokinetic Parameters [ Time Frame: Baseline through study completion (approximately 2 years) ]
   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.
3. Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) [ Time Frame: Baseline through completion of Part I of the study (approximately 2 years) ]

   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.
4. Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) [ Time Frame: Entry to Part II of the study through study completion (approximately 22 days) ]

   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.

5. Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways [ Time Frame: Baseline and at progression with LGX818 single agent treatment ]
   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.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, Tennessee

Sarah Cannon Research Institute Onc Dept

Nashville, Tennessee, United States, 37203

Australia, Victoria

Novartis Investigative Site

East Melbourne, Victoria, Australia, 3002

Canada, Alberta

Novartis Investigative Site

Edmonton, Alberta, Canada, T6G 1Z2

Germany

Novartis Investigative Site

Heidelberg, Germany, 69120

Spain

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08035

Switzerland

Novartis Investigative Site

Zuerich, Switzerland, 8091

Sponsors and Collaborators

Array BioPharma

Investigators

• Study Director: Array BioPharma; 303-381-6604

More Information

• Responsible Party: Array BioPharma
• ClinicalTrials.gov Identifier: NCT01820364
• Other Study ID Numbers: CLGX818X2102; 2012-004798-17 ( EudraCT Number )
• First Posted: March 28, 2013
• Results First Posted: January 9, 2017
• Last Update Posted: January 9, 2017
• Last Verified: November 2016

Keywords provided by Array BioPharma:

open-label study; BRAF inhibitor; LGX818; MEK1620; MAPK1/2 inhibitor; Pi3K inhibitor; FGFR; c-Met; CDK4/6; metastatic melanoma; BRAF; V600

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas