Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites

NCT01978236 | Terminated Phase 2 Results

• 1 other identifier: 116521
• Study Type: interventional
• Target: 6
• Locations: 2 countries
• Sites: 3

Brief Summary

This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

Conditions

Melanoma and Brain Metastases

Keywords

BRAF V600E mutation; brain metastases; BRAF V600K mutation; Metastatic melanoma; BRAF inhibitor; brain neoplasms; GSK2118436

Outcome Measures

Primary Outcomes (3)

• Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma)

  Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib were collected on day of surgical resection of the brain metastasis(es), Two samples were collected before surgery and 2 samples after surgery with one hour gap in between. Upon collection blood was placed on wet ice. Plasma was isolated within 60 minutes of collection and frozen at -20 degree celsius.

  Pre-surgery and post-surgery on Day 15

• Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Parenchymal Brain Metastases

  Concentrations of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and possibly other drug-related species were quantified in the pharmacokinetic tissue sample by an investigative Liquid chromatography- mass spectrometry (LC-MS)/MS method. The spatial distribution of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib and possibly other drug-related species in the tissue samples were determined using an investigative matrix assisted laser desorption ionization (MALDI) analysis method. Parenchymal brain metastases and extracranial metastases using MALDI imaging was not determined for all participants (completed by GSK for the first two participants enrolled)

  Day 15

• Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) and Trametinib (Cohort B Only) in CSF Samples.

  Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib and trametinib (as appropriate), were planned but not collected.

  Pre-surgery and post-surgery on Day 15

Secondary Outcomes (13)

• Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) in Cerebrospinal Fluid (CSF) Samples

  Day 15

• Number of Participants With Changes in Mitogen-activated Protein Kinase (MAPK) Pathway Markers

  Up to Day 15

• Number of Participants With Changes in Radiographic Tumors

  Up to 2 years

• Percent Change From Baseline to Pre-surgery in the Sum of the Longest Diameters (SLD) of Intracranial Target Lesions

  Up to 2 years

• Maximum Percent Change From Baseline in the SLD of Unresected Intracranial Target Lesions

  Up to 2 years

Study Arms (2)

Cohort A

EXPERIMENTAL

The first cohort of 15 subjects will receive oral dabrafenib 150 mg twice daily orally for 7 to 14 days prior to surgery in Cohort A; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery

Drug: Dabrafenib 150 mg

Cohort B

EXPERIMENTAL

The second cohort of 15 subjects will receive dabrafenib 150 mg twice daily combined with trametinib 2 mg once daily (Cohort B) orally for 7 to 14 days prior to surgery; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery

Drug: Dabrafenib 150 mg; Drug: Trametinib 2.0 mg

Interventions

Dabrafenib 150 mg DRUG

Dabrafenib will be provided for oral administration as 50 mg and 75 mg capsules. Dabrafenib will be dosed orally with approximately 200 mL of water, twice a day. Dabrafenib should be administered under fasting conditions.

Cohort A; Cohort B

Trametinib 2.0 mg DRUG

Trametinib study treatment will be provided as 0.5 mg and 2.0 mg tablets. should be taken orally with approximately 200 mL of water under fasting conditions, either one hour before or two hours after a meal.

Cohort B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed written informed consent
• Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. Previously performed certified BRAF testing is acceptable. If no prior BRAF mutation testing results are available, testing of a distant metastasis is preferred, but testing of a regional metastasis or primary tumor is also acceptable
• At least one intracranial lesion \>=1.0 cm but \<=4.0 cm that can be treated with surgical resection in the opinion of the treating physicians, and for which immediate local therapy is not clinically indicated
• At least two extracranial lesions that are easily accessible for biopsy, in the judgment of the treating physician. Easily accessible tumors may include cutaneous, subcutaneous, and superficial lymph node metastases.
• Age \>18 years of age.
• Able to swallow and retain oral medication
• Women with child-bearing potential must be willing to practice acceptable methods of birth control during the study
• Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment.
• Must be able to understand and comply with protocol requirements and instructions
• Eastern Co-operative Oncology Group (ECOG) performance status of 0-2
• Must have adequate organ function as defined by the following screening values (Retesting of borderline screening organ function and treatment with blood transfusions, growth factors etc. will be allowed):
• Absolute neutrophil count (ANC) \>=1.2x10\^9/L
• Hemoglobin \>=9 g/dL
• Platelets \>=100x10\^9/L
• Serum bilirubin \<=1.5 x upper limit of normal (ULN)

You may not qualify if:

• Neurological symptoms related to brain metastasis that are not controlled with a stable or decreasing dose of oral steroids for at least 7 days prior to starting GSK2118436
• Prior Central Nervous System (CNS)-directed local therapies, including surgical resection, whole brain radiation (WBRT), Stereotactic radiosurgery (SRS), or gamma knife (GK)
• Previous treatment with a BRAF or MEK inhibitor
• Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer drugs within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks, preceding the first dose of study treatment.
• Current or expected use of a prohibited medication, including enzyme-inducing antiepileptic drugs (EIAEDs) during treatment with GSK2118436.
• Presence of leptomeningeal disease or dural metastases.
• History of another active malignancy within the past 5 years, or any malignancy with a confirmed activating RAS mutation. The prospective RAS mutation testing is not required, however, if results of previous RAS testing are known, they must be used in assessing eligibility. Subjects with a history of completely resected non-melanoma skin cancer are eligible.
• Known allergies against contrast agents required for magnetic resonance imaging (MRI) of intracranial lesions, or other contraindications for MRI, i.e., pacemaker
• Current use of therapeutic warfarin. Low-molecular-weight heparin and prophylactic low-dose warfarin are permitted
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs.
• History of a prior symptomatic stroke, dementia, or other significant central neurologic condition (i.e. multiple sclerosis)
• A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
• Current acute infection requiring intravenous antibiotics
• A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

Pittsburgh, Pennsylvania, 15232, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

North Sydney, New South Wales, 2060, Australia

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2013
• First Posted: November 7, 2013
• Study Start: April 8, 2014
• Primary Completion: April 26, 2017
• Study Completion: April 26, 2017
• Last Updated: August 17, 2018
• Results First Posted: August 17, 2018

Record last verified: 2018-07

Locations

AU (1); US (2)