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

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ClinicalTrials.gov Identifier: NCT01978236
Recruitment Status : Completed
First Posted : November 7, 2013
Last Update Posted : September 26, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Melanoma and Brain Metastases Drug: Dabrafenib 150 mg Drug: Trametinib 2.0 mg Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain
Study Start Date : April 8, 2014
Actual Primary Completion Date : April 26, 2017
Actual Study Completion Date : April 26, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Cohort A
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
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.

Experimental: Cohort B
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
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.

Drug: Trametinib 2.0 mg
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.




Primary Outcome Measures :
  1. Concentrations of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) [ Time Frame: Between Day 8 and Day 15 (Day of surgery) ]
    Brain tissue, extracranial metastases and plasma samples collected during surgery, two blood samples collected prior to surgery, and 2 blood samples collected after surgery; samples will be separated in time by at least 1 hour

  2. Tissue distribution of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) [ Time Frame: Between Day 8 and Day 15 (Day of surgery) ]
    Brain tissue and extracranial metastases samples collected during surgery, two blood samples collected prior to surgery, and 2 blood samples collected after surgery; samples will be separated in time by at least 1 hour


Secondary Outcome Measures :
  1. Concentrations of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib) and trametinib (Cohort B only) in CSF samples. [ Time Frame: Between Day 8 and Day 15 (Day of surgery) ]
    Cerebrospinal fluid (CSF) (in subjects who agree to optional collection of CSF at the time of brain tumor resection

  2. Changes in MAPK pathway markers [ Time Frame: Pre-dose, Between Day 8 to Day 15 (Day of surgery) ]
    Changes in MAPK pathway markers in paired extracranial biopsies taken pre-treatment, during craniotomy, and at disease progression, and changes in markers between post-operative intracranial and extracranial biopsies.

  3. Comparison of radiographic tumor changes [ Time Frame: Screening, 1 to 3 days prior to Surgery, Day 3 after Surgery, Week 4 and every 4 weeks, Discontinuation ]
    Changes in the radiographic characteristics of the tumors will be compared to (1) levels of dabrafenib, its metabolites and trametinib (where appropriate) in the brain metastases, plasma, and CSF, and (2) MAPK pathway activation status in tumors at the time of surgery. Results will also be compared to the analysis of early clinical responses in extracranial metastases, as determined by the PET-CT imaging.

  4. Overall extracranial response rate in unresected lesions [ Time Frame: Approximately 2 years or death ]
    The overall extracranial response rate in unresected lesions is defined as the percentage of subjects with a confirmed overall CR or PR by investigator assessment using modified Response Evaluation Criteria In Solid Tumours (RECIST)

  5. Overall Survival [ Time Frame: Approximately 2 years or death ]
    Overall Survival: defined as the time from randomization until death due to any cause

  6. Safety and tolerability as assessed by vital signs [ Time Frame: Screening, Day Prior to Surgery, Day 30 after Surgery, Week 4 and every 4 weeks, Discontinuation ]
    Vital sign measurements will include temperature, respiratory rate, systolic and diastolic blood pressure, and pulse rate.

  7. Safety and tolerability as assessed by physical examinations [ Time Frame: Screening, Day 30 after Surgery, Week 4 and every 4 weeks, Discontinuation ]
    A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and extremities. Height and weight will also be measured and recorded.

  8. Safety as assessed by 12-lead ECG [ Time Frame: Screening ]
    Electrocardiograph (ECG) is a machine that measures the electrical activity of the heart and records changes in the hearts' rhythm.

  9. Safety and tolerability as assessed by ECHO [ Time Frame: Screening, Week 8 and every 16 weeks till discontinuation ]
    Echocardiogram (ECHO) will include an evaluation for LVEF and both right- and left-sided valvular lesions.

  10. Safety and tolerability as assessed by abnormal clinical laboratory assessments [ Time Frame: Screening, Day Prior to Surgery, Day 3 after Surgery, Day 30 after Surgery, Week 4 and every 4 weeks, Discontinuation ]
    Clinical laboratory tests will include hematology, coagulation tests and clinical chemistry

  11. Safety and tolerability as assessed by nature and frequency of AEs [ Time Frame: Approximately 2 years or death ]
    Adverse events (AEs) will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice.

  12. Change from baseline to pre-surgery in the sum of the longest diameters (SLD) of intracranial target lesions [ Time Frame: Screening, 1-3 days prior to Surgery, Day 3 after Surgery, every 8 weeks, and Discontinuation ]
    Changes in tumor size of the intracranial target lesions will be assessed by MRI of the brain and whole-body PET-CT imaging. It will be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate

  13. Maximum change from baseline in the sum of longest diameters of unresected intracranial target lesions [ Time Frame: Screening, 1-3 days prior to Surgery, Day 3 after Surgery, every 8 weeks, and Discontinuation ]
    The maximum change from baseline in the sum of the longest diameters (SLD) of unresected intracranial target lesions will be calculated as a percentage change from the baseline SLD. It will be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate



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

Inclusion Criteria:

  • 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)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5xULN
  • Serum creatinine <=1.5 mg/dL (If serum creatinine is >1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault Method Creatinine clearance must be >50 mL/min)
  • Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) <=1.3xULN
  • Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN)

Exclusion Criteria:

  • 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
  • The history or evidence of following cardiac abnormalities:
  • Corrected QT (QTc) interval using Bazett's Formula; (QTcB) >= 480 msecs
  • A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
  • Coronary angioplasty or stenting within the past 12 weeks
  • Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  • Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (ECHO)
  • History of or evidence of clinically significant uncontrolled cardiac arrhythmias
  • Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy
  • Subjects with intra-cardiac defibrillators or permanent pacemakers
  • Pregnant, lactating or breastfeeding females
  • Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2118436 or excipients that contraindicate their participation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01978236


Locations
United States, Pennsylvania
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15232
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
Australia, New South Wales
GSK Investigational Site
North Sydney, New South Wales, Australia, 2060
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01978236     History of Changes
Other Study ID Numbers: 116521
First Posted: November 7, 2013    Key Record Dates
Last Update Posted: September 26, 2017
Last Verified: September 2017

Keywords provided by GlaxoSmithKline:
BRAF V600E mutation
brain metastases
BRAF V600K mutation
Metastatic melanoma
BRAF inhibitor
brain neoplasms
GSK2118436

Additional relevant MeSH terms:
Melanoma
Neoplasm Metastasis
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplastic Processes
Pathologic Processes
Trametinib
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action