Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma

  • STATUS
    Recruiting
  • End date
    Jun 1, 2022
  • participants needed
    58
  • sponsor
    National Cancer Institute (NCI)
Updated on 14 June 2021
Investigator
Rachel C. Brennan, MD
Primary Contact
Saint Jude Children's Research Hospital (128.6 mi away) Contact
+53 other location
platelet count
cancer
anticonvulsants
MRI
glomerular filtration rate
BRAF
epilepsy
neutrophil count
immunohistochemistry
tumor cells
blood transfusion
seizure
glioblastoma multiforme
astrocytoma
malignant glioma
anaplastic astrocytoma
astrocytoma, anaplastic
trametinib
gangliogliomas
ganglioglioma
dabrafenib

Summary

This phase II trial studies how well the combination of dabrafenib and trametinib works after radiation therapy in children and young adults with high grade glioma who have a genetic change called BRAF V600 mutation. Radiation therapy uses high energy rays to kill tumor cells and reduce the size of tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking BRAF and MEK, respectively, which are enzymes that tumor cells need for their growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.

Description

PRIMARY OBJECTIVE:

I. To estimate the event-free survival (EFS) distribution for newly-diagnosed patients with BRAFV600-mutant high-grade glioma (HGG) without H3 K27M mutations excluding anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic ganglioglioma (aGG) treated with radiation therapy followed by a maintenance combination of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) and to compare this EFS to contemporary historical controls.

SECONDARY OBJECTIVES:

I. To describe the overall survival (OS) distribution for newly-diagnosed patients with BRAFV600-mutant HGG without H3 K27M mutations excluding aPXA and aGG treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib.

II. To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAFV600E-mutant aPXA and aGG without H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib.

III. To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAFV600E-mutant HGG including aPXA and aGG with H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib.

IV. To define and evaluate the toxicities of combination therapy with dabrafenib and trametinib after radiation therapy in newly-diagnosed patients with HGG.

EXPLORATORY OBJECTIVE:

I. To bank tumor specimens and body fluids (blood, urine and cerebrospinal fluid) for future studies.

OUTLINE

Patients undergo standardized local radiation therapy (RT) 5 days a week (Monday-Friday) for 6-7 weeks. Four weeks after completion of RT, patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at disease relapse, every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, then annually for years 4-5.

Details
Condition Astrocytoma, Glioma, Glioblastoma Multiforme, High Grade Glioma, WHO Grade III Glioma, Anaplastic Glioma, Anaplastic Ganglioglioma, Anaplastic Pleomorphic Xanthoastrocytoma, Gliomas, anaplastic astrocytoma, malignant glioma, glioblastoma, astrocytoma, anaplastic
Treatment radiation therapy, Dabrafenib, Trametinib, Dabrafenib Mesylate, Trametinib Dimethyl Sulfoxide
Clinical Study IdentifierNCT03919071
SponsorNational Cancer Institute (NCI)
Last Modified on14 June 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having localized newly-diagnosed HGG, excluding metastatic disease
PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A
PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Specimens obtained at the time of diagnostic biopsy must be submitted through APEC14B1 as soon as possible (ASAP), preferably within 13 calendar days of the procedure
Patients must be >= 3 years and =< 21 years of age at the time of enrollment
Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
Newly diagnosed high-grade glioma with BRAFV600-mutation
Positive or negative results for H3 K27M by immunohistochemistry (IHC)
Histologically confirmed high-grade glioma (World Health Organization [WHO] grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS)
Patients must have had histologic verification of a high-grade glioma diagnosis. Cerebrospinal fluid (CSF) cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible
A pre- and post-operative brain magnetic resonance imaging (MRI) with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)
Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to enrollment)
Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL)
Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
Age 13 to 16 < years (Male 1.5 mg/dL, Female 1.4 mg/dL)
Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study
Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Patients with intrinsic brainstem or primary spinal cord tumors will be excluded
Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded
Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids
Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor
Patients with a history of a malignancy with confirmed activating RAS mutation
History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients
Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol
Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs
History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled)
History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following
Recent myocardial infarction (within the last 6 months)
Uncontrolled congestive heart failure
Unstable angina (within last 6 months)
Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular [AV] block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment
Coronary angioplasty or stenting (within last 6 months)
Intra-cardiac defibrillators
Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram
Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension)
Patients with presence of interstitial lung disease or pneumonitis
Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities
Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy. Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used
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