Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma
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|ClinicalTrials.gov Identifier: NCT03919071|
Recruitment Status : Recruiting
First Posted : April 18, 2019
Last Update Posted : March 17, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Anaplastic Astrocytoma Anaplastic Astrocytoma, Not Otherwise Specified Anaplastic Ganglioglioma Anaplastic Pleomorphic Xanthoastrocytoma Glioblastoma Malignant Glioma WHO Grade 3 Glioma||Procedure: Biospecimen Collection Drug: Dabrafenib Mesylate Procedure: Lumbar Puncture Procedure: Magnetic Resonance Imaging Radiation: Radiation Therapy Drug: Trametinib Dimethyl Sulfoxide||Phase 2|
I. To estimate the event-free survival (EFS) distribution for newly-diagnosed patients with BRAF^V600-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.
I. To describe the overall survival (OS) distribution for newly-diagnosed patients with BRAF^V600-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 BRAF^V600E-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 BRAF^V600E-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.
I. To bank tumor specimens and body fluids (blood, urine and cerebrospinal fluid) for future studies.
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 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a magnetic resonance imaging (MRI) at baseline, on day 1 of cycles 1, 3, 5, 7, 11, 14, 17, 20, and 23 while on treatment, then at time of relapse, every 3 months for year 1, every 4 months for year 3, every 6 months for year 3, and annually for years 4-5. Patients may also undergo lumbar puncture for cerebral spinal fluid (CSF) testing during treatment. Patients also undergo collection of blood on study.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||58 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2 Study of Dabrafenib (NSC# 763760) With Trametinib (NSC# 763093) After Local Irradiation in Newly-Diagnosed BRAF V600-Mutant High-Grade Glioma (HGG)|
|Actual Study Start Date :||October 2, 2019|
|Estimated Primary Completion Date :||September 30, 2027|
|Estimated Study Completion Date :||September 30, 2027|
Experimental: Treatment (radiation therapy, dabrafenib, trametinib)
Patients undergo standardized local RT 5 days a week (Monday-Friday) for 6-7 weeks. Four weeks after completion of RT, patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI at baseline, on day 1 of cycles 1, 3, 5, 7, 11, 14, 17, 20, and 23 while on treatment, then at time of relapse, every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, and annually for years 4-5. Patients may also undergo lumbar puncture for CSF testing during treatment. Patients also undergo collection of blood on study.
Procedure: Biospecimen Collection
Undergo collection of blood
Drug: Dabrafenib Mesylate
Procedure: Lumbar Puncture
Undergo lumbar puncture
Procedure: Magnetic Resonance Imaging
Radiation: Radiation Therapy
Drug: Trametinib Dimethyl Sulfoxide
Other Name: Mekinist
- Event-free survival (EFS) for stratum 1 [ Time Frame: From the date of diagnosis until disease progression date, secondary malignant neoplasm occurrence date, death date of any cause, or last follow-up, assessed up to 5 years ]The EFS curve for the new treatment cohort (Stratum 1) will be estimated by Kaplan Meier estimates. A 2-sample, 1 sided log-rank test will be used to test whether the EFS distribution is better in new treatment compared with historical control. Calculation of the EFS will be based on the site determination as central review will be performed retrospectively.
- Overall survival (OS) for stratum 1, stratum 2, and stratum 3 [ Time Frame: From the date of diagnosis until death date of any cause or last follow up date, assessed up to 5 years ]The OS curve for the new treatment cohort (stratum 1) will be estimated by Kaplan Meier estimates. A 2-sample, 1 sided log-rank test will be used to test whether the OS distribution is better in new treatment compared with historical control. For stratum 2 and stratum 3, Kaplan Meier estimates will be provided for OS distribution.
- Event-free survival (EFS) for stratum 2 and stratum 3 [ Time Frame: Follow up date, assessed up to 5 years ]For stratum 2 and stratum 3, Kaplan Meier estimates will be provided for EFS distribution.
- Incidence of adverse events [ Time Frame: Up to 5 years ]Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Grade 3 and higher toxicities observed by cycle will be listed for each stratum separately. The grade 3 and higher toxicities observed by cycle and by system organ class for the eligible patients will also be listed for each stratum separately. Toxicity data will be reported separately for the radiation therapy phase versus the maintenance therapy phase for clarity of attribution. Toxicity monitoring will include toxicities such as grade 2 or higher pyrexia, uveitis, retinal vein occlusion, retinal pigment epithelial detachment, and decreased left ventricular ejection fraction.
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|Ages Eligible for Study:||12 Months to 21 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patients must be >= 12 months and =< 21 years of age at the time of enrollment on Step 0
- Note: This age range encompasses pre-screening for all HGG patients. Individual treatment protocols may have different age 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): The specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 as soon as possible (ASAP), preferably within 5 calendar days of the procedure.
- Please note: See the APEC14B1 Manual of Procedures for a full list of detailed instructions for submitting required materials and for shipping details.
- 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 BRAF^V600-mutation
- Results for H3 K27M by immunohistochemistry (IHC) or sequencing
- 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. 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 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.
- All patients and/or their parents or legal guardians must sign a written informed consent
- 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.
- 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.
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): NCT03919071
|Principal Investigator:||Rishi R Lulla||Children's Oncology Group|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2019-02289 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACNS1723 ( Other Identifier: Children's Oncology Group )
ACNS1723 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
|First Posted:||April 18, 2019 Key Record Dates|
|Last Update Posted:||March 17, 2023|
|Last Verified:||January 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
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