Clinical Trials /

Dabrafenib With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed BRAF V600-Mutant High-Grade Glioma

NCT03919071

Description:

This phase II trial studies how well dabrafenib with trametinib work after radiation therapy in treating patients with a type of genetic mutation (BRAF V600-mutant) and newly-diagnosed, high-grade glioma. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in helping to get rid of or shrinking tumors in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dabrafenib With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed BRAF V600-Mutant High-Grade Glioma
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-02289
  • SECONDARY ID: NCI-2019-02289
  • SECONDARY ID: ACNS1723
  • SECONDARY ID: ACNS1723
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03919071

Conditions

  • Anaplastic Astrocytoma
  • Anaplastic Ganglioglioma
  • Anaplastic Pleomorphic Xanthoastrocytoma
  • BRAF NP_004324.2:p.V600X
  • Glioblastoma
  • H3 K27M Negative
  • Malignant Glioma
  • WHO Grade III Glioma

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436Treatment (radiation therapy, dabrafenib, trametinib)
Dabrafenib MesylateDabrafenib Methanesulfonate, GSK2118436 Methane Sulfonate Salt, GSK2118436B, TafinlarTreatment (radiation therapy, dabrafenib, trametinib)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (radiation therapy, dabrafenib, trametinib)
Trametinib Dimethyl SulfoxideTreatment (radiation therapy, dabrafenib, trametinib)

Purpose

This phase II trial studies how well dabrafenib with trametinib work after radiation therapy in treating patients with a type of genetic mutation (BRAF V600-mutant) and newly-diagnosed, high-grade glioma. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib with trametinib after radiation therapy may work better than treatments used in the past in helping to get rid of or shrinking tumors in patients with newly-diagnosed BRAF V600-mutant high-grade glioma.

Detailed Description

      PRIMARY OBJECTIVES:

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

      EXPLORATORY OBJECTIVES:

      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. Starting 4 weeks later, 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (radiation therapy, dabrafenib, trametinib)ExperimentalPatients undergo standardized local RT 5 days a week (Monday-Friday) for 6-7 weeks. Starting 4 weeks later, patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Dabrafenib
  • Dabrafenib Mesylate
  • Trametinib
  • Trametinib Dimethyl Sulfoxide

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having
             localized newly-diagnosed HGG, excluding intrinsic brainstem or spinal cord tumors, or
             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 submitted through APEC14B1 as soon as possible (ASAP),
             preferably within 13 calendar days of definitive surgery.

          -  Patients must have eligibility confirmed by Rapid Central Pathology and Molecular
             Screening Reviews performed on APEC14B1

               -  Newly diagnosed high-grade glioma with BRAFV600-mutation

               -  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

          -  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]) =< 3 x
             upper limit of normal (ULN) for age (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 diagnostic surgery (day 0). For patients who have a
             biopsy followed by resection, the date of resection will be considered the date of
             definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be
             considered the date of definitive diagnostic 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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS)
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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From the date of diagnosis until death date of any cause or last follow up date, assessed up to 5 years
Safety Issue:
Description: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.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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