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Trial record 11 of 22 for:    Recruiting, Enrolling by invitation Studies | Interventional Studies | glioma | United States | First posted from 04/01/2019 to 07/31/2019

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 : October 23, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
Anaplastic Astrocytoma Anaplastic Ganglioglioma Anaplastic Pleomorphic Xanthoastrocytoma Glioblastoma Malignant Glioma WHO Grade III Glioma Drug: Dabrafenib Drug: Dabrafenib Mesylate Radiation: Radiation Therapy Drug: Trametinib Drug: Trametinib Dimethyl Sulfoxide Phase 2

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. 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.


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Study Type : Interventional
Estimated Enrollment : 58 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 : June 1, 2022
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
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. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Dabrafenib
Given PO
Other Names:
  • BRAF Inhibitor GSK2118436
  • GSK-2118436
  • GSK-2118436A
  • GSK2118436

Drug: Dabrafenib Mesylate
Given PO
Other Names:
  • Dabrafenib Methanesulfonate
  • GSK2118436 Methane Sulfonate Salt
  • GSK2118436B
  • Tafinlar

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • irradiated
  • Irradiation
  • Radiation
  • Radiotherapeutics
  • radiotherapy
  • RT
  • Therapy, Radiation

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist

Drug: Trametinib Dimethyl Sulfoxide
Given PO




Primary Outcome Measures :
  1. 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 ]
    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. For Stratum 2, Kaplan Meier estimates will be provided for EFS distribution.


Secondary Outcome Measures :
  1. 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 ]
    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, Kaplan Meier estimates will be provided for OS distribution.

  2. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 be 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.

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): NCT03919071


Locations
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United States, Arkansas
Arkansas Children's Hospital Recruiting
Little Rock, Arkansas, United States, 72202-3591
Contact: Site Public Contact    501-364-7373      
Principal Investigator: David L. Becton         
United States, California
Kaiser Permanente-Oakland Recruiting
Oakland, California, United States, 94611
Contact: Site Public Contact    877-642-4691    Kpoct@kp.org   
Principal Investigator: Laura A. Campbell         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    303-764-5056    josh.b.gordon@nsmtp.kp.org   
Principal Investigator: Kathleen M. Dorris         
United States, Florida
Saint Mary's Hospital Recruiting
West Palm Beach, Florida, United States, 33407
Contact: Site Public Contact    561-881-2815      
Principal Investigator: Narayana Gowda         
United States, Georgia
Memorial Health University Medical Center Recruiting
Savannah, Georgia, United States, 31404
Contact: Site Public Contact    912-350-7887    clayter1@memorialhealth.com   
Principal Investigator: Andrew L. Pendleton         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Susan N. Chi         
United States, Michigan
C S Mott Children's Hospital Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Site Public Contact    800-865-1125      
Principal Investigator: Carl J. Koschmann         
Helen DeVos Children's Hospital at Spectrum Health Recruiting
Grand Rapids, Michigan, United States, 49503
Contact: Site Public Contact    616-391-1230    crcwm-regulatory@crcwm.org   
Principal Investigator: Kathleen J. Yost         
Bronson Methodist Hospital Recruiting
Kalamazoo, Michigan, United States, 49007
Contact: Site Public Contact    616-391-1230    crcwm-regulatory@crcwm.org   
Principal Investigator: Kathleen J. Yost         
United States, Ohio
Children's Hospital Medical Center of Akron Recruiting
Akron, Ohio, United States, 44308
Contact: Site Public Contact    330-543-3193      
Principal Investigator: Steven J. Kuerbitz         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Site Public Contact    503-494-1080    trials@ohsu.edu   
Principal Investigator: Kellie J. Nazemi         
United States, Rhode Island
Rhode Island Hospital Recruiting
Providence, Rhode Island, United States, 02903
Contact: Site Public Contact    401-444-1488      
Principal Investigator: Jennifer J. Greene Welch         
United States, Tennessee
East Tennessee Childrens Hospital Recruiting
Knoxville, Tennessee, United States, 37916
Contact: Site Public Contact    865-541-8266      
Principal Investigator: Ray C. Pais         
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Site Public Contact    866-278-5833    info@stjude.org   
Principal Investigator: Santhosh A. Upadhyaya         
United States, Texas
UT Southwestern/Simmons Cancer Center-Dallas Recruiting
Dallas, Texas, United States, 75390
Contact: Site Public Contact    214-648-7097    canceranswerline@UTSouthwestern.edu   
Principal Investigator: Daniel C. Bowers         
Children's Hospital of San Antonio Recruiting
San Antonio, Texas, United States, 78207
Contact: Site Public Contact       helpdesk@childrensoncologygroup.org   
Principal Investigator: Timothy C. Griffin         
United States, Virginia
Children's Hospital of The King's Daughters Recruiting
Norfolk, Virginia, United States, 23507
Contact: Site Public Contact    757-066-8724    CCBDCresearch@chkd.org   
Principal Investigator: Eric J. Lowe         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Rishi R Lulla Children's Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03919071     History of Changes
Other Study ID Numbers: NCI-2019-02289
NCI-2019-02289 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACNS1723 ( Other Identifier: Childrens Oncology Group )
ACNS1723 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: April 18, 2019    Key Record Dates
Last Update Posted: October 23, 2019
Last Verified: October 2019
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.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioma
Glioblastoma
Astrocytoma
Ganglioglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Trametinib
Dabrafenib
Dimethyl Sulfoxide
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cryoprotective Agents
Protective Agents
Physiological Effects of Drugs
Free Radical Scavengers
Antioxidants