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Nervous System Neoplasms

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Central Nervous System Diseases

Anaplastic Astrocytoma

Neuroepithelioma

CHEMORADIOTHERAPY: Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor PO on 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. After a 2-week rest period, patients proceed to Maintenance. Patients undergo a MRI and may undergo a biopsy during screening.

MAINTENANCE: Patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity. Patients undergo a MRI on study and during follow-up.

Biopsy

Magnetic Resonance Imaging

Radiation Therapy

Selinexor

Site Public Contact

Girish Dhall

Joseph C. Torkildson

David L. Becton

Albert Kheradpour

Jacqueline N. Casillas

Tom B. Davidson

Caroline A. Hastings

Aarati V. Rao

Elyssa M. Rubin

William D. Roberts

Adam L. Green

Michael S. Isakoff

Asher M. Marks

Scott M. Bradfield

Jeffrey S. Dome

Emad K. Salman

Matthew D. Hall

Jaime M. Libes-Bander

Stacie L. Stapleton

Robert C. Castellino

Wade T. Kyono

Martha M. Pacheco

Susan L. Cohn

Prerna Kumar

Sandeep Batra

Samantha L. Mallory

David S. Dickens

James T. Badgett

Ashok B. Raj

Lolie C. Yu

Daniel L. Callaway

Nadav L. Kastle

Kenneth J. Cohen

Karen D. Wright

Carl J. Koschmann

Hamza Gorsi

Kathleen J. Yost

Michael K. Richards

Christopher L. Moertel

Betty L. Herrington

Keith J. August

William S. Ferguson

Andrew S. Cluster

Robin D. Hanson

Jill C. Beck

Derek R. Hanson

Kathryn L. Laurie

Scott Moerdler

Teena Bhatla

Alissa Kahn

Lauren R. Weintraub

Alice Lee

Clare J. Twist

Julie I. Krystal

Sameer Farouk Sait

Melanie A. Comito

Jessica A. Bell

Thomas W. McLean

Samuel J. Milanovich

Erin Wright

Peter M. de Blank

Duncan S. Stearns

Mark A. Ranalli

Jamie L. Dargart

Rene Y. McNall-Knapp

Jason M. Glover

Linda C. Stork

Cassie Kline

Gregory E. Halligan

James T. Felker

Jennifer J. Welch

Stuart L. Cramer

Aniket Saha

Kayelyn J. Wagner

Kelsey Bertrand

Jennifer A. Domm

Shannon M. Cohn

Stanton C. Goldman

Ashley Bui

Sibo Zhao

Patricia A. Baxter

Najat C. Daw

Timothy C. Griffin

Shafqat Shah

Priya Chan

Eric J. Lowe

Sarah E. Leary

Judy L. Felgenhauer

Robert G. Irwin

Kenneth B. De Santes

Sarah Rumler

Marianne B. Phillips

Adam L Green

This phase I/II trial tests the safety, side effects, and best dose of selinexor given in combination with standard radiation therapy in treating children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) with a genetic change called H3 K27M mutation. It also tests whether combination of selinexor and standard radiation therapy works to shrink tumors in this patient population. Glioma is a type of cancer that occurs in the brain or spine. Glioma is considered high risk (or high-grade) when it is growing and spreading quickly. The term, risk, refers to the chance of the cancer coming back after treatment. DIPG is a subtype of HGG that grows in the pons (a part of the brainstem that controls functions like breathing, swallowing, speaking, and eye movements). This trial has two parts. The only difference in treatment between the two parts is that some subjects treated in Part 1 may receive a different dose of selinexor than the subjects treated in Part 2. In Part 1 (also called the Dose-Finding Phase), investigators want to determine the dose of selinexor that can be given without causing side effects that are too severe. This dose is called the maximum tolerated dose (MTD). In Part 2 (also called the Efficacy Phase), investigators want to find out how effective the MTD of selinexor is against HGG or DIPG. Selinexor blocks a protein called CRM1, which may help keep cancer cells from growing and may kill them. It is a type of small molecule inhibitor called selective inhibitors of nuclear export (SINE). Radiation therapy uses high energy to kill tumor cells and shrink tumors. The combination of selinexor and radiation therapy may be effective in treating patients with newly-diagnosed DIPG and H3 K27M-Mutant HGG.

PRIMARY OBJECTIVES:

I. To define toxicities and estimate the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of selinexor administered as an oral formulation in combination with standard of care radiation therapy (RT), to pediatric patients with newly diagnosed high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). (Dose-finding phase/phase I) II. To estimate the event-free survival (EFS) distribution for diffuse midline glioma (DMG)/HGG patients and overall survival (OS) distribution for DIPG patients associated with selinexor plus RT, followed by selinexor in patients with newly diagnosed HGG (H3 K27M mutant DMG or H3 K27-wild type HGG) or DIPG, and to compare those outcomes to historical controls. (Efficacy phase/phase II)

EXPLORATORY OBJECTIVE:

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

OUTLINE: This is a phase I dose-escalation study of selinexor followed by a phase II study.

CHEMORADIOTHERAPY: Patients receive standard of care radiation therapy 5 days per week for 5-7 weeks. Starting on day 4 or 5 of radiation therapy, patients receive selinexor orally (PO) on days 1, 8, 15, 22, 29, 36, 43, and 50 in the absence of disease progression or unacceptable toxicity. After a 2-week rest period, patients proceed to Maintenance. Patients undergo a magnetic resonance imaging (MRI) and may undergo a biopsy during screening.

MAINTENANCE: Patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for up to 24 cycles of maintenance therapy in the absence of disease progression or unacceptable toxicity. Patients undergo a MRI on study and during follow-up.

After completion of study treatment, patients are followed every 3 months for year 1 (i.e., 3, 6, 9, 12 months), then every 6 months for years 2-3 (i.e., 18, 24, 30, 36 months), and finally once yearly for years 4-5 of this study.

A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)

A Phase 1/2 Trial of Selinexor (KPT-330) and Radiation Therapy in Newly-Diagnosed Pediatric Diffuse Intrinsic Pontine Glioma (DIPG) and High-Grade Glioma (HGG)

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

Defined as the highest dose of selinexor in combination with standard of care radiation therapy (RT) that does not cause unacceptable side effects.

Will be calculated for diffuse midline glioma (DMG)/ high grade glioma (HGG) patients. EFS curve will be estimated by Kaplan Meier estimates.

Will be calculated for diffuse intrinsic pontine glioma (DIPG) patients. The OS curve will be estimated by Kaplan Meier estimates.

Defined as the proportion of patients whose best response is partial response or complete response.

National Cancer Institute (NCI)

Ganglioglioma

Pleomorphic Xanthoastrocytoma

Anaplastic Pleomorphic Xanthoastrocytoma

Anaplastic Ganglioglioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Dimethyl Sulfoxide

Protein Kinase Inhibitors

Enzyme Inhibitors

Protective Agents

Antioxidants

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.

Biospecimen Collection

Dabrafenib Mesylate

Lumbar Puncture

Trametinib Dimethyl Sulfoxide

Lindsey M. Hoffman

Hung N. Tran

Fataneh (Fae) Majlessipour

Jay Michael S. Balagtas

Alyssa T. Reddy

Kathleen M. Dorris

Farzana Pashankar

Iftikhar Hanif

Julio C. Barredo

Ziad A. Khatib

Fouad M. Hajjar

Andrew J. Galligan

Don E. Eslin

Matthew D. Ramirez

Tobey J. MacDonald

Andrew L. Pendleton

Angela J. Waanders

Wendy S. Darlington

Jessica F. Goodman

Craig Lotterman

Allen I. Stering

David H. Ebb

Susan N. Chi

Laura K. Gowans

Jonathan D. Schwartz

Jessica M. Valdez

Nobuko Hijiya

Douglas J. Scothorn

Joel A. Kaplan

Andrea R. Whitfield

Rabi Hanna

Mukund G. Dole

Jacob A. Troutman

Lisa M. McGregor

Jane E. Minturn

Rishi R Lulla

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.

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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.

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 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.

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

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)

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.

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.

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.

For stratum 2 and stratum 3, Kaplan Meier estimates will be provided for EFS distribution.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)	NCT05099003	Anaplastic Astr... Anaplastic Astr... Diffuse Intrins... Diffuse Midline... Glioblastoma Glioblastoma, N... Malignant Gliom...	Biopsy Magnetic Resona... Radiation Thera... Selinexor	12 Months - 21 Years	National Cancer Institute (NCI)
A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)	NCT05099003	Anaplastic Astr... Anaplastic Astr... Diffuse Intrins... Diffuse Midline... Glioblastoma Glioblastoma, N... Malignant Gliom...	Biopsy Magnetic Resona... Radiation Thera... Selinexor	12 Months - 21 Years	National Cancer Institute (NCI)
Dabrafenib Combined With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed High-Grade Glioma	NCT03919071	Anaplastic Astr... Anaplastic Astr... Anaplastic Gang... Anaplastic Pleo... Glioblastoma Malignant Gliom... WHO Grade 3 Gli...	Biospecimen Col... Dabrafenib Mesy... Lumbar Puncture Magnetic Resona... Radiation Thera... Trametinib Dime...	12 Months - 21 Years	National Cancer Institute (NCI)

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