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

Glioblastoma Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05099003
• Other study ID #: NCI-2021-11337
• Secondary ID: NCI-2021-11337AC
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: May 31, 2022
• Est. completion date: June 30, 2027

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 210
• Est. completion date: June 30, 2027
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 21 Years

Eligibility

Inclusion Criteria:

• PRE ENROLLMENT: Patients must be =< 25 years of age at the time of enrollment on APEC14B1 part A cnetral nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening

• Please note:

• This required age range applies to pre-enrollment eligibility for all HGG patients. Individual treatment protocols may have different age criteria.

• Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are >= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).

• PRE ENROLLMENT: Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG

• Please note: there are specific radiographic criteria for DIPG patient enrollment on ACNS1821 (Step 1)

• PRE ENROLLMENT:

• For patients with non-pontine tumors: Patients and/or their parents or legal guardians must have signed informed consent for eligibility screening on APEC14B1 Part A.

• For patients with DIPG: Patients and/or their parents or legal guardians must have signed informed consent for ACNS1821.

• PRE ENROLLMENT:

• For patients with non-pontine tumors only, the specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery

• STEP 1: Patients must be >= 12 months and =< 21 years of age at the time of enrollment

• STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).

• STEP 1: Stratum DIPG

• Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.

• Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS], and/or H3 K27M-mutant) by institutional diagnosis.

• STEP 1: Stratum DMG (with H3 K27M mutation)

• Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1

• Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.

• STEP 1: Stratum HGG (without H3 K27M mutation)

• Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1

• Please note:

• Patients who fall in this category and who are >= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available

• Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment

• STEP 1: 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. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• STEP 1: Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to step 1 enrollment)

• STEP 1: Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)

• STEP 1: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to step 1 enrollment)

• STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) or

A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):

• Age / Maximum Serum Creatinine (mg/dL)

• 1 to < 2 years / male: 0.6; female: 0.6

• 2 to < 6 years / male: 0.8; female: 0.8

• 6 to < 10 years / male: 1; female: 1

• 10 to < 13 years / male: 1.2; female: 1.2

• 13 to < 16 years / male: 1.5; female: 1.4

• >= 16 years / male: 1.7; female: 1.4

• STEP 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

• STEP 1: Serum amylase =< 1.5 x ULN

• STEP 1: Serum lipase =< 1.5 x ULN

• STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination.

• STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.

• STEP 1: Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (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.

Exclusion Criteria:

• STEP 1: Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.

• STEP 1: Patients who are currently receiving another investigational drug are not eligible.

• STEP 1: Patients who are currently receiving other anti-cancer agents are not eligible.

• STEP 1: Patients >=18 years of age who have H3 K27M-wild type HGG.

• STEP 1: Patients who have an uncontrolled infection.

• STEP 1: Patients who have received a prior solid organ transplantation.

• STEP 1: Patients with grade > 1 extrapyramidal movement disorder.

• STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.

• STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and without contrast must be performed if metastatic disease is suspected by the treating physician.

• STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.

• STEP 1: Patients who are not able to receive protocol specified radiation therapy.

• STEP 1:

• 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. It is not known whether selinexor is excreted in human milk.

• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.

• Sexually active patients of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control (including a medically accepted barrier method of contraception, e.g., male or female condom) for the duration of their study participation and for 90 days after the last dose of selinexor. Abstinence is an acceptable method of birth control.

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Astrocytoma
• Diffuse Intrinsic Pontine Glioma
• Diffuse Midline Glioma, H3 K27M-Mutant
• Glioblastoma
• Glioma
• Malignant Glioma

Intervention

Procedure:
• Biopsy
Undergo a biopsy
• Magnetic Resonance Imaging
Undergo a MRI

Radiation:
• Radiation Therapy
Undergo radiation therapy

Drug:
• Selinexor
Given orally

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Perth Children's Hospital	Perth	Western Australia
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)	Quebec
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Miami Cancer Institute	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose	Defined as the highest dose of selinexor in combination with standard of care radiation therapy (RT) that does not cause unacceptable side effects.	From day 1 of selinexor treatment until the start of maintenance therapy, assessed up to 10 weeks from treatment start date
Primary	Event free survival (EFS)	Will be calculated for diffuse midline glioma (DMG)/ high grade glioma (HGG) patients. EFS curve will be estimated by Kaplan Meier estimates.	From the date of diagnosis until disease progression date, secondary malignant neoplasm occurrence date, death date of any cause, or last follow-up date, assessed up to 5 years
Primary	Overall Survival (OS)	Will be calculated for diffuse intrinsic pontine glioma (DIPG) patients. The OS curve will be estimated by Kaplan Meier estimates.	From the date of diagnosis until death date of any cause or last follow-up date, assessed up to 5 years
Primary	Overall response rate (ORR)	Defined as the proportion of patients whose best response is partial response or complete response.	Up to 5 years