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Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

Study Purpose

This phase I trial studies the side effects and the best dose of adavosertib when given together with local radiation therapy in treating children with newly diagnosed diffuse intrinsic pontine gliomas. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving adavosertib with local radiation therapy may work better than local radiation therapy alone in treating diffuse intrinsic pontine gliomas.

Recruitment Criteria

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Accepts Healthy Volunteers
No

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Study Type
Interventional
Eligible Ages 37 Months - 21 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

- Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible without histologic confirmation - Patients with brainstem tumors that do not meet these criteria or are not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible - Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician - Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date - Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment - Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 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 - Patients must not have received any prior chemotherapy, radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG; prior dexamethasone and/or surgery are allowed - Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 - Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or - A serum creatinine based on age/gender as follows: - 0.8 mg/dL (3 to < 6 years of age) - 1.0 mg/dL (6 to < 10 years of age) - 1.2 mg/dL (10 to < 13 years of age) - 1.5 mg/dL (male) or 1.4 mg/dl (female) (13 to < 16 years of age) - 1.7 mg/dL (male) or 1.4 mg/dl (female) (>= 16 years of age) - Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN = 135 units per liter (U/L); for the purpose of this study, the ULN for SGPT is 45 U/L - Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] =< 3 x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L - Serum albumin >= 2 g/dL - Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled - Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) resulting from prior therapy must be =< grade 2 with the exception of tendon reflex (deep tendon reflex [DTR]); any grade of DTR is eligible - Corrected QT interval (QTc) =< 480 msec - All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

- Pregnant or breast-feeding women may not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; negative serum or urine pregnancy test within 3 days prior to enrollment - Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive methods as follows: fertile females of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation; male patients willing to abstain or use barrier contraception (i.e. condoms) for the duration of the study and for 3 months after treatment stops - Patients receiving corticosteroids are eligible for this trial - Patients who are currently receiving another investigational drug are not eligible - Patients who are currently receiving other anti-cancer agents are not eligible - Patients must not currently be receiving enzyme inducing anticonvulsants - Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades De Pointes; if possible, alternative agents should be considered; patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available - Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of CYP3A4, sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are not eligible; the use of aprepitant or fosaprepitant as an antiemetic is prohibited due to early drug interaction data demonstrating increased exposure to AZD1775; the use of hydroxymethylglutary (HMG) coenzyme-A (Co-A) inhibitors such as atorvastatin is prohibited - Herbal preparations are not allowed throughout the study; these herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications 7 days prior to study enrollment - Any known hypersensitivity or contraindication to the components of the study drug AZD1775 - Patients must not receive metformin for at least 5 days prior to enrollment and for the duration of study treatment - Patients must be able to swallow capsules; nasogastric or gastrostomy feeding (G) tube administration is not allowed - Patients who have an uncontrolled infection are not eligible - Patients who have received a prior solid organ transplantation are not eligible - Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial - Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) =< 7 days; no waiting period required following port-a-cath or other central venous access placement - Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Trial Details

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

Trial ID:
NCT01922076

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase
Phase 1

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Lead Sponsor
National Cancer Institute (NCI)

The person who is responsible for the scientific and technical direction of the entire clinical study.

Principal Investigator
Sabine Mueller
Principal Investigator Affiliation COG Phase I Consortium

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Agency Class
NIH
Overall Status Recruiting
Countries Canada, United States

The disease, disorder, syndrome, illness, or injury that is being studied.

Conditions
Anaplastic Astrocytoma, Anaplastic Oligoastrocytoma, Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant, Glioblastoma, Gliosarcoma, Untreated Childhood Anaplastic Astrocytoma, Untreated Childhood Anaplastic Oligoastrocytoma, Untreated Childhood Glioblastoma, Untreated Childhood Gliosarcoma
Additional Details

PRIMARY OBJECTIVES:

  • I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of the adavosertib (Wee1 inhibitor AZD1775 [MK-1775]) administered concurrently with radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).
  • II. To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with radiation therapy in children with newly diagnosed DIPG.
  • III. To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with newly diagnosed DIPG when given concurrently with radiation therapy.
SECONDARY OBJECTIVES:
  • I. To preliminarily define the antitumor activity of AZD1775 (MK-1775) within the confines of a phase 1 study, including response rate, progression free survival, and overall survival of treated patients.
  • II. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of phosphorylated-cell division cycle 2 G1 to S and G2 to M (p-CDC2) (cyclin-dependent kinase 1 [CDK1]) and phosphorylated-histone H3 (p-HH3) in peripheral blood mononuclear cells (PBMCs) before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.
  • III. To assess the biologic activity of AZD1775 (MK-1775) by measuring expression of gamma-H2A histone family, member X (H2AX) in PBMCs, a marker of deoxyribonucleic acid (DNA) double-strand breaks (dsDNA), before and after administration of AZD1775 (MK-1775) in children with newly diagnosed DIPG.
OUTLINE: This is a dose-escalation study of adavosertib. Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib orally (PO) on days 1-5 of weeks 1, 3, and 5; days 1-5 of weeks 1, 3, and 5 AND days 1, 3, and 5 of weeks 2, 4, and 6; OR days 1-5 of weeks 1-6 depending on dose level assignment. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 2 months for 6 months, and then every 3 months thereafter.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Children's Hospital of Alabama, Birmingham, Alabama

Status

Recruiting

Address

Children's Hospital of Alabama

Birmingham, Alabama, 35233

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

Children's Hospital Los Angeles, Los Angeles, California

Status

Suspended

Address

Children's Hospital Los Angeles

Los Angeles, California, 90027

Children's Hospital of Orange County, Orange, California

Status

Suspended

Address

Children's Hospital of Orange County

Orange, California, 92868

UCSF Medical Center-Parnassus, San Francisco, California

Status

Active, not recruiting

Address

UCSF Medical Center-Parnassus

San Francisco, California, 94143

UCSF Medical Center-Mission Bay, San Francisco, California

Status

Suspended

Address

UCSF Medical Center-Mission Bay

San Francisco, California, 94158

Children's Hospital Colorado, Aurora, Colorado

Status

Suspended

Address

Children's Hospital Colorado

Aurora, Colorado, 80045

Children's National Medical Center, Washington, District of Columbia

Status

Suspended

Address

Children's National Medical Center

Washington, District of Columbia, 20010

Atlanta, Georgia

Status

Suspended

Address

Children's Healthcare of Atlanta - Egleston

Atlanta, Georgia, 30322

Lurie Children's Hospital-Chicago, Chicago, Illinois

Status

Suspended

Address

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611

Riley Hospital for Children, Indianapolis, Indiana

Status

Recruiting

Address

Riley Hospital for Children

Indianapolis, Indiana, 46202

Site Contact

Site Public Contact

800-248-1199

Dana-Farber Cancer Institute, Boston, Massachusetts

Status

Suspended

Address

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

C S Mott Children's Hospital, Ann Arbor, Michigan

Status

Suspended

Address

C S Mott Children's Hospital

Ann Arbor, Michigan, 48109

Minneapolis, Minnesota

Status

Suspended

Address

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, 55455

Washington University School of Medicine, Saint Louis, Missouri

Status

Suspended

Address

Washington University School of Medicine

Saint Louis, Missouri, 63110

New York, New York

Status

Suspended

Address

Columbia University/Herbert Irving Cancer Center

New York, New York, 10032

Cincinnati, Ohio

Status

Suspended

Address

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229

Oregon Health and Science University, Portland, Oregon

Status

Suspended

Address

Oregon Health and Science University

Portland, Oregon, 97239

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Status

Suspended

Address

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104

Pittsburgh, Pennsylvania

Status

Recruiting

Address

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224

Site Contact

Site Public Contact

ctsucontact@westat.com

888-823-5923

St. Jude Children's Research Hospital, Memphis, Tennessee

Status

Suspended

Address

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105

Houston, Texas

Status

Suspended

Address

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, 77030

Seattle Children's Hospital, Seattle, Washington

Status

Suspended

Address

Seattle Children's Hospital

Seattle, Washington, 98105

Children's Hospital of Wisconsin, Milwaukee, Wisconsin

Status

Suspended

Address

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226

International Sites

Hospital for Sick Children, Toronto, Ontario, Canada

Status

Active, not recruiting

Address

Hospital for Sick Children

Toronto, Ontario, M5G 1X8

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