AzTrials
AzTrials

Anaplastic AstrocytomaPhase 1NCT01922076

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

A Phase 1 study testing Adavosertib, Laboratory Biomarker Analysis and Pharmacological Study in people with Anaplastic Astrocytoma and Anaplastic Oligoastrocytoma, run by National Cancer Institute (NCI) at 24 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 37 months to 21 years
What is being tested?
Adavosertib, Laboratory Biomarker Analysis and Pharmacological Study
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
46 participants
Where
24 sitesin 2 countries
Study dates
3 Sep 2013to 30 Sep 2022
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 37 months to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
Show all 24Show fewer
  • Patients must not have received any prior anti-cancer therapy such as 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

Who cannot join

  • 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
Show all 17Show fewer
  • 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 locations and contacts

24 sites in 2 countries.

24 sites in 2 countries

United States23 sites

  • C S Mott Children's Hospital

    Ann Arbor, Michigan, 48109

  • Children's Healthcare of Atlanta - Egleston

    Atlanta, Georgia, 30322

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Children's Hospital of Alabama

    Birmingham, Alabama, 35233

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Lurie Children's Hospital-Chicago

    Chicago, Illinois, 60611

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

    Houston, Texas, 77030

  • Riley Hospital for Children

    Indianapolis, Indiana, 46202

  • Children's Hospital Los Angeles

    Los Angeles, California, 90027

  • Saint Jude Children's Research Hospital

    Memphis, Tennessee, 38105

  • Children's Hospital of Wisconsin

    Milwaukee, Wisconsin, 53226

  • University of Minnesota/Masonic Cancer Center

    Minneapolis, Minnesota, 55455

  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

    New York, New York, 10032

  • Children's Hospital of Orange County

    Orange, California, 92868

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15224

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • UCSF Medical Center-Parnassus

    San Francisco, California, 94143

  • UCSF Medical Center-Mission Bay

    San Francisco, California, 94158

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

Canada1 site

  • Hospital for Sick Children

    Toronto, Ontario, M5G 1X8

Other trials in Canada

About this study

Official title: A Phase 1 Study of AZD1775 (MK-1775) Concurrent With Local Radiation Therapy for the Treatment of Newly Diagnosed Children With Diffuse Intrinsic Pontine Gliomas

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

Being tested
Adavosertib, Laboratory Biomarker Analysis, Pharmacological Study, Radiation Therapy
Medical subject headings
Astrocytoma, Diffuse Intrinsic Pontine Glioma, Glioblastoma, Gliosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AdavosertibDrug

    Also called AZD-1775, AZD1775, MK-1775, MK1775

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • Radiation TherapyRadiation

    Also called Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate

    Undergo radiation therapy

Study groups in NCT01922076
Study groupRoleWhat they receive
Treatment (adavosertib, radiation therapy)ExperimentalPatients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive adavosertib 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.
Receives: Drug: Adavosertib; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Radiation: Radiation Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose of Adavosertib

    MTD will be defined as the maximum dose at which fewer than one-third of patients experience a dose-limiting toxicity graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

    Measured: Up to 42 days

  2. Number of Dose Limiting Toxicity With Adavosertib

    Number of patients with dose limiting toxicity stratified by dose level and the toxicity will be graded using the NCI CTCAE version 4.0.

    Measured: Up to 42 days

  3. Area Under the Time Concentration Curve of Adavosertib

    Median (min, max) of the area under the concentration time curve adavosertib assessed at 1, 2, 4, 6, 8, and 24 hours post dose on day 1 stratified by dose level and study part.

    Measured: up to 24 hours

Secondary outcomes (6)

  1. Number of Patients With Response to Adavosertib

    Number of participants with response (CR/PR) by maximal 2-dimensional measures with CR: disappearance of all abnormal signal within the brainstem; PR: at least 50% decrease in the sum o the products of the two perpendicular diameters of the target lesion.

    Measured: Up to 4 years

  2. Progression-free Survival (PFS) of Adavosertib

    Median (95% CI) time to progression or death stratified by dose level and study part. PFS was defined as time from start date of the first treatment to the date of disease progression or death due to any causes which ever occurred first.

    Measured: Up to 4 years

  3. Overall Survival (OS) of Adavosertib

    Median (95% CI) time to progression or death stratified by dose level and study part.

    Measured: Up to 4 years

  4. Change in p-CDC2 of Adavosertib

    Median (min, max) change in expression of p-CDC2 in peripheral blood mononuclear cells (PBMCs) before and after administration by dose level and study part.

    Measured: Baseline to day 8

  5. Change in Expression of p-HH3 of Adavosertib

    Median (min, max) change in expression of p-HH3 in peripheral blood mononuclear cells (PBMCs) before and after administration by dose level and study part

    Measured: Baseline to day 8

  6. Change in Expression of ɤ(Gamma)-H2AX of Adavosertib

    Median (min, max) relative change in expression of gamma-H2AX of adavosertib by dose level and study part.

    Measured: Baseline to day 8

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Aug 2013 (estimated)
  2. Study start3 Sep 2013
  3. Primary completion31 Dec 2020
  4. Study completion30 Sep 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
46 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01922076
Sponsor's protocol ID
NCI-2013-01602
Other IDs
NCI-2013-01602, COG-ADVL1217, ADVL1217, ADVL1217, UM1CA097452
Status last verified
Jan 2024
First submitted
12 Aug 2013
Last updated
31 Jan 2024
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Adavosertib, Laboratory Biomarker Analysis and Pharmacological Study in people with Anaplastic Astrocytoma and Anaplastic Oligoastrocytoma, run by National Cancer Institute (NCI) at 24 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose of Adavosertib (time frame: Up to 42 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01922076.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2024.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in