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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT01922076
Collaborator
(none)
46
Enrollment
24
Locations
1
Arm
1.9
Patients Per Site

Study Details

Study Description

Brief 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. 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.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Adavosertib
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Radiation: Radiation Therapy
Phase 1

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).

  2. To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with radiation therapy in children with newly diagnosed DIPG.

  3. 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.

  2. 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.

  3. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
46 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Sep 3, 2013
Actual Primary Completion Date :
Dec 31, 2020

Arms and Interventions

ArmIntervention/Treatment
Experimental: Treatment (adavosertib, radiation therapy)

Patients 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.

Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Other: Pharmacological Study
    Correlative studies

    Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Outcome Measures

    Primary Outcome Measures

    1. Maximum tolerated dose (MTD) [Up to 42 days]

      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.

    2. Incidence and grade of adverse events [Up to 4 years]

      Adverse events will be graded using the NCI CTCAE version 4.0.

    Other Outcome Measures

    1. Pharmacokinetic (PK) parameters of adavosertib [Pre-dose, 1, 2, 4, 6, 8, and 24 hours on day 1; pre-dose, 1, 2, 4, 6, and 8 hours on day 5; and pre-dose on day 8]

      A descriptive analysis of PK parameters of adavosertib will be performed to define systemic exposure and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

    2. Response rate (partial response, complete response, or stable disease) [Up to 4 years]

      Disease response will be reported descriptively.

    3. Progression-free survival (PFS) [Up to 4 years]

      PFS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.

    4. Overall survival (OS) [Up to 4 years]

      OS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.

    5. Change in p-CDC2, p-HH3 and gamma-H2AX expression [Baseline to day 8]

      Will be assessed using flow cytometry. Paired analysis methods will be used.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    37 Months to 21 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 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

    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Children's Hospital of AlabamaBirminghamAlabamaUnited States35233
    2Children's Hospital Los AngelesLos AngelesCaliforniaUnited States90027
    3Children's Hospital of Orange CountyOrangeCaliforniaUnited States92868
    4UCSF Medical Center-ParnassusSan FranciscoCaliforniaUnited States94143
    5UCSF Medical Center-Mission BaySan FranciscoCaliforniaUnited States94158
    6Children's Hospital ColoradoAuroraColoradoUnited States80045
    7Children's National Medical CenterWashingtonDistrict of ColumbiaUnited States20010
    8Children's Healthcare of Atlanta - EglestonAtlantaGeorgiaUnited States30322
    9Lurie Children's Hospital-ChicagoChicagoIllinoisUnited States60611
    10Riley Hospital for ChildrenIndianapolisIndianaUnited States46202
    11Dana-Farber Cancer InstituteBostonMassachusettsUnited States02215
    12C S Mott Children's HospitalAnn ArborMichiganUnited States48109
    13University of Minnesota/Masonic Cancer CenterMinneapolisMinnesotaUnited States55455
    14Washington University School of MedicineSaint LouisMissouriUnited States63110
    15NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer CenterNew YorkNew YorkUnited States10032
    16Cincinnati Children's Hospital Medical CenterCincinnatiOhioUnited States45229
    17Oregon Health and Science UniversityPortlandOregonUnited States97239
    18Children's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUnited States19104
    19Children's Hospital of Pittsburgh of UPMCPittsburghPennsylvaniaUnited States15224
    20Saint Jude Children's Research HospitalMemphisTennesseeUnited States38105
    21Baylor College of Medicine/Dan L Duncan Comprehensive Cancer CenterHoustonTexasUnited States77030
    22Seattle Children's HospitalSeattleWashingtonUnited States98105
    23Children's Hospital of WisconsinMilwaukeeWisconsinUnited States53226
    24Hospital for Sick ChildrenTorontoOntarioCanadaM5G 1X8

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Sabine Mueller, COG Phase I Consortium

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01922076
    Other Study ID Numbers:
    • NCI-2013-01602
    • NCI-2013-01602
    • COG-ADVL1217
    • ADVL1217
    • ADVL1217
    • UM1CA097452
    First Posted:
    Aug 14, 2013
    Last Update Posted:
    Dec 1, 2021
    Last Verified:
    Nov 1, 2021

    Study Results

    No Results Posted as of Dec 1, 2021