Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
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|ClinicalTrials.gov Identifier: NCT01922076|
Recruitment Status : Completed
First Posted : August 14, 2013
Last Update Posted : November 14, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioblastoma Gliosarcoma||Drug: Adavosertib Other: Laboratory Biomarker Analysis Other: Pharmacological Study Radiation: Radiation Therapy||Phase 1|
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||46 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 :||September 3, 2013|
|Actual Primary Completion Date :||December 31, 2020|
|Actual Study Completion Date :||September 30, 2022|
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.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Radiation: Radiation Therapy
Undergo radiation therapy
- Maximum tolerated dose (MTD) [ Time Frame: 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.
- Incidence and grade of adverse events [ Time Frame: Up to 4 years ]Adverse events will be graded using the NCI CTCAE version 4.0.
- Pharmacokinetic (PK) parameters of adavosertib [ Time Frame: 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).
- Response rate (partial response, complete response, or stable disease) [ Time Frame: Up to 4 years ]Disease response will be reported descriptively.
- Progression-free survival (PFS) [ Time Frame: Up to 4 years ]PFS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
- Overall survival (OS) [ Time Frame: Up to 4 years ]OS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
- Change in p-CDC2, p-HH3 and gamma-H2AX expression [ Time Frame: Baseline to day 8 ]Will be assessed using flow cytometry. Paired analysis methods will be used.
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|Ages Eligible for Study:||37 Months to 21 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01922076
|Principal Investigator:||Sabine Mueller||COG Phase I Consortium|
Documents provided by National Cancer Institute (NCI):
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2013-01602 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1217 ( Other Identifier: Pediatric Early Phase Clinical Trial Network )
ADVL1217 ( Other Identifier: CTEP )
UM1CA097452 ( U.S. NIH Grant/Contract )
|First Posted:||August 14, 2013 Key Record Dates|
|Last Update Posted:||November 14, 2022|
|Last Verified:||November 2022|
Diffuse Intrinsic Pontine Glioma
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Brain Stem Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Central Nervous System Diseases
Nervous System Diseases
Molecular Mechanisms of Pharmacological Action