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 : Active, not recruiting
First Posted : August 14, 2013
Last Update Posted : December 17, 2020
|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)|
|Estimated Enrollment :||77 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|
|Estimated Primary Completion Date :||October 31, 2021|
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.
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|