WEE1 Inhibitor AZD1775 and Local Radiation Therapy in Treating Younger Patients With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
|Diffuse Intrinsic Pontine Glioma Untreated Childhood Anaplastic Astrocytoma Untreated Childhood Anaplastic Oligoastrocytoma Untreated Childhood Glioblastoma Untreated Childhood Gliosarcoma||Other: Laboratory Biomarker Analysis Other: Pharmacological Study Radiation: Radiation Therapy Drug: WEE1 Inhibitor AZD1775||Phase 1|
|Study Design:||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|
- Incidence and grade of adverse events using the NCI CTCAE version 4.0 [ Time Frame: Up to 4 years ]
- MTD, 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 [ Time Frame: Up to 42 days ]
- Change in p-CDC2, p-HH3 and gamma-H2AX expression using flow cytometry [ Time Frame: Baseline to day 8 ]Paired analysis methods will be used.
- Overall survival (OS) [ Time Frame: Up to 4 years ]OS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
- Pharmacokinetic (PK) parameters of WEE1 inhibitor AZD1775 [ 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 WEE1 inhibitor AZD1775 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).
- Progression-free survival (PFS) [ Time Frame: Up to 4 years ]PFS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
- Response rate (partial response, complete response, or stable disease) [ Time Frame: Up to 4 years ]Disease response will be reported descriptively.
|Actual Study Start Date:||September 3, 2013|
|Estimated Primary Completion Date:||October 31, 2021 (Final data collection date for primary outcome measure)|
Experimental: Treatment (WEE1 inhibitor AZD1775, radiation therapy)
Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive WEE1 inhibitor AZD1775 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
Correlative studiesOther: Pharmacological Study
Correlative studiesRadiation: Radiation Therapy
Undergo radiation therapyDrug: WEE1 Inhibitor AZD1775
I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose and schedule of the WEE1 inhibitor AZD1775 (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 WEE1 inhibitor AZD1775 (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.
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 WEE1 inhibitor AZD1775.
Patients undergo radiation therapy 5 days a week for 6 weeks (up to 30 fractions). Patients also receive WEE1 inhibitor AZD1775 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01922076
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|Principal Investigator:||Sabine Mueller||COG Phase I Consortium|