This phase I clinical trial studies the side effects and best dose of AZD1390 and to see how well it works when given together with radiation therapy for the treatment of pediatric patients with high grade glioma, diffuse midline glioma or diffuse intrinsic pontine glioma. AZD1390 is in a class of medications called kinase inhibitors. It works by blocking the signals that cause cancer cells to repair deoxyribonucleic acid damage caused by cancer treatments, such as radiation therapy. This may help overcome resistance to therapy seen in these cancers and therefore lead to increased death of cancer cells. Radiation therapy uses high energy x-rays or particles to kill cancer cells and shrink tumors. Giving AZD1390 with radiation may be safe, tolerable, and effective in treating pediatric patients with high grade glioma, diffuse midline glioma or diffuse intrinsic pontine glioma.
COHORT A and COHORT B: For the dose escalation phase, patients must be ≥ 12 months and < 18 years of age at the time of study enrollment
COHORT C and COHORT D: For the disease expansion phase, patients must be ≥ 12 months and < 22 years of age at the time of study enrollment
Patients with newly diagnosed primary high-grade glioma (HGG), diffuse midline glioma (DMG) (excluding primary spinal tumors), or diffuse intrinsic pontine glioma (DIPG) who are eligible to receive 54-59.4 Gray (Gy) fractionated radiation at 1.8 Gy/day. Patients must have had histologic verification of malignancy at original diagnosis except in patients with DIPG as defined below.
Patients with newly diagnosed HGG (including diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma, IDH-wildtype): or non-pontine DMG (including diffuse midline glioma, H3 K27-altered; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma, IDH-wildtype) require histologic diagnosis.
Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Women of childbearing potential should use adequate contraception during study participation and for 6 months after the last dose of AZD1390. Male patients with female partners of childbearing potential should use adequate contraception during study participation and for 16 weeks after the last dose of AZD1390
Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible
Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible with the exception of corticosteroids
Anti-graft versus host disease (GVHD) agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
Single group
ATM Kinase Inhibitor AZD1390
DrugGiven PO
Biospecimen Collection
Procedure/SurgeryUndergo blood and cerebrospinal fluid collection
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Radiation Therapy
RadiationUndergo radiation therapy
Survey Administration
Other interventionAncillary studies
Maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of ATM Kinase Inhibitor AZD1390 (AZD1390) for pediatric supratentorial high-grade gliomas
The maximum tolerated dose or recommended phase 2 dose will be estimated by the isotonic estimates of toxicity probabilities for which the estimate of the DLT/RP2D rate is closed to the target rate of 25% in children and adolescents with supratentorial tumors.
Maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AZD1390 for pediatric infratentorial high-grade gliomas
The maximum tolerated dose or recommended phase 2 dose will be estimated by the isotonic estimates of toxicity probabilities for which the estimate of the DLT/RP2D rate is closed to the target rate of 25% in children and adolescents with infratentorial tumors.
Incidence of adverse events for AZD1390 for pediatric supratentorial high-grade gliomas
Frequency (%) of evaluable patients with toxicity at least possibly attributable to study agent stratified by study part and dose level using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0).
Incidence of adverse events for AZD1390 for pediatric infratentorial high-grade gliomas
Frequency (%) of evaluable patients with toxicity at least possibly attributable to study agent stratified by study part and dose level using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v 5.0).
Progression free survival (PFS) for patients with supratentorial high-grade gliomas
Median (95% confidence interval) of the time to progression for patients with supratentorial high-grade gliomas.
Overall survival (OS) for patients with supratentorial high-grade gliomas
Median (95% confidence interval) of the time to death due to any cause for patients supratentorial high-grade gliomas.
Overall radiographic response (ORR) for patients with supratentorial high-grade gliomas
Best overall response (CR, PR, SD, PD) will be summarized by frequency (%) of response-evaluable patients with supratentorial high-grade gliomas.
PFS for patients with infratentorial high-grade gliomas
Median (95% confidence interval) of the time to progression for patients with infratentorial high-grade gliomas.
Change in Neurocognitive function
Median (min, max) change in scores for each of detection, identification, on-back, one-card learning, and Groton maze learning test stratified by disease cohort (supratentorial and infratentorial) and dose level at 22-weeks and 44-weeks versus baseline.
Change in patient reported outcomes measurement information system
Median (min, max) change in PROMIS scores for each subdomain (Cognitive function, global health, 29 profile, early childhood parent report global health, and parent proxy every 8-weeks during the first 12-months and then every 3-4 months versus baseline.
Alternative lengthening of telomeres phenotype
Frequency (%) of patients with alternative lengthening of telomeres (ALT) phenotype.
Genomic, transcriptomic, proteomic, and cytokine markers, including homologous recombination deficiency and associated mutational signatures and TP53/related deoxyribonucleic acid (DNA) repair gene mutational status
Median (min, max) genomic, transcriptomic, proteomic, and cytoking markers stratified by patient best overall response.
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