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Report for Clinical Trial NCT01922076

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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

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.

NCT01922076 Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioblastoma Gliosarcoma
MeSH: Glioblastoma Glioma Astrocytoma Gliosarcoma
HPO: Astrocytoma Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

4 Interventions

Name: Adavosertib

Description: Given PO

Type: Drug

Treatment (adavosertib, radiation therapy)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Treatment (adavosertib, radiation therapy)

Name: Pharmacological Study

Description: Correlative studies

Type: Other

Treatment (adavosertib, radiation therapy)

Name: Radiation Therapy

Description: Undergo radiation therapy

Type: Radiation

Treatment (adavosertib, radiation therapy)


Primary Outcomes

Description: 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.

Measure: Maximum tolerated dose (MTD)

Time: Up to 42 days

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

Measure: Incidence and grade of adverse events

Time: Up to 4 years

Other Outcomes

Description: 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).

Measure: Pharmacokinetic (PK) parameters of adavosertib

Time: 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

Description: Disease response will be reported descriptively.

Measure: Response rate (partial response, complete response, or stable disease)

Time: Up to 4 years

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

Measure: Progression-free survival (PFS)

Time: Up to 4 years

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

Measure: Overall survival (OS)

Time: Up to 4 years

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

Measure: Change in p-CDC2, p-HH3 and gamma-H2AX expression

Time: Baseline to day 8

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 K27M

Paired analysis methods will be used.. 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 --- K27M ---

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 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 --- K27M ---

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 Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant Glioblastoma Gliosarcoma Glioblastoma Glioma Astrocytoma Gliosarcoma PRIMARY OBJECTIVES: 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). --- K27M ---



HPO Nodes


HPO:
Astrocytoma
Genes 27
TSC2 APC MSH3 BRCA2 MLH1 TSC1 PMS2 APC IDH1 MSH6 POT1 TSC2 CDKN2A NF2 IFNG MSH3 APC TSC1 NF1 APC TP53 MSH2 ERBB2 IDH1 APC IDH2 NF2
Glioblastoma multiforme
Genes 23
FAN1 APC BMPR1A KRAS BRCA2 RPS20 MLH1 MSH2 MSH6 EPCAM PMS2 MLH1 MLH3 PMS2 PMS1 MSH6 TP53 MSH2 TGFBR2 PIK3CA SEMA4A ERBB2 IDH1
Glioma
Genes 50
TSC2 GLI3 BRCA2 TSC1 LRP5 MLH1 PMS2 APC IDH1 MSH6 POT1 TSC2 CDKN2A NF2 MSH3 MSH6 APC NF1 EPCAM TSC1 TGFBR2 SEMA4A IDH1 IDH2 FAN1 APC MSH3 BMPR1A KRAS MLH1 MSH2 C11ORF95 PMS2 MLH3 PIK3CA NBN RELA SETBP1 IFNG RPS20 NF1 PMS1 CHEK2 APC TP53 MSH2 NBN ERBB2 APC NF2
Subependymal giant-cell astrocytoma
Genes 2
TSC1 TSC2