Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT01922076

Collaborator

(none)

Enrollment

Locations

Arm

1.9

Patients Per Site

Study Details

Study Description

Brief Summary

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.

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

Detailed Description

PRIMARY OBJECTIVES:

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).
To define and describe the toxicities of AZD1775 (MK-1775) given concurrently with radiation therapy in children with newly diagnosed DIPG.
To characterize the pharmacokinetics of AZD1775 (MK-1775) in children with newly diagnosed DIPG when given concurrently with radiation therapy.

SECONDARY OBJECTIVES:

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.
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.
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 Design

Study Type:

Interventional

Actual Enrollment :

46 participants

Allocation:

N/A

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

Actual Study Start Date :

Sep 3, 2013

Actual Primary Completion Date :

Dec 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Adavosertib Given PO Other Names: AZD-1775 AZD1775 MK-1775 MK1775 Other: Laboratory Biomarker Analysis Correlative studies Other: Pharmacological Study Correlative studies Radiation: Radiation Therapy Undergo radiation therapy Other Names: Cancer Radiotherapy ENERGY_TYPE Irradiate Irradiated Irradiation Radiation Radiation Therapy, NOS Radiotherapeutics Radiotherapy RT Therapy, Radiation

Arm

Intervention/Treatment

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.

Drug: Adavosertib

Given PO

Other Names:

AZD-1775

AZD1775

MK-1775

MK1775

Other: Laboratory Biomarker Analysis

Correlative studies

Other: Pharmacological Study

Correlative studies

Radiation: Radiation Therapy

Undergo radiation therapy

Other Names:

Cancer Radiotherapy

ENERGY_TYPE

Irradiate

Irradiated

Irradiation

Radiation

Radiation Therapy, NOS

Radiotherapeutics

Radiotherapy

Therapy, Radiation

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) [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 [Up to 4 years]
Adverse events will be graded using the NCI CTCAE version 4.0.

Other Outcome Measures

Pharmacokinetic (PK) parameters of adavosertib [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) [Up to 4 years]
Disease response will be reported descriptively.
Progression-free survival (PFS) [Up to 4 years]
PFS will be summarized using the Kaplan-Meier method and including 95% confidence intervals.
Overall survival (OS) [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 [Baseline to day 8]
Will be assessed using flow cytometry. Paired analysis methods will be used.

Eligibility Criteria

Criteria

Ages Eligible for Study:

37 Months to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 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

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	Children's Hospital of Orange County	Orange	California	United States	92868
4	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
5	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
6	Children's Hospital Colorado	Aurora	Colorado	United States	80045
7	Children's National Medical Center	Washington	District of Columbia	United States	20010
8	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
9	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
10	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
11	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
12	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
13	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
14	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
15	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
16	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
17	Oregon Health and Science University	Portland	Oregon	United States	97239
18	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
19	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
20	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
21	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
22	Seattle Children's Hospital	Seattle	Washington	United States	98105
23	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
24	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8