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

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).

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.

SECONDARY OBJECTIVES:

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.

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