Adavosertib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) of adavosertib (AZD1775 [MK-1775]) in
combination with the current standard of care (radiotherapy/temozolomide for concomitant
therapy and temozolomide for adjuvant therapy) for treating patients with newly diagnosed
glioblastoma.

II. To define the MTD of AZD1775 (MK-1775) in combination with 6 weeks of daily
(Monday-Friday [M-F]) radiotherapy (RT) and concomitant temozolomide (TMZ) administered at 75
mg/m^2/day in patients with newly diagnosed glioblastoma. (Arm 1) III. To define the MTD of
AZD1775 (MK-1775) in combination with adjuvant TMZ administered at 150 mg/m^2/day-200
mg/m^2/day for 5 days every 28 days in patients with glioblastoma after concurrent RT/TMZ.
(Arm 2)

SECONDARY OBJECTIVES:

I. To characterize the safety profile of AZD1775 (MK-1775) in combination with RT and
concomitant TMZ (Arm 1) and AZD1775 (MK-1775) with adjuvant TMZ (Arm 2) in patients with
newly diagnosed glioblastoma.

II. To assess the pharmacokinetic (PK) profile of AZD1775 (MK-1775) in combination with
upfront radiation/TMZ and adjuvant TMZ in patients with newly diagnosed glioblastoma.

TERTIARY OBJECTIVES:

I. To determine the intratumoral concentration of AZD1775 (MK-1775) achieved in patients
treated with the putative MTD.

II. To characterize the time course of AZD1775 (MK-1775) in extracellular fluid within brain
tumors following a single oral dose of drug by microdialysis.

III. To characterize the pharmacodynamic effects of AZD1775 on tumor through
immunohistochemistry (IHC) analysis of pRb (S807/811), proliferation (e.g. Ki-67), pCDC2,
Wee1, and apoptosis (e.g. cleaved caspase 3) on resected tumors exposed to drug.

IV. To characterize MGMT methylation and P53 pathway status, also P-gp and wee1 expression
levels in patients with newly diagnosed glioblastoma treated with standard therapy in
combination with AZD1775 (MK-1775).

V. To explore and analyze adaptive resistance mechanisms to AZD1775 using proteogenomics, and
connect this data to spatially resolved drug distribution through targeted, imaging-based
quantification of drug efficacy and tumor response.

OUTLINE: This is a dose-escalation study of adavosertib. Patients are assigned to 1 of 2
treatment arms.

ARM I:

INITIATION COURSE: Patients receive adavosertib orally (PO) on days 1, 3, and 5 or days 1-5
weekly and temozolomide PO once daily (QD) for 6 weeks. Patients also undergo concurrent
radiation therapy 5 days per week for 6 weeks.

MAINTENANCE COURSES: Beginning in week 10, patients receive temozolomide PO QD on days 1-5.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity.

ARM II: Patients receive adavosertib PO QD on days 1, 3, and 5 or 1-5 weekly, and
temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 2 years, and
then every 6 months thereafter.

Inclusion Criteria:

- Patients must have a tumor tissue form indicating availability of archived tissue from
initial resection at diagnosis of glioblastoma completed and signed by a pathologist

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal; if above the institutional upper limit of
normal but =< 3 times institutional upper limit of normal, the decision to initiate
temozolomide treatment should carefully consider the benefits and risks for the
individual patient

- Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60
ml/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5
x institutional upper limit of normal

- Patients must be able to provide written informed consent

- Patients must have magnetic resonance imaging (MRI) within 21 days of starting
treatment

- Women of childbearing potential must have a negative serum pregnancy test prior to
study entry; women of childbearing potential and men must agree to use two birth
control methods (either two barrier methods or a barrier method plus a hormonal
method) or abstinence prior to study entry and for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must be maintained on a stable corticosteroid regimen (no increase for 5
days) prior to the start of treatment

- Patients must be able to swallow whole capsules

- PHASE I PATIENTS:

- Must have histologically proven glioblastoma

- Must have recovered from the immediate post-operative period

- Patients going on Arm 1 or combination dose cohort must not have received prior
radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent
(including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists,
interferons, interleukins, tumor infiltrating lymphocytes [TIL], lymphokine-activated
killer [LAK] or gene therapy), or hormonal therapy for their brain tumor;
glucocorticoid therapy is allowed

- Patients going on Arm 2 must have received planned treatment with radiation therapy
and concomitant temozolomide at least 28 days but no more than 49 days prior to
starting treatment on this study; patients must have received at least 80% of planned
temozolomide and radiation therapy with no grade 3 or grade 4 toxicity (except
lymphopenia) attributed to the temozolomide; Arm 2 patients may not have received any
other prior chemotherapy, immunotherapy or therapy with biologic agent (including
immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons,
interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor;
prior Gliadel wafers are allowed; glucocorticoid therapy is allowed

- INTRATUMORAL DRUG DISTRIBUTION STUDY PATIENTS:

- Patients must have prior histologically proven glioblastoma that is progressive or
recurrent following radiation therapy +/- chemotherapy

- Patients must be undergoing repeat surgery that is clinically indicated as determined
by their care providers

- Patients must have measurable contrast-enhancing progressive or recurrent glioblastoma
by MRI within 21 days of starting treatment; patient must be able to tolerate MRIs

- Patients may have an unlimited number of prior therapy regimens

- Patients must have recovered from severe toxicity of prior therapy; the following
intervals from previous treatments are required to be eligible:

- 12 weeks from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not Food and Drug Administration
[FDA]-approved) agents

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g.,
Tarceva, hydroxychloroquine, bevacizumab, etc.)

Exclusion Criteria:

- Patients receiving any other investigational agents are ineligible

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to temozolomide or AZD1775 (MK-1775) are ineligible;
the AZD1775 (MK-1775) investigator brochure and the temozolomide package insert can be
referenced for more information

- Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic
drugs or not be taking any anti-epileptic drugs; patients previously treated with
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the
first dose of AZD1775 (MK-1775)

- Patients may not be on drugs known to be moderate or potent inhibitors/inducers of
CYP3A4, sensitive substrates of CYP3A4, or substrates of CYP3A4 with narrow
therapeutic windows

- Patients may not be on anti-coagulants (warfarin, etc.) other than low-molecular
weight heparin (LMWH)

- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements, are ineligible

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with AZD1775 (MK-1775)

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible