MDM2 Inhibitor AMG-232 in Treating Patients With Recurrent or Newly Diagnosed Glioblastoma

PRIMARY OBJECTIVES:

I. Determine the concentration and variability in concentration of MDM2 inhibitor AMG-232
(AMG 232) in brain and brain-associated tissue in patients with recurrent glioblastoma (GBM).
(Part 1) II. Determine the maximum tolerated dose (MTD) of AMG 232 given in combination with
standard radiation following surgery for patients with newly diagnosed GBM harboring
unmethylated MGMT promoters and wild-type TP53. (Part 2)

SECONDARY OBJECTIVES:

I. Determine the safety and toxicity of AMG 232 in patients with recurrent GBM. (Part 1) II.
Assess the variability of AMG 232 concentration in tumor enhancing versus (vs.) infiltrative
tissue. (Part 1) III. Assess the pharmacodynamic effect of AMG 232 on p21 elevation. (Part 1)
IV. Determine the safety of AMG 232 given concurrently with radiation therapy (RT) and
adjuvantly as monotherapy for patients with newly diagnosed GBM harboring unmethylated MGMT
promoters and wild-type TP53. (Part 2) V. Assess AMG 232 exposure and correlations with PD
effect PD effect on p21 elevation. (Part 2) VI. Assess pharmacodynamic (PD) effect on MIC-1
elevation in serum. (Part 2)

OUTLINE: This is a phase 0, intratumoral pharmacokinetic (PK)/ pharmacodynamic (PD) study of
MDM2 inhibitor AMG-232 followed by a phase I dose-escalation study.

PART I: Patients with recurrent glioblastoma receive MDM2 inhibitor AMG-232 orally (PO) once
daily (QD) for 2 days. Within 3-6 hours of the last dose, patients undergo standard of care
surgery. Upon recovery (within 45 days), patients with TP53 wild-type tumors continue to
receive MDM2 inhibitor AMG-232 PO QD on days 1-7. Courses repeat every 21 days in absence of
disease progression or unacceptable toxicity.

PART II: Within 6 weeks of standard of care surgery, patients with newly diagnosed
glioblastoma undergo radiation therapy daily during weeks 1-6. Patients also receive MDM2
inhibitor AMG-232 PO once weekly for 6 weeks or 3 times weekly on days 2, 3, and 5 for 6
weeks or 2 times weekly on days 2 and 4 for 6 weeks during radiation therapy.

PART II (EXPANSION COHORT): Patients receive MDM2 inhibitor AMG-232 PO QD on days 1-7.
Courses repeat every 21 days in absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 2 months for the first two
years from the off-treatment date, and then every 6 months until death.

Inclusion Criteria:

- 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/ul

- Platelets >= 100,000/ul

- Hemoglobin >= 10 g/dL (transfuse as necessary to raise levels, no transfusions within
7 days of start)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN

- Alkaline phosphatase < 2.0 x ULN

- Creatinine =< institutional ULN

- 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 ULN

- Corrected QT interval (QTc) =< 470 msec (based on average of screening triplicates)

- Patients must be able to provide written informed consent

- Patients must have magnetic resonance imaging (MRI) within 21 days of starting
treatment; patients must be able to tolerate MRI with gadolinium

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

- Women of childbearing potential must have a negative serum pregnancy test prior to
study entry; women of child-bearing potential must agree to use adequate contraception
prior to study entry and for the duration of study participation through 5 weeks
(women) after receiving the last dose of AMG 232; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately; men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 3 months after completion of AMG 232
administration; adequate methods of effective birth control include sexual abstinence
(men, women); vasectomy; or a condom with spermicide (men) in combination with barrier
methods, hormonal birth control or intrauterine device (IUD) (women); bilateral tubal
ligation (women)

- 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 able to swallow oral medications

- PART 1 PATIENTS (SURGICALLY ELIGIBLE RECURRENT GBM)

- Part 1 patients must have prior histologically proven glioblastoma that is progressive
or recurrent following radiation therapy +/- chemotherapy

- Part 1 patients must be undergoing repeat surgery that is clinically indicated as
determined by their care providers

- Part 1 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

- Part 1 patients may have an unlimited number of prior therapy regimens

- Part 1 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 or mitomycin C

- 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, except
bevacizumab/ vascular endothelial growth factor receptor (VEGFR) inhibitors
(e.g., erlotinib, hydroxychloroquine, etc.)

- 6 weeks from bevacizumab/VEGFR inhibitors

- PART 2 PATIENTS (NEWLY DIAGNOSED GBM)

- Part 2 patients must have histologically confirmed glioblastoma or gliosarcoma

- Part 2 patients must have recovered from the immediate post-operative period

- Part 2 patients must have tumor MGMT methylation status of unmethylated; results of
routinely used methods for MGMT methylation testing (e.g. mutagenically separated
polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are
acceptable

- Part 2 patient must show evidence of wild-type (WT) p53 status on somatic tissue
specimens as assessed by deoxyribonucleic acid (DNA) sequencing

- Part 2 patients 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

Exclusion Criteria:

- Patients receiving any other investigational agents are ineligible

- Part 1 patients who have not recovered to < Common Terminology Criteria for Adverse
Events (CTCAE) grade 2 toxicities related to prior therapy are ineligible

- Patients with a history of hypersensitivity or allergic reactions attributed to
compounds of similar chemical or biologic composition to AMG 232 are ineligible

- 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 AMG 232

- Patients may not use herbal or non-traditional medications while receiving AMG 232
therapy; all herbal medicines (e.g., St. John's wort), vitamins, and supplements
consumed by the subject within the 30 days prior to receiving the first dose of AMG
232 should be reviewed by the principal investigator

- Drugs known to be CYP3A4 substrates with narrow therapeutic windows (such as
alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus,
or terfanide) or CYP2C8 substrates are not allowed; patients must be switched to
alternative drugs at least 14 days prior to receiving the first dose of AMG 232; those
patients who cannot switch to alternative drugs will be excluded from the study

- Treatment with medications known to cause QTc interval prolongation within 7 days of
study day 1 is not permitted unless approved by the sponsor; use of ondansetron is
permitted for treatment of nausea and vomiting

- Patients may not be on warfarin, factor Xa inhibitors and direct thrombin inhibitors;
Note: low molecular weight heparin and prophylactic low dose warfarin are permitted;
APTT/PTT must meet the inclusion criteria; subjects taking warfarin must have their
international normalized ratio (INR) followed closely

- 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; patients with active infection
requiring IV antibiotics within 2 weeks of study day 1 are excluded; patients with
myocardial infarction within 6 months of study day 1, symptomatic congestive heart
failure (New York Heart Association [NYHA] class III and higher), unstable angina, or
cardiac arrhythmia requiring medication are excluded

- Patients with gastrointestinal (GI) tract disease causing the inability to take oral
medication, malabsorption syndrome, requirement for intravenous alimentation, prior
surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g.,
Crohn's disease, ulcerative colitis), are ineligible

- Patients with history of bleeding diathesis are ineligible

- Patients with positive hepatitis B surface antigen (HepBsAg), positive hepatitis total
core antibody with negative HBsAG, or detectable hepatitis C virus ribonucleic acid
(RNA) by a polymerase-chain reaction (PCR) assay (screening is generally done by
hepatitis C antibody (HepCAb), followed by hepatitis C virus RNA by PCR if HepCAb is
positive)

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with AMG 232 through 1 week after receiving the last dose of
study drug

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
AMG 232; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy

- Patients with a planned use of Novo-TTF (Optune) are ineligible