Testing the Ability of AMG 232 (KRT 232) to Get Into the Tumor in Patients With Brain Cancer

Inclusion Criteria:

• Patients must be 18 years of age or older

• Patients must have a Karnofsky performance status >= 60% (i.e. the patient must beable 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 transfusionswithin 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 aboveinstitutional normal

• Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5 x institutional ULN

• Patients must be able to provide written informed consent

• Patients must have MRI within 21 days before starting treatment; patients must beable to tolerate MRI with gadolinium

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

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

• Patients must have no concurrent malignancy except curatively treated basal orsquamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, orbladder; 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 isprogressive or recurrent following radiation therapy +/- chemotherapy

• Part 1 patients must be undergoing repeat surgery that is clinically indicated asdetermined by their care providers

• Part 1 patients must have a tumor tissue form indicating availability of archivedtissue from initial resection at diagnosis of glioblastoma completed and signed by apathologist

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

• Part 1 patients must have recovered from severe toxicity of prior therapy; thefollowing 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, exceptbevacizumab/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 ofroutinely used methods for MGMT methylation testing (e.g. mutagenically separatedpolymerase 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 tissuespecimens 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], LAK or gene therapy), orhormonal 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 AdverseEvents (CTCAE) grade 2 toxicities related to prior therapy are ineligible

• Patients with a history of hypersensitivity or allergic reactions attributed tocompounds of similar chemical or biologic composition to AMG 232 (KRT 232) areineligible; the AMG 232 (KRT 232) investigator brochure can be referenced for moreinformation

• Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible fortreatment on this protocol; patients may be on non-enzyme inducing anti-epilepticdrugs or not be taking any anti-epileptic drugs; patients previously treated withEIAED may be enrolled if they have been off the EIAED for 10 days or more prior tothe first dose of AMG 232 (KRT 232)

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

• Drugs known to be sensitive CYP3A4 substrates with narrow therapeutic windows (suchas alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine,sirolimus, or terfenadine) are not allowed; patients must be switched to alternativedrugs at least 14 days prior to receiving the first dose of AMG 232 (KRT 232); thosepatients who cannot switch to alternative drugs will be excluded from the study;please note that the list of drugs above is not an exhaustive list; refer toreliable sources such as the FDA website (Drug development and drug interactions),or Micromedex when evaluating potential drug-interactions

• Treatment with medications known to cause corrected QT (QTc) interval prolongationwithin 7 days of study day 1 is not permitted unless approved by the sponsor; use ofondansetron is permitted for treatment of nausea and vomiting

• Patients may not be on warfarin, factor Xa inhibitors and direct thrombininhibitors; Note: low molecular weight heparin and prophylactic low dose warfarinare permitted; APTT/PTT must meet the inclusion criteria; subjects taking low dosewarfarin 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 anginapectoris, cardiac arrhythmia, or psychiatric illness/social situations that wouldlimit compliance with study requirements, are ineligible; patients with activeinfection requiring intravenous (IV) antibiotics within 2 weeks of study day 1 areexcluded; patients with myocardial infarction within 6 months of study day 1,symptomatic congestive heart failure (New York Heart Association [NYHA] class IIIand higher), unstable angina, or cardiac arrhythmia requiring medication areexcluded

• Patients with gastrointestinal (GI) tract disease causing the inability to take oralmedication, malabsorption syndrome, requirement for intravenous alimentation, priorsurgical 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 hepatitistotal core antibody with negative HBsAG, or detectable hepatitis C virus ribonucleicacid (RNA) by a polymerase-chain reaction (PCR) assay are ineligible (screening isgenerally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNAby PCR if HepCAb is positive)

• Pregnant women are excluded from this study as no studies evaluating thereproductive toxicity of AMG 232 (KRT 232) have been conducted to date; theteratogenic potential of AMG 232 (KRT 232) in laboratory animals, if any, isunknown; because there is an unknown but potential risk for adverse events innursing infants secondary to treatment of the mother with AMG 232 (KRT 232),breastfeeding should be discontinued if the mother is treated with AMG 232 (KRT 232)through 1 week after receiving the last dose of study drug

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviraltherapy are ineligible because of the potential for pharmacokinetic interactionswith AMG 232 (KRT 232); in addition, these patients are at increased risk of lethalinfections when treated with marrow-suppressive therapy

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