WP1066 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

Inclusion Criteria:

• Newly diagnosed, histologically confirmed World Health Organization (WHO)glioblastoma multiforme (GBM), IDH wild-type

• External pathology reports are permitted for confirmation of histologicaldiagnosis

• Documentation of isocitrate dehydrogenase (IDH) wild-type status will be byIDH1 R123H immunohistochemistry, except for patients =< age 54 for whom IDHsequencing will be required to detect noncanonical IDH mutations

• Documentation of O6-methylguanine-DNA methyltransferase (MGMT) unmethylated statusper testing at any Clinical Laboratory Improvement Amendment (CLIA) certifiedlaboratory

• Cohort 1 only: Patients with prior gross total resection (GTR)

• Cohort 2 only: Patients without prior gross total resection (GTR)

• Cohort 2 only: Measurable disease in the brain (per RANO criteria) on brain magneticresonance imaging (MRI) scan conducted within =< 4 weeks prior to initiating trialtherapy

• Cohort 2 only: Patients who would benefit from non-emergent, palliative surgicalresection, in the opinion of the local site's tumor board

• Able to initiate trial therapy within 8 weeks of the initial brain surgicalprocedure (biopsy or resection) that lead to the patient's initial diagnosis of GBM

• Age >=18 years

• Karnofsky performance scale score >= 60%

• White blood cell (WBC) count >= 3.0 x 10^9/L (within =< 30 days prior toregistration) (without growth factor support and/or receipt of blood products within =< 14 days prior to testing)

• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (within =< 30 days prior toregistration) (without growth factor support and/or receipt of blood products within =< 14 days prior to testing)

• Platelet count >= 75 x 10^9/L (within =< 30 days prior to registration) (withoutgrowth factor support and/or receipt of blood products within =< 14 days prior totesting)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< ULN forsubjects with total bilirubin levels > 1.5 x ULN (within =< 30 days prior toregistration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (within =< 30 days prior to registration)

• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 xULN (within =< 30 days prior to registration)

• Creatinine or creatinine clearance within normal institutional limits. A creatininelevel above the institutional normal limit is acceptable, provided creatinineclearance (CrCl) is >= 60 mL/min/1.73 m^2 (within =< 30 days prior to registration).Creatinine clearance should be calculated using the Cockcroft-Gault formula

• International normalized ratio (INR) =< 1.5 x ULN or for subjects receivinganticoagulant therapy, INR must be within the therapeutic range of intended use ofanticoagulants, as determined by the treating investigator (within =< 30 days priorto registration)

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN or for subjects receivinganticoagulant therapy, aPTT must be within the therapeutic range of intended use ofanticoagulants, as determined by the treating investigator (within =< 30 days priorto registration)

• Willing and able to tolerate brain MRI with contrast. Patients with any known severeallergy to contrast agent(s) should not participate in the study. Patients with mildallergies to contrast agents (e.g., rash only) may participate in the study pertreating investigator discretion; it is recommended that these patients bepretreated with acetaminophen and diphenhydramine [or other institutional standardcombination of agent(s) for allergy prep] prior to injection of the contrast agent

• Willing and able to follow the below contraception requirements:

For Females:

• Female subjects of childbearing potential (defined below) must agree to use adequatecontraception (e.g., abstinence or 2 methods of birth control, such as a barriermethod in combination with hormonal contraception) starting from the time ofinformed consent, throughout the duration of treatment with WP1066, and for 2 monthsafter the last dose of WP1066. They also must agree to not donate/freeze eggs duringthe same timeframe. A female of reproductive potential is any woman (regardless ofsexual orientation, having undergone a tubal ligation, or remaining celibate bychoice) who meets both of the following two criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy

• Has had menses at any time in the preceding 12 consecutive months (andtherefore has not been naturally postmenopausal for > 12 months)

For Males:

• Male subjects must agree to use adequate contraception (e.g., abstinence or 2methods of birth control, such as a barrier method in combination with partner's useof hormonal contraception) starting from the time of informed consent, throughoutthe duration of treatment with WP1066, and for 4 months after the last dose ofWP1066. They also must agree to not donate sperm during the same timeframe Note: Theeffects of WP1066 on the developing human fetus are unknown. WP1066 couldpotentially be teratogenic or have abortifacient effects. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately

• Subject (or subject's legally authorized representative if subject has impaireddecision-making capacity) must have the ability to understand and thewillingness to sign a written informed consent document

• Both men and women of all races and ethnic groups may participate in this trial

Exclusion Criteria:

• Receipt of investigational agents within =< 2 weeks prior to registration

• Prior receipt of gene therapy, at any time

• Prior receipt of bevacizumab, at any time

• Prior receipt of Gliadel, at any time

• Patients who are on active therapy with Optune and who are unable to safelydiscontinue Optune prior to initiating trial therapy Note: Patients who can safelydiscontinue Optune prior to initiating trial therapy may participate

• Patients who are on active therapeutic anti-cancer therapy and who are unable todiscontinue the anti-cancer therapy prior to initiating trial therapy Note: Patientswho discontinue anti-cancer therapy prior to initiating trial therapy mayparticipate. Patients with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen for this trial may participate

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to WP1066 or its excipients

• Human immunodeficiency virus (HIV)-positive patients receiving combinationantiretroviral therapy Note: These patients are ineligible because of the potentialfor pharmacokinetic interactions with WP1066. (HIV testing is not required, unlessmandated by a local health authority.)

• Patients who have received drugs that significantly interact with CYP450 enzyme(s)within =< 2 weeks prior to planned first study treatment day Note: Patients who areable to safely discontinue the aforementioned agents > 2 weeks prior to initiatingtreatment with WP1066 may participate. The enzymatic metabolism profile of WP1066 isunknown. Drugs that have a minor interaction with CYP450 are allowed, and drugs witha moderate interaction are allowed at the principal investigators (PI's) discretion.Zofran (ondansetron) is allowed

• Patients who have received any of the following agents within 7 days of plannedfirst study treatment day:

• Agents that are predominantly CYP2D6, 2C9, or 2C19 substrates

• Agents that are strong inhibitors or inducers of CYP2D6, 2C9, or 2C19

• Agents that are sensitive substrates of CYP3A4 with narrow therapeutic rangeNote: Patients who are able to safely discontinue the aforementioned agents > 7days prior to initiating treatment with WP1066 may participate. The enzymaticmetabolism profile of WP1066 is unknown. Drugs that are minor CYP2D6, 2C9 or 2C19 substrates; minor inhibitors or inducers of CYP2D6, 2C9, or 2C19; or minorsubstrates of CYP3A4 are allowed. Moderate drugs will be allowed per PI'sdiscretion. Zofran (ondansetron) is allowed

• Patients on corticosteroids who require escalation of the corticosteroid dose Note:Patients receiving a stable or decreasing dose for at least one week mayparticipate. Zofran (ondansetron) is allowed

• History of brain hemorrhage, unless the following exception is met:

• Exception: Small, asymptomatic brain hemorrhage may be permitted, providedwritten documentation of PI approval has been obtained Note: The potential forfurther hemorrhaging with the use of WP1066 is unknown. It will be at the PIsdiscretion to enroll a patient who has a small, asymptomatic brain hemorrhage,but patients who have had symptomatic hemorrhages will be excluded

• Uncontrolled seizures or seizure requiring escalation or addition of anti-epilepticdrug

• Lesion(s) larger than 50 mm in maximal diameter on MRI, or with midline shiftexceeding 5 mm, or with hydrocephalus

• Diffuse leptomeningeal disease Note: Because one of the objectives is PFS based onradiographic volumetric analysis of the tumor, the presence of diffuseleptomeningeal disease is excluded. This is secondary to the inadequacy of measuringthe extent of the tumor burden within this setting and the very poor prognosis ofthese patients

• Corrected QT (QTc) B interval >= 450 ms These patients are excluded because thecardiac toxicities of WP1066 are unknown. Concomitant use of agents that prolong theQT interval should be avoided whenever feasible, or used with caution. Zofran (ondansetron) is allowed

• Subjects who are at increased risk for radiation therapy (RT)-associated toxicities,such as those with known active collagen vascular disease (e.g., scleroderma,Sjogren's disease, etc.) or other inherited RT-hypersensitivity syndromes (e.g.,Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)

• For female patients of childbearing potential only:

Patients with a positive serum beta-human chorionic gonadotropin (HCG) pregnancy test within =< 2 days prior to planned start date for trial therapy or who are immediately planning to become pregnant

• Breastfeeding patients who are unwilling/unable to discontinue breastfeeding whilereceiving WP1066 Note: Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with WP1066,breastfeeding should be discontinued if the mother is treated with WP1066. Patientswho discontinue breastfeeding prior to initiating treatment with WP1066 mayparticipate

• Uncontrolled intercurrent illness or condition including, but not limited to any ofthe following:

Ongoing or active infection requiring systemic treatment, except uncomplicated urinary tract infection;

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Cardiac arrhythmia

• Psychiatric illness/social situation that would limit compliance with studyrequirements

• Any other illness or condition that the treating investigator feels would interferewith study compliance or would compromise the subject's safety or study endpoints