VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM

Inclusion Criteria:

1. Patient must agree to testing of GBM tumor promoter methylation status of the MGMTgene and tumor (IDH1) gene mutation status. Tissue may be tested at study entry, ifnot done previously, or data may be obtained from last known test result for MGMT andIDH1. IDH1 status may be assessed at study entry, but MGMT status is required prior torandomization.
2. Agree to allow the sponsor to collect data on all GBM-related treatments receivedafter the patient comes off the current study, and to collect survival data after thepatient comes off the current study.
3. Patient must be ≥ 18 years old.
4. Histologically confirmed initial diagnosis of primary glioblastoma multiforme (GBM) orgliosarcoma (GS), now recurrent. Patients with recurrent/progressive disease whoseinitial diagnostic pathology confirmed GBM or GS will not need re-biopsy. Patientswith prior low-grade glioma or anaplastic glioma are eligible, if histologicassessment demonstrates transformation to GBM or GS.
5. Patient has previously received standard of care chemo-radiation with temozolomide, ±adjuvant temozolomide and bevacizumab and now has radiographic evidence ofrecurrent/progressive GBM or GS during or after bevacizumab.
6. Patient must have bi dimensionally measurable disease, per the proposed ResponseAssessment in NeuroOncology (RANO; Appendix C) (Wen et al., 2010), with measurement of >1 cm in one diameter and ≤5 cm diameter in any plane on MRI performed within 2 weeksprior to randomization.
7. At least 4 weeks from last chemotherapy or bevacizumab (Avastin®) therapy (6 weeks fornitrosourea or mitomycin C), or for chemotherapy regimens given continuously or on aweekly basis with limited potential for delayed toxicity, at least 2 weeks from lastdose.
8. If the patient has been using the Optune™ device, it will be discontinued at leastfour days prior to commencing treatment with VAL-083, and the patient must haverecovered from all treatment-related toxicities to Grade 1 or less.
9. Baseline MRI must be obtained ≥ 4 weeks after surgical resection but within 2 weeksprior to randomization.
10. Adequate recovery from all recent surgery is required; at least 1 week must haveelapsed from the time of a minor surgery; at least 21 days must have elapsed from thetime of a major surgery. Patients must have recovered from all surgery-relatedtoxicities to Grade 1 or less.
11. Prior therapy with Laser-Induced Thermal Therapy (LITT) is allowed but at least 21days must have elapsed from last LITT, with recovery from all LITT-related toxicitiesto Grade 1 or less and subsequent histologic documentation of recurrence.
12. Greater than 12 weeks from radiotherapy, to minimize the potential for MRI changesrelated to radiation necrosis that might be misdiagnosed as pseudoprogression ofdisease, unless the recurrence is a new lesion, outside the primary radiation field orthe patient fulfills criteria for early progressive disease by RANO ((Wen et al., 2010); Appendix C).
13. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but atleast 2 weeks must have elapsed from the time of treatment, and the patient must havesubsequent post-radiotherapy histologic documentation of recurrence in the irradiatedfield, unless the recurrence is a new lesion outside the irradiated field.
14. If receiving corticosteroids, patients must be on a stable or decreasing dose ofcorticosteroids for ≥ 5 days prior to baseline MRI.
15. At least 28 days or 5 half-lives (whichever is shorter) since prior investigationalanti-cancer drugs. A minimum of 21 days between termination of the investigationaldrug and administration of VAL-083 is required.
16. Must have recovered from all treatment-related toxicities to Grade 1 or less.
17. Patients must have a Karnofsky performance status (KPS; Appendix D) of ≥ 70%
18. KPS must have been stable during the period from wash-out of prior therapy torandomization. A declining KPS is defined by reduction of 10 points or more over atleast a 28-day period.
19. Patient must have a predicted life expectancy of at least 12 weeks.
20. Laboratory values as follows at screening and within 7 days of planned first dose oftherapy:
21. Absolute neutrophil count (ANC) ≥1500/μL.
22. Hemoglobin (HgB) ≥9 g/dL.
23. Platelets ≥100,000/μL (≥150,000/μL, if within 12 weeks of prior nitrosoureatreatment).
24. Serum creatinine ≤1.5 x upper limit of normal or creatinine clearance >60 mL/min (measured or calculated by the Cockcroft-Gault formula) (Cockcroft DW et al, 1976).
25. AST, ALT must be <2 x ULN.
26. Total bilirubin <1.5 x the institutional ULN, unless the subject has documentedunconjugated bilirubin disorder such as Gilbert's syndrome.
27. Subjects with known Gilbert's syndrome who have serum bilirubin ≤ 3 x ULN (NCICTCAE v4.03 Grade 2) may be enrolled.
28. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastintime (aPTT) ≤ 1.5 x the ULN.
29. QTc <450 msec on screening ECG.
30. No clinically significant cardiac conduction disorder on screening.
31. Female patients of child-bearing potential must have a negative serum or urinepregnancy test within 7 days prior to planned first dose of treatment, and agree touse dual method of contraception through 90 days after study drug treatment. Approvedmethods of contraception include an IUD with spermicide, a female condom withspermicide, a diaphragm with spermicide, a cervical cap with spermicide, use of acondom with spermicide by sexual partner or a sterile sexual partner. Women ofchildbearing potential are defined to include any female who:
32. Has experienced menarche and has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy); and
33. Is not post-menopausal (defined as amenorrhea >12 consecutive months).
34. If male, patient must be sterile or willing to use an approved method of contraceptionfrom the time of Informed Consent to 90 days after study drug treatment. Males must bewilling to refrain from sperm donation within 90 days after study treatment.

Exclusion Criteria:

1. Current history of neoplasm other than the entry diagnosis. Exceptions are:
2. Curatively treated basal cell/squamous cell skin cancer
3. Carcinoma in situ of the cervix
4. Patients with previous solid and hematologic tumors, that have been treated withno evidence of recurrence within the last 5 years, are permitted.
5. Evidence of diffuse subependymal disease or tumor in the brainstem, cerebellum, spinalcord, or CSF.
6. Radiological evidence of multifocal disease, tumors extending into or crossing thecorpus callosum or leptomeningeal disease.
7. Need for urgent palliative intervention for primary disease (e.g., impendingherniation).
8. Evidence of recent hemorrhage on baseline MRI of the brain with the followingexceptions:
9. Presence of hemosiderin.
10. Resolving hemorrhagic changes related to surgery.
11. Presence of punctate hemorrhage in the tumor.
12. Concurrent severe, intercurrent illness including, but not limited to unstablesystemic disease, including ongoing or active infection, uncontrolled hypertension,serious cardiac arrhythmia requiring medication, or psychiatric illness/socialsituations that would limit compliance with study requirements.
13. Any of the following cardiac conditions:
14. History of myocardial infarction, acute coronary syndromes (including unstableangina), coronary angioplasty, and/or stenting up to 12 weeks before Cycle 1, Day
16. Class III or IV heart failure as defined by the New York Heart Associationfunctional classification system up to 6 months before Cycle 1, Day 1.
17. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, orrecent peripheral arterial thrombosis) within 6 months prior to Day 1 of treatment.
18. History of stroke or transient ischemic attack within 6 months prior to beginningtreatment.
19. Patients receiving prohibited concomitant medications at the start of the study
20. Patients with steroid myopathy.
21. Patients who are HIV positive with an active AIDS-related illness are excluded;patients who are HIV positive but on stable therapy are not excluded.
22. Patients with a known sensitivity to any of the products to be administered duringtreatment and assessments.
23. Women who are pregnant or lactating.
24. Patients unable to undergo an MRI of the brain with contrast.