A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma

Newly Diagnosed Inclusion Criteria:

• Age ≥ 18 years.

• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDHwild-type by immunohistochemistry [IHC] or sequencing for IDH) established followingeither a surgical resection or biopsy. An MRI scan with the required imagingsequences performed within 21 days prior to randomization preferably. Thepost-operative MRI scan performed within 96 hours of surgery or the MRI scanperformed for radiation therapy planning may serve as the MRI scan performed duringscreening if all required imaging sequences were obtained.

• Karnofsky performance status ≥ 60% performed within a 14-day window prior torandomization.

• Availability of tumor tissue representative of GBM from definitive surgery orbiopsy.

Recurrent Inclusion Criteria:

• Age ≥ 18 years.

• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDHwild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or secondrecurrence after initial standard, control or experimental therapy that includes ata minimum radiation therapy (RT).

• Evidence of recurrent disease demonstrated by disease progression using slightlymodified Response Assessment in Neuro-Oncology (RANO) criteria.

• Two scans to confirm progression are required: at least 1 scan at the time ofprogression and 1 scan prior to the time of progression.

• Karnofsky performance status ≥ 70% performed within a 14-day window prior torandomization.

• Availability of tumor tissue representative of GBM from initial definitive surgeryand/or, recurrent surgery, if performed.

Newly Diagnosed Exclusion Criteria:

• Received any prior treatment for glioma including: a. Prior prolifeprospan 20 withcarmustine wafer. b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent. c. Prior radiation treatment for GBM or lower-grade glioma. d. Priorchemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional,concurrent, active therapy for GBM outside of the trial.

• Extensive leptomeningeal disease.

• QTc > 470 msec

• History of another malignancy in the previous 2 years, with a disease-free intervalof < 2 years. Patients with prior history of in situ cancer or basal or squamouscell skin cancer are eligible.

Recurrent Exclusion Criteria:

• Early disease progression prior to 3 months (12 weeks) from the completion of RT.

• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st lineadjuvant setting, combination of temozolomide (TMZ) with an experimental agent, isconsidered one line of chemotherapy.)

• Received any prior treatment with lomustine, agents part of any of the experimentalarms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGFreceptor-mediated targeted agent.

• Any prior treatment with prolifeprospan 20 with carmustine wafer.

• Any prior treatment with an intracerebral agent.

• Receiving additional, concurrent, active therapy for GBM outside of the trial

• Extensive leptomeningeal disease.

• QTc > 470 msec

• History of another malignancy in the previous 2 years, with a disease-free intervalof < 2 years. Patients with prior history of in situ cancer or basal or squamouscell skin cancer are eligible.