This is a phase II, open label trial of radiation therapy in combination with WP1066 in newly diagnosed IDH wild-type, MGMT-unmethylated glioblastoma patientsThere are two cohorts/treatment arms:~Cohort 1: Radiation therapy + WP1066 (in patients with prior gross total resection)~Cohort 2: Radiation therapy + WP1066 ± optional secondary surgical resection (in patients without prior gross total resection who are candidates for non-emergent palliative surgical resection) Radiation therapy is standard of care in this patient population. WP1066 is an oral, small molecule inhibitor of p-STAT3 and is investigational.~A safety lead-lead has been designed, wherein the first 6 subjects in Cohorts 1 or 2 who receive combination therapy with RT + WP1066 will be observed for 10 weeks for dose limiting toxicities (DLTs), in order to ensure the safety of the combination. If an unacceptable frequency of DLTs are observed, a protocol amendment to explore alternate dosing schemes may be considered. If a patient in the safety lead-in permanently discontinues RT or WP1066 prior to completing the intended 6-week regimen of RT + WP1066 for reasons other than having experienced a DLT, then such subject will not be evaluable for the DLT analysis, and an additional subject will be added to the safety lead-in, provided overall accrual to Cohort 1 does not exceed 25 patients, and provided overall accrual to Cohort 2 does not exceed 14 patients.~Cohort 1 Treatment Plan: Radiation therapy + WP1066:~For Cohort 1, patients with prior gross total resection will receive standard of care radiation therapy (2 Gy per fraction x 30 fractions = 60 Gy) over 6 weeks (± 1 week). Patients also will self-administer concurrent WP1066 by mouth (PO), three days a week during the 6-week course of radiation therapy. The starting dose of WP1066 is 8 mg/kg twice daily (BID) on days 1, 3, and 5 of each week, with dose reductions to 6 mg/kg and 4 mg/kg permitted. Upon completion of the 6-week regimen of radiation therapy and WP1066, patients will take a 4-week recovery break during which time no therapy will be administered. Following the 4-week recovery, patients will enter the adjuvant phase of treatment, during which they will resume WP1066 treatment for up to 12 cycles (or longer, per PI discretion). Each cycle of adjuvant WP1066 will be 28-days, and WP1066 will be given BID, on days 1, 3, 5, 8, 10, and 12 of each adjuvant cycle. Trial therapy with WP1066 may continue until Response Assessment in Neuro-Oncology (RANO) disease progression, intolerable toxicity, subject withdrawal, or other discontinuation criterion is met; whichever occurs first.~Cohort 2 Treatment Plan: Radiation therapy + WP1066 ± optional secondary surgical resection:~For Cohort 2, patients without prior gross total resection and who are candidates for non-emergent palliative surgical resection will receive standard of care radiation therapy (2 Gy per fraction x 30 fractions = 60 Gy) over 6 weeks (± 1 week). Patients also will self-administer concurrent WP1066 by mouth (PO), three days a week during the 6-week course of radiation therapy. The starting dose of WP1066 is 8 mg/kg twice daily (BID) on days 1, 3, and 5 of each week, with dose reductions to 6 mg/kg and 4 mg/kg permitted. Upon completion of the 6-week regimen of radiation therapy and WP1066, patients will take a 4-week recovery break. During this recovery period, patients with lesions amenable to surgery will undergo a secondary surgical resection or open biopsy 1 week (± 1 week) after completing radiation therapy. Following the 4-week recovery, patients will enter the adjuvant phase of treatment, during which they will resume WP1066 treatment for up to 12 cycles (or longer, per PI discretion). Each cycle of adjuvant WP1066 will be 28-days, and WP1066 will be given BID on days 1, 3, 5, 8, 10, and 12 of each adjuvant cycle. Trial therapy with WP1066 may continue until RANO disease progression, intolerable toxicity, subject withdrawal, or other discontinuation criterion is met; whichever occurs first.~Safety Lead-In: To exclude prohibitive toxicity, a safety lead-in will be conducted in the first 6 subjects in Cohort 1 or 2. If an unacceptable frequency of DLTs observed, a protocol amendment to explore alternate dosing schemes may be considered.
This is a phase II, open label, multi-arm trial of radiation therapy in combination with WP1066 in newly diagnosed IDH wild-type, MGMT-unmethylated glioblastoma patients, with multiple cohorts. Patients will be stratified into Cohort 1 versus Cohort 2 based on gross total resection (GTR) status.~Cohort 1: Radiation therapy (RT) + WP1066 in glioblastoma patients with gross total resection Sample size for Cohort 1: Up to 25 patients may be enrolled in order to obtain 21 patients who are evaluable for the primary objective.~Cohort 2: RT + WP1066 ± optional secondary surgical resection post-RT in glioblastoma patients without gross total resection who are candidates for non-emergent palliative surgical resection Sample size for Cohort 2: Up to 14 patients may be enrolled in order to obtain 10 patients who undergo secondary surgical resection.