This is an open-label, multi-center Phase 0/1b study that will enroll up to 18 participants with recurrent WHO grade 4 glioblastoma (rGBM) IDH-wildtype (IDH-WT), Arm A, and 12 participants with presumed newly-diagnosed WHO grade 4 glioblastoma (nGBM) IDH-WT, Arm B. The trial will be composed of a Phase 0 component (subdivided into Arms A and B), and an Expansion Phase 1b. Patients with tumors demonstrating a positive pharmacokinetic (PK) response in the Phase 0 component of the study will graduate to an Expansion Phase that combines therapeutic dosing of quisinostat plus standard-of-care fractionated radiotherapy (RT).
Eligible participants (rGBM in Arm A and nGBM in Arm B) will enroll in the Phase 0 study and receive quisinostat prior to a planned resection. Arm A includes a 3+3 design to determine optimal time interval (OTI) of final dose prior to surgery. Further rGBM participants and nGBM participants will enroll at OTI once established. Blood, tumor, and cerebrospinal fluid (CSF) samples will be collected during surgery, and blood and CSF samples will be collected after surgery, to measure the amount of drug that is present in the samples. Participants with tumors demonstrating PK response will continue with therapeutic dosing of quisinostat treatment on Monday, Wednesday, Friday of 5-day cycles after surgery concurrently with their standard of care (SOC) fractionated RT. Participants will continue to receive quisinostat and SOC RT for their physician-directed duration of RT, (2-3 weeks for rGBM and 5-6 weeks form nGBM). The Phase 0 Primary Objective is to evaluate concentration of quisinostat in gadolinium-non-enhancing tumor tissue, and the Expansion Phase Primary Objective is to determine the 6-month progression free survival (PFS6) rate in rGBM participants who had positive PK response in Phase 0. The Phase 0 Secondary Objective is to evaluate concentration of quisinostat in CSF, and the Expansion Phase Secondary Objectives are to monitor safety and tolerability of quisinostat and examine overall survival (OS) in participants.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
a highly potent and orally active HDAC inhibitor
St. Joseph's Hospital and Medical Center
Phoenix, Arizona, United States
RECRUITINGQuisinostat Concentration in Tumor Tissue
Total and unbound quisinostat concentration will be quantified in Gd-enhancing and Gd-non-enhancing tumor tissue collected during Phase 0 surgery.
Time frame: Phase 0 surgery
6-Month Progression Free Survival (PFS6) Rate in Participants
The rate of 6-month progression-free survival of participants that had a positive PK response (defined as unbound concentrations of quisinostat equal or greater than 0.5 nM in Gd-non-enhancing tumor tissue) will be quantified.
Time frame: From date of Phase 0 surgery to date of disease recurrence or death, assessed over 16 months
Quisinostat Concentration in Cerebrospinal Fluid (CSF)
Quisinostat concentration will be quantified in cerebrospinal fluid collected during Phase 0 surgery and throughout study duration of participants with an Ommaya reservoir and shunt placed during surgery.
Time frame: From date of Phase 0 surgery through study completion, assessed over 4 months
Number of Participants with Drug-Related Toxicity
Safety and tolerability of quisinostat will be assessed by tabulating the number of drug-related toxicities (graded per CTCAE version 5) which include: * Grade 2 or higher cardiac disorder * Grade 4 or higher hematological or nonhematological toxicity * Febrile neutropenia * Unacceptable toxicity as determined by the Investigator * Any Grade 3 or higher non-hematologic toxicity, excluding the following: Grade 3 nausea, vomiting, or diarrhea for less than 72 hours with adequate supportive care; Grade 3 fatigue for longer than 1 week; Grade 3 or higher electrolyte abnormality lasting up to 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional treatment
Time frame: From date of first dose until 30 days after last dose, assessed over 4 months
Number of Treatment-Emergent Adverse Events
Safety and tolerability of quisinostat will be assessed by tabulating participants that had treatment-emergent adverse events according to the highest Grade observed per patient for each event or category (graded per CTCAE version 5).
Time frame: From date of enrollment until 30 days after last dose, assessed over 6 months
Number of Treatment-Related Adverse Events
Safety and tolerability of quisinostat will be assessed by tabulating participants that had treatment-related adverse events (defined as those events definitely, probably, or potentially related to study treatment) according to the highest Grade observed per patient for each event or category (graded per CTCAE version 5).
Time frame: From date of first dose until 30 days after last dose, assessed over 4 months
Number of Participants with Clinical Laboratory Abnormalities
Safety and tolerability of quisinostat will be assessed by tabulating participants that had clinical laboratory abnormalities stratified by each event or abnormal result.
Time frame: From date of first dose until 30 days after last dose, assessed over 4 months
Number of Serious Adverse Events and Deaths
Safety and tolerability of quisinostat will be assessed by aggregating and tabulating participants that died during study participation (due to any cause), and participants that had serious adverse events according to the highest Grade observed per patient for each event or category (graded per CTCAE version 5).
Time frame: From date of enrollment until 30 days after last dose, assessed over 6 months
Overall Survival during Expansion Phase
Overall Survival of participants that had a positive PK response (defined as unbound concentrations of quisinostat equal or greater than 0.5 nM in Gd-non-enhancing tumor tissue) will be summarized using Kaplan-Meier Curves and Estimates.
Time frame: From date of surgery until death, assessed up to 16 months
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