Novel Indenoisoquinolone CMYC/TOPOISOMERASE 1 Inhibitor (LMP744) in Recurrent Glioblastoma

Background: Glioblastoma is a common brain cancer in adults. Treatment includes surgery, radiation, and chemotherapy. But this cancer can return after treatment and is often fatal. Researchers want to know if a study drug (LMP744) can kill glioblastoma tumor cells. Objective: To test LMP744 in people with glioblastoma. Eligibility: People aged 18 years or older with glioblastoma that returned after treatment. Design: Participants will be screened. They will have a surgery to remove a small sample of tumor tissue (biopsy) from the brain. This will be done under protocol 03-N-0164. They will stay in the clinic for 1 night. They will also have imaging scans and tests of their heart function. Participants will have a central line installed: A flexible tube will be inserted into a vein in the chest. It will be attached to a port under the skin. This port will be used to draw blood and give medicines without having to insert new needles into a vein. LMP744 will be given through the central line for 5 days in a row. Participants will remain in the clinic for this time. Participants will then have a second surgery to remove as much of their tumor as possible. They will remain in the clinic until they recover from the surgery. Then they will recover at home after surgery. Participants will return to the clinic to receive the study drug for 5 days in a row through the central line, once a month for up to 12 months. Blood tests, heart function tests, and periodic imaging scans will be repeated during these visits. Participants will continue to have telehealth visits every 3 months after they stop taking the drug.

Study Description: Patients will undergo pathological confirmation of recurrent glioblastoma via stereotactic or open biopsy (Visit 1, Day 1) to obtain baseline reference tissue. Following confirmation of recurrent glioblastoma by histopathological tissue analysis by a pathologist, study participants with confirmed histopathologically recurrent glioblastoma will be readmitted (Visit 2, Day 1). Patients will receive an initial cycle of 190 mg/m\^2/day LMP744 infused over 1 hour for 5 consecutive days (Visit 2, Days 2-6). Participants will then undergo biopsy or surgical resection as clinically appropriate within 7 calendar days of the 5th dose of LMP744, but no earlier than 24 hours after the 5th dose of LMP744 (Visit 2, between Days 7 and 13 inclusive). Tissue, CSF, and plasma will be collected at 2nd surgery for molecular analysis. Patients will then be discharged from the hospital. Following a 3-8-week period of recuperation, study participants will then resume LMP744 (5 days on; 23 days off; 12 cycles) and be followed until death. A comparative pharmacodynamic analysis will be conducted on the pre- and post-treatment tissue to evaluate the biological response to LMP744 and correlate pharmacodynamic changes with clinical outcomes. Objectives: Primary Objective: -To evaluate objective response rate (ORR) in patients with recurrent glioblastoma treated with 12 cycles of LMP744. Secondary Objectives: * To evaluate progression-free survival in patients with recurrent glioblastoma treated with 12 cycles of LMP744 compared to historical controls. * To evaluate overall survival (OS) in patients with recurrent glioblastoma treated with 12 cycles of LMP744 compared to historical controls. * To assess the pharmacologic (PK/PD) response by exploring molecular and metabolic changes in pre- versus posttreatment glioblastoma tissue following administration of LMP744. * To assess the impact of LMP744 treatment on self-reported quality of life (QOL) as measured by the validated SF-36 instrument. Exploratory Objective: * To explore the molecular changes observed in post-treatment tissue with clinical outcomes, aiming to identify potential predictive markers of response to LMP744. * To explore changes in the molecular and metabolic profiles in matched tissue, CSF, and plasma from patients treated with LMP744 compared to their pre-treatment baseline. Safety Outcomes: To descriptively monitor, document, and report adverse events (AEs) and serious adverse events (SAEs) in participants with recurrent glioblastoma treated with LMP744. Endpoints: Primary Endpoint: -Stable disease or Partial response (\>=50% disease reduction) or complete response (100% disease reduction) based on RANO 2.0 criteria Secondary Endpoints: * PFS will be assessed based on the RANO 2.0 criteria for glioblastoma assessment as follows: * Imaging Criteria: * \>=25% or more increase in enhancing lesions despite stable or increasing steroid dose * \>=25% increase in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes * Occurrence of any new lesions * Clinical Features: * Clinical deterioration not attributable to other non-tumor causes or steroid decrease * Overall survival in patients treated with LMP744 * Pharmacologic (PK/PD) response measured by molecular (transcriptomic, proteomic and/or metabolomic) tissue level changes and Differential molecular changes in tissues pre-versus post-LMP744 treatment * Self-reported quality of life (QOL) as measured by the SF-36 survey at baseline, after each treatment cycle, and at study completion.