Trial of Newly Diagnosed High Grade Glioma Treated With Concurrent Radiation Therapy, Temozolomide and BMX-001

Median Overall Survival (OS) is a key clinical outcome measure used to assess the efficacy of BMX-001 in combination with standard radiotherapy (RT) and temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGG). OS is defined as the time from the date of study enrollment to the date of death from any cause. Survival status was assessed at regular follow-up intervals (e.g., every 3 months post-treatment) through medical records, patient contact, and clinical evaluations. The final analysis was conducted after a pre-specified number of events (deaths) have occurred.

Expected Outcome: Prolonged median OS compared to historical or control data (RT + TMZ alone) would suggest a survival benefit associated with BMX-001.

This is only applicable for the Phase 1 portion of the study. All patients who received at least 1 dose of BMX-001, regardless of dose level, after enrolling on study are included in the analysis.

The Controlled Oral Word Association Test (COWAT) measures verbal fluency which reflects executive functioning, processing speed, mental flexibility, and language output.

The raw score is then adjusted for age, education, and normative data to allow meaningful comparisons across individuals. The standardized score (T-score) is calculated using normative reference tables.

Higher Scores = Better Cognitive Function, lower scores = cognitive impairment. T score range is 0-100.

A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean performance with a standard deviation of 10.

T-scores below 40 suggest clinically significant cognitive decline. Scores range from < 30 (significantly below average), to 30-39 (below average), 40-59 (average), and greater than or equal to 60 is above average.

Stable or improved COWAT scores over time would suggest that adding BMX-001 may help preserve cognitive function.

Part A of the Trails Making Test (TMT) measures visual attention and processing speed by requiring the patient to connect numbers sequentially (1 → 2 → 3, etc.) as quickly as possible. This is a widely used neuropsychological test that measures visual attention, processing speed, and psychomotor function.

Raw scores are measured in seconds (time to complete the task), but T-scores are derived by converting time-based results into a normed distribution accounting for age and education.

Mean (SD) change in cognitive assessment in T-Scores is reported and the range is 0-100.

T score interpretation and range is < 30 (significantly impaired), 30-39 (mildly impaired), 40-59 (Average), >/= 60 (Above average). A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean performance with a standard deviation of 10.

Higher scores = better performance.

The Trails Making Test (TMT) Part B is a widely used neuropsychological test that measures set-shifting ability, processing speed, and working memory. While Part A focuses on speed, visual scanning, and attention.

Prolonged completion time or an increase in errors compared to baseline or age-adjusted norms would indicate cognitive decline.

Raw scores are measured in seconds (time to complete the task), but T-scores are derived by converting time-based results into a normed distribution accounting for age and education.

Mean (SD) change in T score is reported, range is 0-100. T score interpretation and range is < 30 (significantly impaired), 30-39 (mildly impaired), 40-59 (Average), >/= 60 (Above average). A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean performance with a standard deviation of 10.

Higher scores = better performance.

Hopkins Verbal Learning Test- Revised (HVLT-R) is a standardized neuropsychological assessment that measures verbal learning and memory, including total (immediate recall). Total Recall T-score is derived from the sum of correctly recalled words across three learning trials and is normalized based on age-adjusted normative data. This provides insight into immediate verbal memory performance and learning ability.

Total Recall (Immediate Memory \& Learning) is Sum of correctly recalled words across three learning trials and is a measurement of immediate recall capacity and learning efficiency.

Raw score range is 0-36, T score range is 0-100. T scores >/= 60 are above average and T scores < 40 are below average. A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean with a standard deviation of 10

To assess the safety and tolerability of standard RT and TMZ in combination with BMX-001 compared to standard RT and TMZ alone in newly diagnosed HGG patients. The phase 2 portion of this study has two adverse event endpoints:

1. The proportion of patients who experience any grade 3 or 4 adverse event during radiation and temozolomide treatment, and
2. The proportion of patients who experience a grade 3 or 4 adverse event that is definitely, possibly, or probably related to BMX-001 treatment during this same period.

This outcome measure does not apply to the Phase 1 portion of the study, as it was not designated as an outcome for Phase 1 but was specified only for Phase 2.

To assess the safety and tolerability of standard RT and TMZ in combination with BMX-001 compared to standard RT and TMZ alone in newly diagnosed HGG patients.

This outcome is measured to test the proportion of patients who experience a grade 3 or 4 adverse event that is definitely, possibly, or probably related to BMX-001 treatment during this same period.

This outcome measure does not apply to the Phase 1 portion of the study, as it was not designated as an outcome for Phase 1 but was specified only for Phase 2. It also only applies to Arm A in the study as Arm B did not receive the study drug.

Hopkins Verbal Learning Test- Revised (HVLT-R) is a standardized neuropsychological test that measures verbal learning and memory, including total (immediate recall), delayed recall, and recognition discrimination. It is scored using a T-score which are calculated based on raw scores (e.g., number of words recalled) and standardized using normative data adjusted for age, education, and sometimes sex. T-score range is 0-100. T-scores >/= 60 are above average and T scores < 40 are below average. Higher scores are better. Total recall interpretation - T ≥ 60: above average; T < 40: below average. Delayed recall - T < 30 may suggest memory consolidation issues, and recognition discrimination - T < 30 may indicate impaired recognition memory. A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean performance with a standard deviation of 10.

Mean (SD) change in cognitive assessment is reported.

This Controlled Oral Word Association Test (COWAT) measure verbal fluency which reflects executive functioning, processing speed, mental flexibility, and language output.

The raw score is adjusted for age, education, and normative data to allow meaningful comparisons across individuals. The standardized score (T-score) is calculated using normative reference tables.

Higher Scores = Better Cognitive Function, lower scores = cognitive impairment. T-score range is 0-100 A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean performance with a standard deviation of 10.

T-scores below 40 suggest clinically significant cognitive decline. Scores range from < 30 (significantly below average), to 30-39 (below average), 40-59 (average), and greater than or equal to 60 is above average.

Stable or improved COWAT scores over time would suggest that adding BMX-001 may help preserve cognition.

Phase 1 is reported separately. Neurocognitive testing was done and reported here for the Trails Test A and B Part A: Visual attention and processing speed Part B: Executive functioning, task switching, and divided attention. Part A testing time is typically 20-90 sec, and Part B time is typically 40-180 sec.

Raw scores are measured in seconds (time to complete the task), but T-scores are derived by converting time-based results into a normed distribution accounting for age and education.

Mean (SD) change in cognitive assessment in T-Scores is reported T score interpretation and range is < 30 (significantly impaired), 30-39 (mildly impaired), 40-59 (Average), >/60 (above average) A T-score of 50 represents the mean performance in the normative population, this means a score of 50 indicates the population mean performance with a standard deviation of 10.

Lower times = better

This was not a secondary outcome in Phase 1 and therefore only applies to Phase 2. The proportion of patients who experience grade 3 or 4 thrombocytopenia during concurrent temozolomide and radiation will be recorded within each treatment group. The proportion of patients who experience a platelet count less than 100K during concurrent temozolomide and radiation will also be recorded within each treatment group. For both endpoints described above, a chi-square or Fisher's exact test was conducted to compare the prevalence of such thrombocytopenia observed in patients with and without BMX-001.

The primary analysis of PFS will consider all patients, and consider them in their assigned treatment arm regardless of compliance. This approach to analysis is consistent with an intent-to-treat analysis approach. Progression-Free Survival (PFS) is defined as the time from randomization (Phase 2) or study enrollment (Phase 1) to the first occurrence of either disease progression (as determined by standardized radiographic criteria, the RANO [Response Assessment in Neuro-Oncology] criteria) or death from any cause, whichever occurs first. Patients who have not experienced progression or death at the time of analysis will be censored at their last known follow-up date. PFS will be estimated using the Kaplan-Meier method, providing median PFS and corresponding 95% confidence intervals (CI).

The guidelines and criteria for radiographic response will be based on the updated RANO criteria for newly diagnosed GBM. MRI brain with and without contrast will be obtained at enrollment, 2-4 weeks after standard RT and TMZ, and every 8 weeks during adjuvant TMZ. Since this is a study in newly diagnosed patients with HGG, the baseline imaging will be designated as the imaging obtained 2 to 4 weeks after the completion of standard RT and TMZ. At each time point, based on RANO criteria, the subject response will be characterized as Complete Response, Partial Response, Progressive Disease, Stable Disease, or Not Evaluable.