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

Phase 1

Completed

Conditions: Glioblastoma
High Grade Glioma
Astrocytoma, Grade III

Interventions: Drug: BMX-001
Radiation: Radiation Therapy
Drug: Temozolomide

Registration Number: NCT02655601

Lead Sponsor: BioMimetix JV, LLC

Brief Summary: This is a Phase 2 study of newly diagnosed patients with high grade glioma (HGG) undergoing standard radiation therapy and temozolomide treatment. BMX-001 added to radiation therapy and temozolomide has the potential not only to benefit the survival of high grade glioma patients but also to protect against deterioration of cognition and impairment of quality of life. BMX-001 will be given subcutaneously first with a loading dose zero to four days prior to the start of chemoradiation and followed by twice a week doses at one-half of the loading dose for the duration of radiation therapy plus two weeks. Both safety and efficacy of BMX-001 will be evaluated. Impact on cognition will also be assessed. Eighty patients will be randomized to the treatment arm that will receive BMX-001 while undergoing chemoradiation and 80 patients randomized to receive chemoradiation alone. The sponsor hypothesizes that BMX-001 when added to standard radiation therapy and temozolomide will be safe at pharmacologically relevant doses in patients with newly diagnosed high grade glioma. The sponsor also hypothesizes that the addition of BMX-001 will positively impact the overall survival and improve objective measures of cognition in newly diagnosed high grade glioma patients.

Detailed Description: 160 patients will be enrolled and randomized with a treatment arm allocation ratio of 1:1 in the Phase 2 study. At enrollment, patients will be assessed with medical history, physical/neurological examinations, standard laboratory evaluations (CBC with differential and comprehensive metabolic panel (CMP)), baseline brain MRI with and without gadolinium, cognitive testing and patient-reported outcome questionnaires of HRQoL. On the first day of BMX-001 (loading dose), patients will be evaluated with medical history, patient physical/neurological examinations, and standard laboratory evaluations (CBC with differential and CMP), and ECG. Patients in Arm A will be administered BMX-001 subcutaneously first as a loading dose before the start of chemoradiation and then at maintenance dose (50% of the loading dose) twice a week for 8 weeks. Because oxidative stress continues to occur for up to several weeks following RT, the proposed protocol includes administering BMX-001 both before the start of RT and continuing for 2 weeks after the completion of RT and TMZ. TMZ will be dosed at 75 mg/m2 orally daily for 42 days and RT will be delivered in daily fractions of 1.8-2 Gy given 5 days a week for 6 weeks for a total of 59.4-60 Gy. During standard RT and TMZ, CBC with differential and CMP will be obtained weekly. Two weeks after the completion of standard RT and TMZ and every 8 weeks during adjuvant TMZ, patients will be evaluated with the following: medical history, physical/neurological examinations, Brain MRI with and without gadolinium, cognitive testing and patient-reported outcome questionnaires of HRQoL. Two weeks after the completion of chemoradiation, patients will transition to adjuvant chemotherapy with TMZ dosed at 150-200 mg/m2 orally for 5 days of a 28-day cycle for a total of 12 cycles. In light of the findings that BMX-001 can spare radiation-induced hair loss in a mouse model \[41\], we will evaluate and describe hair loss as an exploratory outcome in HGG patients by evaluating hair at baseline and then every 8 weeks. Patients will be discontinued from the study if they experience progression of disease, death or withdraw informed consent.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 177

Inclusion Criteria

Subjects must have histologically confirmed diagnosis of World Health Organization (WHO) grade III or IV malignant glioma
Subjects must be planning to start standard of care radiation therapy and chemotherapy
Subjects must be within 12 weeks of last major neurosurgical procedure for the high-grade glioma (craniotomy, open biopsy, or stereotactic biopsy)
Subjects must have had a definitive resection with residual radiographic contrast enhancement on post-resection CT or MRI of less than or equal to 3 cm in any two perpendicular planes on any images
Age * 18 years
Karnofsky Performance Status (KPS) ≥ 70%
Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,500 cells/µl, platelets ≥ 125,000 cells/µl
Serum creatinine ≤ 1.5 mg/dl, serum glutamate oxaloacetate transaminase (SGOT) and bilirubin ≤ 1.5 times upper limit of normal
Signed informed consent approved by the Institutional Review Board
If sexually active, patients must agree to use appropriate contraceptive measures for the duration of the study and for 12 months afterwards as stated in the informed consent
Stable and/or decreasing dose of corticosteroids for greater than or equal to 7 days.

Exclusion Criteria

Pregnancy or breast-feeding
Active infection requiring IV antibiotics 7 days before enrollment
Signs of wound-healing problems or infection at the craniotomy/biopsy site.
Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
Prior treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor
Evidence of > grade 1 CNS hemorrhage on baseline MRI on CT scan
Systemic treatment with inducers or strong inhibitors of cytochrome P450 within four days before enrollment or planned treatment during the time period of the study.
Metal in the body (except dental fillings) e.g., pacemaker, infusion pump, metal aneurysm clip, metal prosthesis, joint, rod or plate.
Severe allergy to contrast agent.
Inadequately controlled hypertension
Active or history of postural hypotension and autonomic dysfunction
Clinically significant (i.e. active) cardiovascular disease or cerebrovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment
History or evidence upon physical/neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment
A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >480 milliseconds (ms) (CTCAE grade 1)
A known history of additional risk factors for Torsades de Pointes (TdP) (e.g., congestive heart failure, hypokalemia, known family history of Long QT Syndrome).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 2 Arm A: Radiation Therapy, TMZ and BMX-001	BMX-001	Patients will receive standard of care radiation therapy plus temozolomide (TMZ). BMX-001 will be given by subcutaneous injection with a loading dose of 28 mg/subject given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses at half the loading dose for a total of 8 weeks. A total of 80 subjects will receive BMX-001 in this phase.
Phase 2 Arm A: Radiation Therapy, TMZ and BMX-001	Temozolomide	Patients will receive standard of care radiation therapy plus temozolomide (TMZ). BMX-001 will be given by subcutaneous injection with a loading dose of 28 mg/subject given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses at half the loading dose for a total of 8 weeks. A total of 80 subjects will receive BMX-001 in this phase.
Phase 2 Arm B: Radiation Therapy and TMZ	Radiation Therapy	In this arm, one-half of the study subjects will not receive BMX-001 but will undergo all components of standard therapy (radiation therapy plus temozolomide \[TMZ\]). A total of 80 subjects will be in this study arm.
Phase 2 Arm A: Radiation Therapy, TMZ and BMX-001	Radiation Therapy	Patients will receive standard of care radiation therapy plus temozolomide (TMZ). BMX-001 will be given by subcutaneous injection with a loading dose of 28 mg/subject given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses at half the loading dose for a total of 8 weeks. A total of 80 subjects will receive BMX-001 in this phase.
Phase 2 Arm B: Radiation Therapy and TMZ	Temozolomide	In this arm, one-half of the study subjects will not receive BMX-001 but will undergo all components of standard therapy (radiation therapy plus temozolomide \[TMZ\]). A total of 80 subjects will be in this study arm.
Phase 1	BMX-001	All subjects enrolled will receive BMX-001 at one of 4 different dose levels. BMX-001 will be given by subcutaneous injection with a loading dose given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses (half the dosing dose) for a total of 8 weeks. Subjects will also undergo standard therapy (radiation therapy plus temozolomide \[TMZ\])
Phase 1	Radiation Therapy	All subjects enrolled will receive BMX-001 at one of 4 different dose levels. BMX-001 will be given by subcutaneous injection with a loading dose given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses (half the dosing dose) for a total of 8 weeks. Subjects will also undergo standard therapy (radiation therapy plus temozolomide \[TMZ\])
Phase 1	Temozolomide	All subjects enrolled will receive BMX-001 at one of 4 different dose levels. BMX-001 will be given by subcutaneous injection with a loading dose given within 4 days prior to initiation of radiation therapy and followed by biweekly maintenance doses (half the dosing dose) for a total of 8 weeks. Subjects will also undergo standard therapy (radiation therapy plus temozolomide \[TMZ\])

Primary Outcome Measures

Name	Time	Method
Phase 2: Overall Survival, Intent to Treat (ITT) Population	From the time between randomization and death, or the date of last follow-up if the patient remains alive. Per protocol, patients will be followed indefinitely	This is applicable for Phase 2 only. It was a secondary objective of Phase 1 and that is reported as a separate outcome measure. Assessment of overall survival. With standard treatment, the median survival of Grade IV patients is expected to be 14.6 months, and the median survival of Grade III is approximately 36 months. Given that we anticipate that approximately 10% of patients to be Grade III, we estimate that the overall median survival with standard treatment to be roughly 16.7 months.
Phase 1: Maximum Tolerated Dose (MTD) of BMX-001 Administered in Combination With Standard RT and TMZ in Newly Diagnosed HGG Patients	From the time the subject signs the informed consent form through 30 days after completion of the final BMX-001 treatment (up to approximately 16 weeks)	This was a dose escalation study in which patients were enrolled to receive 1 of 4 doses in dose ascending order. MTD was defined as the dose level that has an estimated DLT rate nearest to 0.25. This is applicable to the Phase 1 part of the study only. Note that an actual MTD was not reached, however a Phase 2 recommended dose was selected based on the dose that was most tolerable to patients.

Secondary Outcome Measures

Name	Time	Method
Phase 1: Examine the Impact on Cognition of BMX-001 in Combination With Standard RT and TMZ in Treatment of Newly Diagnosed HGG Patients Via the Normalized Score Achieved on the Trails Making Test (TMT): Part A	From the time the subject signs the informed consent form through 6 months after completion of the final BMX-001 treatment (up to approximately 40 weeks)	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.
Phase 1: Examine the Impact on Cognition of BMX-001 in Combination With Standard RT and TMZ in Treatment of Newly Diagnosed HGG Patients Via the Normalized Score Achieved on the Trail Making Test (TMT): Part B	From the time the subject signs the informed consent form through 6 months after completion of the final BMX-001 treatment (up to approximately 40 weeks)	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.
Phase 2: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Adverse events occurring from baseline through 30 days post completion of treatment (approximately 12 weeks total).	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.
Phase 2: Protection/Improvement of Cognition Using Hopkins Verbal Learning-Revised	Baseline and Week 24	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.
Phase 2: Protection of Bone Marrow Against Chemotherapy-Induced Thrombocytopenia	Approximately 12 weeks (from Baseline to 30 days post completion of treatment)	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.
Phase 1 and Phase 2: Progression-free Survival (PFS)	up to 5 years	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).
Phase 2: Protection/Improvement of Cognition Via the Controlled Oral Word Association Test (COWAT)	Baseline and Week 24	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 2: Protection/Improvement of Cognition - Trails Making Test A and B	Baseline and Week 24 Baseline and Week 24 Baseline and Week 24	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
Phase 1: Examine the Impact on Cognition of BMX-001 in Combination With Standard RT and TMZ in Treatment of Newly Diagnosed HGG Patients Via the Adjusted Change T Score Achieved on the Controlled Oral Word Association Test (COWAT).	From the time the subject signs the informed consent form through 6 months after completion of the final BMX-001 treatment (up to approximately 40 weeks)	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.
Phase 1: Examine the Impact on Cognition of BMX-001 in Combination With Standard RT and TMZ in Treatment of Newly Diagnosed HGG Patients Via the Normalized Total Recall Change T-score Achieved on the Hopkins Verbal Learning Test- Revised (HVLT-R)	From the time the subject signs the informed consent form through 6 months after completion of the final BMX-001 treatment (up to approximately 40 weeks)	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
Phase 2: Incidence of Treatment-Emergent Adverse Events Related to BMX-001	Adverse events occurring from baseline through 30 days post completion of treatment (approximately 12 weeks total).	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.
Phase 1 and 2: Complete or Partial Radiographic Response to Tumor	12 weeks	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.
Phase 1: Median Overall Survival	From the time between enrollment and death, or the date of last follow-up if the patient remains alive.	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.
Phase 1: Number of Participants Who Experiences a Dose-limiting Toxicity (DLT).	From the time the subject signs the informed consent form through 30 days after completion of the final BMX-001 treatment (up to approximately 16 weeks)	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.

Trial Locations

Locations (9): University of Alabama- Birmingham
🇺🇸
Birmingham, Alabama, United States
University of California San Francisco
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San Francisco, California, United States
University of Kentucky
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Lexington, Kentucky, United States
St. Luke's Hospital
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Kansas City, Missouri, United States
University of Nebraska Medical Center
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Omaha, Nebraska, United States
Duke Cancer Institute
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Durham, North Carolina, United States
Ohio State University
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Columbus, Ohio, United States
Huntsman Cancer Institute
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Salt Lake City, Utah, United States
University of Washington
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Seattle, Washington, United States
University of Alabama- Birmingham
🇺🇸Birmingham, Alabama, United States