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

Study Overview
=================
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.

Official Title
-----------------
A Phase 2 Trial for Patients With Newly Diagnosed High Grade Glioma Treated With Concurrent Radiation Therapy, Temozolomide, and BMX-001

Conditions
-----------------
High Grade Glioma, Astrocytoma, Grade III, Glioblastoma

Intervention / Treatment
-----------------
* Drug: BMX-001
* Radiation: Radiation Therapy
* Drug: Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation Therapy, TMZ and BMX-001<br>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. | Drug: BMX-001<br>* BMX-001 consists of a porphyrin ring with pyridyl groups attached at each of the four methane bridge carbons. The nitrogen in the pyridyl ring is at the 2 position and has a side chain consisting of six carbons with an ether linkage. A manganese atom is chelated into the porphyrin ring and is the active center of the molecule. This molecule is an enzymatic scavenger of free radical species operating at close to diffusion-limited rates.<br>* Other names: manganese butoxyethyl pyridyl porphyrin;Radiation: Radiation Therapy<br>* 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.<br>Drug: Temozolomide<br>* Initially, temozolomide (TMZ) will be dosed at 75 mg/m2 orally daily for 42 days. 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.<br>* Other names: TMZ;|
| Active Comparator: Radiation Therapy and TMZ<br>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. | Radiation: Radiation Therapy<br>* 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.<br>Drug: Temozolomide<br>* Initially, temozolomide (TMZ) will be dosed at 75 mg/m2 orally daily for 42 days. 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.<br>* Other names: TMZ;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 - Overall survival | 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. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Safety and tolerability of BMX-001 in combination with standard radiation therapy and temozolomide in newly diagnosed high grade glioma patients will be assessed as the proportion of patients with a serious adverse event (SAE). | 10 weeks | 
| Progression-free survival | Progression-free survival will be assessed as the time between initiation of protocol treatment and the first recurrence of disease or death. | 2 years | 
| Protection/improvement of cognition | Neurocognitive testing will be done using Brief Assessment of Cognition (BAC) through the NeuroCog app. This battery consists of the six tests listed below. Verbal memory & learning test will assess verbal learning, memory for words, and recall. Working memory test will assess digital sequencing when presented with auditory clusters of numbers. Motor function test will assess motor skills using manipulation of tokens. Verbal fluency test includes both semantic fluency (number of words generated in a given category) and letter fluency (number of words beginning with a given letter). Speed of processing will be tested using ability to match corresponding numbers with a series of symbols. Executive function will be assessed by a Tower of London subtest. Cognitive testing will be obtained at screening, 2 weeks after the completion of standard RT and TMZ, and every 8 weeks during adjuvant TMZ. | 1 year | 
| Radiographic response to tumor. | 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. | 2 years | 
| Protection of Bone Marrow against Chemotherapy-Induced Thrombocytopenia | Platelet counts will be assessed weekly during the 8 weeks of primary therapy involving BMX-001. Up to 50% of subjects receiving standard of care TMZ will develop thrombocytopenia after 3-5 weeks with platelet counts falling below 100,000 and about 15% will develop severe thrombocytopenia. | 1 year |