MBM-02 (Tempol) is an HIF-1 and HIF-2 inhibitor that is being tested as an addition to
standard of care treatment that includes radiotherapy and TMZ. MBM-02's ability to increase
progression free survival and decrease side effects of TMZ and radiotherapy treatment will be
assessed.
MBM-02 is an HIF-1 and HIF-2 inhibitor that has shown in animal models to turn back on the
apoptosis process (cell death) in cancer.
Hypoxia is well documented in most solid tumors (Vaupel et al., 1991). Acute, intermittent,
and cycling hypoxia are associated with inadequate blood flow, whereas chronic hypoxia is the
consequence of increased oxygen diffusion distance resulting from tumor expansion (Dewhirst
et al., 2008). A study by Chen and colleagues (2015) showed that cycling hypoxia and chronic
hypoxia are important tumor microenvironment phenomena that limit tumor response to
chemotherapy in GBM.
In hypoxic conditions observed in solid state tumors, the hypoxia inducible factors, HIF-1α
and HIF-2α, are upregulated and transcribe a panel of genes associated with cancer survival
and progression, such as vascular endothelial growth factor receptor (VEGFR), platelet
derived growth factor (PDGF), and glucose transporter 1 (GLUT1). These factors are essential
for tumor survival, thereby increasing tumor progression and decreasing apoptosis. Without
the functions of the HIF family of genes, solid-state tumors could not progress and would not
survive. In both Chen et al. (2015) and Sourbier et al. (2012), researchers established that
the active compound in MBM-02 is an inhibitor of both HIF-1α and HIF-2α.
This is an open label multisite trial that will assess MBM-02's ability to increase progress
free survival in patients receiving standard of care for glioblastoma.
Inclusion Criteria:
1. Be > 35 and ≤ 75 years of age;
2. Be newly diagnosed with glioblastoma multiforme within 4 weeks of open
biopsy/resection;
3. Be histologically confirmed to have definitive GBM by partial or complete surgical
resection (i.e. not by biopsy only) within 4 weeks prior to MBM-02 administration;
4. Have recovered from the effects of surgery, post-operative infection, and other
complications before study registration;
5. Have a diagnostic contrast-enhanced MRI or CT scan of the brain performed
preoperatively and postoperatively prior to the initiation of radiotherapy, within 28
days prior to MBM-02 administration;
6. If female and of child bearing potential, must be using an effective birth-control
method as described in section 3.5;
7. If a male with a female partner of child bearing potential, adequate methods of
contraception must be employed as described in section 3.5.
8. If male, no sperm donation for 90 days until after the conclusion of the study;
9. Be properly informed of the nature and risks of the clinical investigation, comply
with all clinical investigation-related procedures, and sign an Informed Consent Form
prior to entering the clinical investigation;
10. Be able to participate for the full term of the clinical investigation;
11. Have a Karnofsky performance status of >70;
12. Have a life expectancy ≥ 6 months; and
13. Have adequate baseline organ function (hematologic, liver, renal, nutritional and
metabolic):
Hematology:
Absolute neutrophil count (ANC) ≥1.5 Hemoglobin ≥ 10 g/dL Platelets ≥ 100,000 per
microliter of blood
Hepatic:
Total bilirubin ≤ 2 x ULN Alanine aminotransferase (ALT) and Aspartate aminotransferase
(AST) ≤2 x ULN
Renal:
creatinine clearance (CrCl) ≥ 60 ml/min within 2 weeks prior to registration determined by
24-hour collection or estimated by Cockcroft-Gault formula: CrCl male = [(140 - age) x (wt
in kg)] [(Serum Cr mg/dl) x (72)] CrCl female = 0.85 x (CrCl male)
Exclusion Criteria:
1. Evidence of recurrent GBM or metastases detected outside of the cranial vault;
2. Patients with histone H3 K27M mutation or gliosarcoma;
3. Patients using the Optune device during study drug administration;
4. Prior cancer diagnosis other than skin basal cell or squamous cell carcinoma
(non-metastatic);
5. Patients unable to undergo MRI because of non-compatible devices;
6. Oxygen dependent chronic obstructive pulmonary disease (COPD);
7. Unstable coronary artery disease (CAD);
8. Diagnosis of midline diffuse glioma (glioblastoma);
9. Insufficient biopsy tissue for full molecular profiling of the tumor;
10. Prior radiation or chemotherapy for glioblastoma or glioma;
11. Prior radiation for cancer of the head and neck that would result in an overlap of
radiation fields;
12. Evidence of a significant medical illness, or a psychiatric illness/social situation
that would, in the investigator's judgment, make the patient inappropriate for this
study;
13. Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel
resection that would preclude adequate absorption of the study drug;
14. Have had a recent, serious, non-malignant medical complication that, in the opinion of
the investigator, makes the individual unsuitable for study participation;
15. Have used an investigational drug within 28 days of the initiation of study treatment;
16. Have a history of a positive blood test for HIV;
17. At the time of screening, have a significant active medical illness which, in the
opinion of the investigator, would preclude completion of the study; and
18. Body weight less than 35 kg (77 lbs.)
