PROJECT SUMMARY—With support from NCI-funded Phase I and Phase II SBIRs, Quadriga Biosciences developed QBS-72S, a novel compound designed to treat glioblastoma multiforme (GBM), even in the 60% of patients who are resistant to temozolomide (TMZ), the current standard of care. Preclinical studies demonstrated QBS-72S meets the three requirements for a globally effective GBM treatment: 1) it has a cytotoxic mechanism of action that is not affected by the DNA repair mechanisms responsible for resistance to TMZ, 2) it penetrates the blood brain barrier (BBB), and 3) it targets GBM while sparing normal tissue. Further development and commercialization of QBS-72S has the potential to deliver the first drug that is effective for improving overall survival in all patients with GBM, including the majority of patients who are resistant to the current standard of care. Resistance to TMZ in both newly-diagnosed and recurrent GBM occurs when O6- methylguanine-DNA-methyltransferase (MGMT) repairs DNA damage produced by TMZ. QBS-72S circumvents this resistance with a nitrogen mustard (N-mustard) that damages DNA by producing numerous inter-strand crosslinks (ICLs) in actively dividing cells. The number of ICLs overwhelms repair mechanisms, and the reliance on cellular division limits off-target toxicity. Many effective chemotherapeutics share these features, but most of them are excluded by the BBB. In contrast, QBS-72S is selectively transported across the BBB by LAT-1, a transporter that is also highly expressed in tumor cells but not in healthy tissues. These features make QBS-72S an ideal candidate for treating GBM, and a first-in-humans study is underway to confirm safety and establish a recommended Phase 2 dose. Following extensive discussions with NCI, Quadriga proposes to use this Phase IIB SBIR to add QBS-72S as a new arm to the INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT), an ongoing, multi-site, adaptive Phase 2 clinical trial designed to demonstrate the safety and efficacy of novel therapeutics as replacements for TMZ in the current standard of care regimen. Aim. Evaluate the effectiveness of QBS-72S in place of TMZ for improving overall survival and progression-free survival in patients with newly diagnosed GBM with unmethylated MGMT promoters. Milestones: 1) recruit patients and complete study—a) recruit up to 70 patients in the QBS-72S arm and up to 70 in the TMZ arm, b) QBS-72S arm not dropped for futility, c) follow up with ³ 80% at 30 days post-treatment; 2) demonstrate efficacy—a) overall survival hazard ratio ≥ 0.6 for QBS-72S (primary endpoint), b) progression-free survival hazard ratio ≥ 0.6 for QBS-72S (secondary); 3) characterize safety—no unexpected dose-limiting toxicities; 4) determine whether defined biomarkers predict QBS-72S benefit—exploratory; 5) complete data analysis, prepare Phase 3 protocol, and submit IND amendment. Impact: Successful completion of these milestones is required to proceed to a Phase 3 trial. Successful completion of a Phase 3 trial and receipt of FDA approval would provide the first drug for GBM that is effective regardless of MGMT status and could establish a new, more effective standard of care.

PROJECT NARRATIVE Half of patients with glioblastoma, a form of brain cancer, only survive 12 to 15 months after diagnosis, and less than 5% survive more than 5 years in part because 60% of patients do not respond to the drugs approved for treating the disease. This study will test a new drug that is designed to overcome the DNA repair mechanisms that prevent current treatments from working in those patients. If the drug is shown to be safe and effective in humans, it will fill a gap in treatment options and improving outcomes for patients with glioblastoma.