Design and initiation of an adaptive, randomized, controlled study of berubicin, a topoisomerase 2 poison that crosses the blood brain barrier (BBB), for the treatment of recurrent glioblastoma multiforme (GBM) after first-line therapy

TPS2083 Background: Berubicin (also known as WP744) is a patented doxorubicin (Dox) analog with evidence that it crosses the BBB and has significant central nervous system (CNS) uptake. Induction of apoptosis and DNA damage by Berubicin was compared with Dox and showed much greater potency of Berubicin in all tested cancer cells, also significantly and consistently showing higher cytotoxicity than Dox. In models of intracranial orthotopic gliomas, Berubicin prolonged survival when compared to temozolomide, currently a standard of care in GBM. Evaluation of these models also showed that Berubicin had greater infiltration into the tumor compared to normal tissue, providing additional justification for its observed improved efficacy. Based on this data, a Phase 1 dose escalation study was conducted in patients with recurrent primary brain tumors. Berubicin was well tolerated, with myelosuppression (neutropenia and thrombocytopenia) as dose-limiting toxicities. Of 25 patients evaluable for efficacy, there was 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease over 6 weeks for a clinical benefit rate of 44%. Methods: CNS Pharmaceuticals, Inc. (“CNSP”) has licensed Berubicin and initiated a randomized, controlled clinical trial of Berubicin vs. Lomustine in adults with recurrent GBM after first line therapy. The primary endpoint of this study, being conducted in the United States and Europe, is overall survival (OS), with a projected 243 patients enrolled in a 2:1 randomization design (Berubicin:Lomustine). This study has pharmacokinetic (PK) evaluations of all patients enrolled, with at least 15 patients undergoing complete PK assessments throughout the initial dosing period (3 days of IV administration of Berubicin over 2 hours, repeated every 3 weeks). Patients will be stratified on the basis of MGMT methylation, there will be documentation of IDH WT status, and no prior administration of bevacizumab will be allowed. An interim analysis will evaluate the comparative effectiveness of these treatments, an adaptive design intended to demonstrate that Berubicin’s efficacy is at least equal to that of Lomustine such that continuation of the study is in patients' best interests (futility analysis). The overall survival endpoint and sample size have been calculated to be able to show a statistical difference between the two therapies as second line treatment for GBM. Additional studies in malignant diseases of the CNS (e.g., pediatric brain tumors, primary CNS lymphoma, metastatic tumors) are also being explored based on the potential for anthracycline activity in these indications. For the present study posted on clinicaltrials.gov as, additional details and contact information is available. Clinical trial information: NCT04762069.