Berubicin Demonstrates Early Promise in Recurrent or Refractory Glioblastoma Multiforme

Sandra Silberman, MD, PhD

Berubicin (RTA 744) was found to have acceptable tolerability when administered as second-line treatment in patients with recurrent or refractory glioblastoma multiforme, according to updated results from an ongoing phase 2 trial (NCT04762069).¹

Data presented during the 2023 SNO/ASCO CNS Cancer Conference showed that any-grade adverse effects (AEs) were reported in 83.8% of those who received berubicin (n = 105) with 46.7% of these effects being grade 3 to 5; in those who received lomustine (Gelostine; n = 46), these rates were 84.8% and 39.1%, respectively.

The most common AEs observed in at least 10% of those on the investigative arm included anemia (any grade, 13.3%; grade 3 to 5, 1.9%), asthenia (10.5%; 2.9%), constipation (9.5%; 0%), fatigue (26.7%; 0%), headache (17.1%; 5.7%), decreased lymphocyte count (13.3%; 8.6%), nausea (17.1%; 0%), decreased neutrophil count (20%; 8.6%), decreased platelet count (4.8%; 1.9%), seizure (9.5%; 4.8%), thrombocytopenia (1%; 0%), and decreased white blood cell count (12.4%; 7.6%).

In the control arm, patients experienced anemia (any grade, 13%; grade 3 to 5, 0%), asthenia (13%; 0%), constipation (10.9%; 0%), fatigue (19.6%; 0%), headache (6.5%; 2.2%), decreased lymphocyte count (21.7%; 13%), nausea (23.9%; 0%), decreased neutrophil count (15.2%; 4.3%), decreased platelet count (30.4%; 8.7%), seizure (15.2%; 6.5%), thrombocytopenia (8.7%; 2.2%), and decreased white blood cell count (19.6%; 6.5%).

“Berubicin has demonstrated its capability to be an innovative treatment in glioblastoma multiforme that is safe and well tolerated, which has the potential to be a novel and effective therapy for this disease,” Sandra Silberman, MD, PhD, chief medical officer of CNS Pharmaceuticals, Inc., stated in a press release.² “Based on the results we’ve seen preclinically and in the clinic thus far, including these updated results from our ongoing potentially pivotal study, we remain optimistic that berubicin may provide a much-needed clinical benefit for patients [with glioblastoma multiforme]. We look forward to upcoming interim results that will evaluable berubicin compared with the current standard of care [of] lomustine for second-line therapy in this disease.”

A doxorubicin analog, berubicin has substantial central nervous system update. In orthotopic mouse intracranial models, the agent has been found to extend survival and have higher infiltration of the tumor vs normal healthy tissue.

The adaptive, multicenter, open-label, randomized, controlled study enrolled adult patients with recurrent glioblastoma multiforme with World Health Organization grade IV disease following failure of standard frontline treatment.

These patients are being randomly assigned 2:1 to receive intravenous berubicin at 7.1 mg/m² as free base via a 2-hour infusion given once daily for 3 consecutive days followed by 18 days off study treatment or lomustine given at the approved dose and regimen per prescribing information.³ Patients will be stratified by MGMT methylation status. Overall survival serves as the primary end point of the research.¹

As of the data cutoff date of June 30, 2023, a total of 151 patients had been enrolled to the trial. Of these patients, 105 were assigned to the berubicin arm and 46 were assigned to the lomustine arm. Patients had comparable demographics for each arm. In the overall population, the mean age was 57.6 years, and most patients were male (68.2%) and White (76.2%). The mean body surface area was 1.98 m². The mean Karnofsky performance score was 84.5% at baseline.

Moreover, 38.4% had MGMT methylation; this allows “for a reasonable comparison of efficacy, irrespective of the arm of the study and impact of this baseline,” study investigators wrote in the poster.

At this time point, 50.3% of patients had completed the study and 37.7% were still on the study. Notably, 9.5% of those in the berubicin arm and 17.4% of those in the lomustine arm withdrew from the study. The primary reasons for withdrawal included toxicity (1.9% vs 4.3%), physician decision (1% vs 2.2%), patient decision (4.8% vs 8.7%), death (1% vs 0%), or another unspecified reason (1% vs 2.2%).

“Approximately 50% of patients on both arms have completed the study…and withdrawal prior to end of treatment is relatively small, although almost twice the percent of patients in the lomustine group compared [with] berubicin have withdrawn,” the investigators added.

When 30% to 50% of patients have been on the study and there have been 44 events or deaths, an interim analysis of OS will be conducted to evaluate the relative efficacy between the 2 agents. A key secondary end point will be safety.

Data from a previous dose-escalation phase 1 trial (NCT00526812) showed that berubicin had a clinical benefit rate of 44% in evaluable patients with recurrent or refractory glioblastoma multiforme or other primary brain cancers (n = 27).^1,4 Notably, 1 patient had a durable complete response and was still in remission over 11 years later. Moreover, 2 patients had partial responses and 9 patients achieved disease stability.

In the study, which utilized an accelerated titration design, evaluated daily doses of berubicin ranging from 1.2 mg/m² to 9.6 mg/m². Neutropenia represented the most frequently observed dose-limiting toxicity (DLT). Minimal nonhematologic AEs were reported. Notably, no instances of neurotoxicity or cardiotoxicity were observed. The maximum tolerated dose of the agent was determined to be 7.5 mg/m² per day. At that dose, 1 of 5 patients had a DLT; 2 of 6 patients who received the agent at the next highest dose of 9.6 mg/m² daily also experienced a DLT.

Pharmacokinetic studies revealed dose-independent clearance, with a 32.3-hour mean half-life and a large volume of distribution of 1842 L/m². The mean maximum plasma concentration and area under the plasma concentration-time curve seemed to increase proportionally as dosing of the agent increased.

References

1. Muzyczenko Z, Hsu S, Picker D, et al. A randomized, controlled trial of berubicin, a novel topoisomerase II inhibitor, after first-line therapy for glioblastoma multiforme (GBM): updated results. CNS Pharmaceuticals, Inc. Accessed August 14, 2023. https://cnspharma.com/wp-content/uploads/2023/08/Berubicin-SNO-ASCO-CNS-Cancer-Conference-2023-poster-FINAL.pdf
2. A study of berubicin in adult subjects with recurrent glioblastoma multiforme. ClinicalTrials.gov. Updated August 7, 2023. Accessed August 14, 2023. https://clinicaltrials.gov/study/NCT04762069
3. CNS Pharmaceuticals (NASDAQ: CNSP) presents updated results from on-going potentially pivotal study of berubicin in adult patients with recurrent GBM (WHO grade IV) after failure of standard first line therapy. CNS Pharmaceuticals, Inc. August 14, 2023. Accessed August 14, 2023. https://ir.cnspharma.com/news-events/press-releases/detail/168/cns-pharmaceuticals-nasdaq-cnsp-presents-updated-results
4. Berubicin. CNS Pharmaceuticals, Inc. Accessed August 14, 2023. https://cnspharma.com/berubicin/