The following is a summary of a randomized clinical study that we undertook, which yielded very promising results regarding the role of Specific Conjugate Particle (SCP) therapy in the management of recurrent high-grade Glioblastoma multiforme (GBM). Despite the use of combined treatment regimens, the prognosis for patients with malignant glioma remains unfavorable. At the time of tumor recurrence, life expectancy is usually reduced to a few months, and todate, chemotherapy in that situation has not demonstrated favorable results, with tumor responses observed in only 10-30% of patients. Major reasons for the low efficacy of chemotherapy for malignant glioma include poor blood-brain barrier penetration by cytotoxic agents and the expression of multidrug resistance genes. Therefore, it is essential that other treatment modalities are developed and evaluated. Given that mandate and the excellent results that we have observed in our other SCP therapy studies, we undertook a prospective Randomized Clinical Trial (RCT).
Entry criteria for the study included that patients must have World Health Organization (WHO) grade III-IV high-grade glioma according to two independent pathology reports, tumor recurrence identified on gadolinium-enhanced magnetic resonance imaging (MRI), be aged between 18-70 years, and a life expectancy more than two months. In addition to undergoing surgery, all patients completed external-beam radiotherapy before being included in the study.
Doxorubicin is one of the most effective agents in-vitro against cell lines derived from malignant glioma; however, it has no significant effect in vivo, and this finding appears to be attributable primarily to poor blood-brain barrier penetration. Patients were randomized to receive either Specific Conjugate Particle Doxorubicin (SCP-Doxorubicin) or the conventionally accepted Pegylated Liposomal Doxorubicin (PEG-Doxorubicin). Patients received 20 mg/m2 of either PEG-Doxorubicin or SCP-Doxorubicin by an intravenous infusion over 30 minutes on day 1. A total of 563 courses of SCP-Doxorubicin and PEG-Doxorubicin were administered, with a range of 1-28 courses per patient.
We enrolled 80 patients to the study with recurrent high-grade Glioblastoma Multiforme and in those subjects we observed two complete responses (CRs) and 2 Partial Responses (PRs). We noted Stable Disease (SD) lasting longer than eight weeks in 28 patients (yielding an aggregate overall response rate of 40%).
We utilized Cox’s Regression Model of life table analysis to assess outcomes, and we confirmed statistical significance via Kaplan-Meier estimates. Patients receiving SCP-Doxorubicin had a significantly better response to therapy (more CR, PR and SD) than those receiving PEG- Doxorubicin (p<0.05). A total of twenty-five adverse events occurred in patients receiving PEG-Doxorubicin, whereas there were only four adverse events in patients who received SCP-Doxorubicin (p<0.05). Palmoplantar erythrodysesthesia was the most common adverse event in both the groups.
In conclusion, our study has produced very promising results regarding the role of SCP-Doxorubicinin managing patients who have recurrent high-grade Glioblastoma Multiforme. We found SCP-Doxorubicin to have superior efficacy to PEG-Doxorubicin independent of the patient’s prior therapeutic regime and stage of carcinoma. Furthermore, SCP-Doxorubicin was found to be a comparatively safer treatment regimen with no major side effects and a significantly lower adverse event rate than PEG-Doxorubicin. Given these findings, we plan to seek a 505(b)(2) expedited route to regulatory approval so that SCP therapy can be made available for the management of this otherwise poor prognosis group of patients. You can view a PowerPoint presentation of this study by clicking on this link .
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