Discussion
CED, tumor, headaches, necrosis, glioblastoma, Lymphopenia
RECURRENCES, DISEASE PROGRESSION, TUMOR, DISEASE, SECONDARY, REMISSION, NECROSIS, REGRESSION, GLIOBLASTOMA, LYMPHOPENIA, RECURRENT TUMOR
This Phase 1 trial with hrBMP4 locally administered in 15 recurrent glioblastoma patients is the first clinical study on pro-differentiation therapy (PDT) in glioblastoma. Local administration of hrBMP4 by CED into the tumor and surrounding brain parenchyma was well-tolerated and safe, without drug-related, severe AEs. Three patients showed durable tumor response, including two patients with complete, sustained regression of the treated tumor and extended survival.The first objective of this trial was to assess the safety and tolerability of intracerebral, local delivery of increasing doses of hrBMP4. This treatment did not cause any drug-related SAEs and no DLTs were observed. Most AEs were mild to moderate in severity and were related to the clinical deterioration typical of recurrent glioblastoma or to other factors, like concomitant medication. The reported headaches are common in trials with intracerebral local drug delivery and they resolved post-infusion. Most treatment-emergent AEs (TEAEs) surfaced in similar proportions in patients across all hrBMP4 dose levels, with no apparent dose-dependent trends in their number or severity. Accordingly, the three patients that had increased systemic levels of hrBMP4 after infusion did not have more or different AEs than patients retaining baseline systemic levels. Lymphopenia, one of grade 3 AEs observed in two patients, was an exacerbation of pre-existing conditions (grade 2) in both patients and no direct correlation between the latter and the circulating BMP4 levels (Supplementary Fig. The secondary objective of this trial was to assess the perspective efficacy of hrBMP4. While no standard treatment has yet been established for glioblastoma recurrences, lomustine is frequently used, leading to a median survival time of 5·6 months. The overall median survival time in our study was 7 months. The potentially beneficial role of hrBMP4 on survival was supported by the analysis of subgroups of responsive patients. Three out of 15 patients (20%) showed either partial response or complete local remission. Although over-interpretation of such results from early-phase trial should be avoided, “subgroup efficacy” is hypothesis-generating, in line with previously published in vitro studies that also proposed subgroup efficacy after treatment with hrBMP4 [Altogether, these findings support the concept that the infusion of hrBMP4 via CED can be safely conducted and may elicit therapeutic effects in glioblastoma patients.One of the limitations of this study was one of the inherent issues with CED, i.e. the difficulty in anticipating the infusate distribution. Especially for recurrent tumors, which have rubbery gliotic boundaries, areas of necrosis, and dispersed islands of rapidly proliferating tissue, optimal target delineation for catheters is challenging. Hence, we analyzed the distribution of the infused hrBMP4 in relation to the patient’s lesions and pattern of disease progression. This revealed that the hrBMP4-treated areas rarely overlapped with those wherein the disease recurred (Fig. Another limitation was that, as typical for a hypothesis-generating Phase I trial, the enrollment criteria did not discriminate between molecular glioblastoma subtypes. Since strong BMPR1B signals and low ADC values may be associated with better survival after hrBMP4, these parameters should be investigated to guide patient stratification.In conclusion, hrBMP4 through CED is safe and well-tolerated in patients with recurrent glioblastoma. While efficacy was not the primary aim of this study, there was a response signal with significant tumor reduction or complete response in three out of 15 patients. Complete remission occurred in the absence of any other continued treatment and tumor appears not to grow in tissue reached by hrBMP4. This supports the rationale for pro-differentiation therapy in glioblastoma and encourages the conduct of Phase 2 trials powered to define the efficacy of hrBMP4 delivered through CED.