Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: a first-in-human phase 1 dose escalation trial

Abstract

Background: This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) - an inhibitory regulator of cancer stem cells (CSCs) - in recurrent glioblastoma.

Methods: In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion.

Results: Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4.

Conclusion: Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs.

Trial registration: ClinicaTrials.gov identifier: NCT02869243.

Keywords: BMP4; CED; Clinical trial; Glioblastoma.

Fig. 1

– Overview of patient survival and progression. (A) Survival after therapy with hrBMP4 depicted in a swimmer plot, TMZ = temozolomide, RT = radiotherapy. Treatment modalities and survival duration before treatment with hrBMP4 are also shown. (B) Kaplan-Meier estimates of OS and (C) PFS in months. (D) Mean ADC on preoperative MRI in patients with and without early tumor progression after hrBMP4 treatment. Median intensity of E BMPR1A, F BMPR1B, G BMPR2 in tumor tissue before treatment with hrBMP4 in relation to the OS of the respective patients. Representative images form patient 3 (orange) and patient 1 (blue) of staining with H BMPR1A, I BMPR1B and J BMPR2 and the respective negative-control samples only stained with secondary antibody

Fig. 2

– Response, recurrence, and CED analysis. (A) Relative tumor volume normalized to the moment of study inclusion of all treated patients with available data. (B, D, F) Individual patient data showing tumor volume in the three patients showing response or stable disease (patient 1, 2, and 15), before and after hrBMP4 treatment. The dotted line indicates the moment of treatment with hrBMP4. (C, E, G) Representative images of the three patients with the best therapeutic response before study inclusion and at 3, 6- and 9-month follow-up. (H) Illustration of hrBMP4 CED concept. (I, J) Preoperative drug distribution planning, planning the simulated drug distribution over time (concentric green rings). (K, L) Postoperative 3D reconstructions showing tumor (red), CED catheters (white), and the ventricular system (blue). (M) Vd/Vi at 24 h of hrBMP4 infusion (gray) and at the end of infusion (black). (N) Coverage of tumor and peritumoral volume at the end of hrBMP4 infusion. (O) Analysis of recurrence location in relation to the volume of hrBMP4 infusion, showing the limited overlap (white) between hrBMP4 treated parenchymal volume (yellow) and recurrence volume (light blue). (P) Representative examples of overlap (white) between gadolinium/hrBMP4 distribution volume (yellow) and recurrence volume (blue), showing that the recurrent tumors largely grew outside of the hrBMP4 treated volume (colors match those in Fig. 2O).