TY - JOUR
T1 - Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma
T2 - a first-in-human phase 1 dose escalation trial
AU - Bos, Eelke M.
AU - Binda, Elena
AU - Verploegh, Iris S. C.
AU - Wembacher, Eva
AU - Hoefnagel, Daphna
AU - Balvers, Rutger K.
AU - Korporaal, Anne L.
AU - Conidi, Andrea
AU - Warnert, Esther A. H.
AU - Trivieri, Nadia
AU - Visioli, Alberto
AU - Zaccarini, Paola
AU - Caiola, Laura
AU - van Wijck, Rogier
AU - van der Spek, Peter
AU - Huylebroeck, Danny
AU - Leenstra, Sieger
AU - Lamfers, Martine L. M.
AU - Ram, Zvi
AU - Westphal, Manfred
AU - Noske, David
AU - Legnani, Federico
AU - DiMeco, Francesco
AU - Vescovi, Angelo Luigi
AU - Dirven, Clemens M. F.
N1 - Funding Information: The clinical trial in this work was sponsored and funded by StemGen Spa, a biotech company based in Milan, Italy. This work was supported by the following grants to ALV: a grant from “Associazione Italiana Cancro” (IG-22027); a Grant from the James S. McDonnel Foundation (USA); a Grant From the Brain Tumor Funders Collaborative Initiative (USA); A grant from “Regione Lombardia (Italy). A grant “Ministero della Salute Italiano” (GR-2011- 02351534 and Progetto Ricerca Corrente 2018–20) to EB also supported this study. Part of this work was supported by Erasmus MC via departmental (Cell Biology) and BIG project funding (together with Erasmus University Rotterdam). Funding Information: We are grateful to all the patients and their families whose precious support allowed the conduct of this study. We are most grateful to Drs. Henry Brem, Alessandro Olivi, Antonino Chiocca, and Jeffrey Bruce for actively participating in an Advisory Board that helped determine the clinical design of this study. We also sincerely thank the members of the Safety Board, Prof. Riccardo Soffietti, University of Turin and Prof. Colin Watts, University of Birmingham, United Kingdom who reviewed the data and assisted in the evaluation of the safety profile throughout this study. We are grateful to Gandino Mencarelli, Riccardo Pracella and Amy Amata Soriano for the technical support. Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - BMP4
KW - CED
KW - Clinical trial
KW - Glioblastoma
UR - http://www.scopus.com/inward/record.url?scp=85167691941&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12943-023-01835-6
DO - https://doi.org/10.1186/s12943-023-01835-6
M3 - Letter
C2 - 37563568
SN - 1476-4598
VL - 22
SP - 129
JO - Molecular Cancer
JF - Molecular Cancer
IS - 1
M1 - 129
ER -