Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: a first-in-human phase 1 dose escalation trial
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Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: a first-in-human phase 1 dose escalation trial. / Bos, Eelke M; Binda, Elena; Verploegh, Iris S C; Wembacher, Eva; Hoefnagel, Daphna; Balvers, Rutger K; Korporaal, Anne L; Conidi, Andrea; Warnert, Esther A H; Trivieri, Nadia; Visioli, Alberto; Zaccarini, Paola; Caiola, Laura; van Wijck, Rogier; van der Spek, Peter; Huylebroeck, Danny; Leenstra, Sieger; Lamfers, Martine L M; Ram, Zvi; Westphal, Manfred; Noske, David; Legnani, Federico; DiMeco, Francesco; Vescovi, Angelo Luigi; Dirven, Clemens M F.
In: MOL CANCER, Vol. 22, No. 1, 10.08.2023, p. 129.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: 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 - © 2023. BioMed Central Ltd., part of Springer Nature.
PY - 2023/8/10
Y1 - 2023/8/10
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 - Humans
KW - Glioblastoma/drug therapy
KW - Quality of Life
KW - Bone Morphogenetic Protein 4/therapeutic use
KW - Neoplasm Recurrence, Local/drug therapy
KW - Brain Neoplasms/pathology
KW - Maximum Tolerated Dose
U2 - 10.1186/s12943-023-01835-6
DO - 10.1186/s12943-023-01835-6
M3 - SCORING: Journal article
C2 - 37563568
VL - 22
SP - 129
JO - MOL CANCER
JF - MOL CANCER
SN - 1476-4598
IS - 1
ER -