NCT03631836: MARELLE01

Phase I Study of Monoclonal Antibondy (GS) 5745, an Matix Metalloproteinase 9 (MMP9) Mab Inhibitor, in Combination With Bevacizumab in Patients With Recurrent Glioblastoma

Status unknown Phase 1 Last updated 17 August 2018

What this trial tests

Phase 1 trial testing Monoclonal antibody in Glioblastoma in 34 participants. Status unknown.

Timeline

1 January 2019

Primary endpoint
1 January 2022

1 January 2022

Quick facts

Lead sponsor	Assistance Publique Hopitaux De Marseille
Phase	Phase 1
Status	Status unknown
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	34
Start date	1 January 2019
Primary completion	1 January 2022
Estimated completion	1 January 2022
Sites	1 location across France

Drugs / interventions tested

• Monoclonal antibody — full drug profile →
• Bevacizumab (Bevacizumab-Bvzr) — full drug profile →
• Blood sample — full drug profile →
• Dynamic Contrast Enhanced magnetic resonance imaging (DCE-MRI)

Conditions studied

• Glioblastoma — all drugs for Glioblastoma →

Sponsor

Assistance Publique Hopitaux De Marseille — full company profile →

Who can join

18 and older, any sex, with Glioblastoma. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

Despite surgery and first-line standard of care which consist of radiotherapy with concomitant and adjuvant temozolomide, all patients with glioblastoma (GB) will experience relapse. At the time of recurrence, therapeutic options include surgery or reirradiation in selected cases, while in other cases, bevacizumab, approved by Food and Drug Administration (FDA) but not European Medicines Agency (EMA), is the preferred option worldwide. Primary and acquired resistance to bevacizumab has been explored without definitive finding.

Biomarkers able to predict response to antiangiogenic agents and particularly to bevacizumab are an unmet medical need. We have showed that a low Matrix metallopeptidase 9 (MMP9) or a high Matrix metallopeptidase 2 (MMP2) baseline plasma levels were associated with a high response rate and a prolonged Progression-free survival (PFS) and overall survival (OS) in recurrent GB patients treated with bevacizumab but not with cytotoxic chemotherapy. We also observed that MMP9 plasma level decreased during bevacizumab treatment and tend to increase at progression. Finally, in a retrospective analysis performed in the Avaglio trial (a randomized phase III trial that tested bevacizumab versus placebo in addition to standard of care in patients with newly diagnosed glioblastoma), a low plasma level of MMP9 at baseline predicted consistently PFS and OS gain associated to bevacizumab.

These results are consistent with the role of MMP9 in vasculogenesis, since MMP9 contribute to the recruitment of circulating endothelial and myeloid precursors, an alternative vascularization process which is in part independent of the vascular endothelial growth factor (VEGF) pathway.

Monoclonal Antibody (GS) 5745 is specifically directed against MMP9. First in human phase I study has been completed. Development is ongoing.

Our results strongly support a role for MMP9 in the primary or acquired resistance to bevacizumab. Therefore, we hypothesize that the Monoclonal Antibody GS5745 may overcome resistance to bevacizumab through a specific inhibition of MMP9. While a preclinical program is initiated in our lab, the proposed phase I study is the first step to analyze the tolerance, determine the recommended dose of the combination and explore the impact of GS5745 on MMP9 plasma levels and multimodal imaging in patients with recurrent glioblastoma.

Objective:

Determine the safety profile and tolerability of GS5745 given in combination with a fixed dose of bevacizumab in patients with recurrent GB in terms of Dose-Limiting Toxicities.

Multicenter, open label, dose-finding study of GS5745 in combination with bevacizumab administered at a fixed dose; both drugs will be administered once every two weeks for a total treatment duration of a maximum of 12 months.

Before initiation of each new dose level, a meeting between the sponsor, the coordinator, the investigators and an independent external expert will take place to decide jointly the next dose.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Concepts of extracellular matrix remodelling in tumour progression and metastasis.
   Winkler J, Abisoye-Ogunniyan A, Metcalf KJ, Werb Z. · · 2020 · cited 1644× · PMID 33037194 · DOI 10.1038/s41467-020-18794-x
2. Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment.
   Delgado-Martín B, Medina MÁ. · · 2020 · cited 129× · PMID 32382477 · DOI 10.1002/advs.201902971
3. The Interplay of the Extracellular Matrix and Stromal Cells as a Drug Target in Stroma-Rich Cancers.
   Kozlova N, Grossman JE, Iwanicki MP, Muranen T. · · 2020 · cited 66× · PMID 32014341 · DOI 10.1016/j.tips.2020.01.001
4. Immunomodulatory roles of metalloproteinases in rheumatoid arthritis.
   Bian Y, Xiang Z, Wang Y, Ren Q, et al · · 2023 · cited 45× · PMID 38035026 · DOI 10.3389/fphar.2023.1285455
5. The Versatile Role of Matrix Metalloproteinase for the Diverse Results of Fibrosis Treatment.
   Chuang HM, Chen YS, Harn HJ. · · 2019 · cited 31× · PMID 31752262 · DOI 10.3390/molecules24224188
6. MMP-9 as Prognostic Marker for Brain Tumours: A Comparative Study on Serum-Derived Small Extracellular Vesicles.
   Dobra G, Gyukity-Sebestyén E, Bukva M, Harmati M, et al · · 2023 · cited 30× · PMID 36765669 · DOI 10.3390/cancers15030712
7. Exploiting the STAT3 Nexus in Cancer-Associated Fibroblasts to Improve Cancer Therapy.
   Allam A, Yakou M, Pang L, Ernst M, et al · · 2021 · cited 27× · PMID 34858425 · DOI 10.3389/fimmu.2021.767939
8. Intrinsic and Microenvironmental Drivers of Glioblastoma Invasion.
   De Fazio E, Pittarello M, Gans A, Ghosh B, et al · · 2024 · cited 24× · PMID 38473812 · DOI 10.3390/ijms25052563