Arenegyr (NGR-hTNF) / AGC Biologics - LARVOL DELTA

INGRID: RCHOP Chemoimmunotherapy Preceded BY BBB Permeabilization by t-NGR Necrosis Factor (clinicaltrials.gov) - P2 | N=28 | Completed | Sponsor: Andres J. M. Ferreri | Unknown status ➔ Completed

Trial completion • CNS Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis. (PubMed, Cancers (Basel)) - "Patients with malignant pleural mesothelioma (MPM) have very poor prognoses, and pemetrexed plus platinum is the standard first-line therapy...Tremelimumab, vorinostat, nivolumab alone, chemotherapy (CTX), asparagine-glycine-arginine-human tumor necrosis factor plus CTX, and nivolumab plus ipilimumab all produced noticeable PFS benefits compared with placebo. Nivolumab plus ipilimumab had the best PFS ranking (SUCRA: 92.3%). Second-line treatment with nivolumab plus ipilimumab provided the OS and PFS outcomes for patients with relapsed MPM."

Journal • Retrospective data • Review • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • TNFA

R-CHOP Preceded By Engineered Tumor Necrosis Factor (TNF) in Patients with Relapsed or Refractory (r/r) Primary CNS Lymphoma (PCNSL): Results of Antitumor Activity, Safety and Blood-Brain Barrier (BBB) Permeabilization in the “Ingrid” Phase II Trial (ASH 2018) - P2; "...Methods : HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 1 course of R-CHOP, followed by 5 courses of R-CHOP21 preceded by NGR-hTNF (0.8 μg/m², 1-h inf)...Rituximab, cyclophosphamide and doxorubicin concentrations on matched CSF/plasma samples collected before/after the 1st, 2nd and 6th courses were tested to exclude a non-specific effect of NGR-hTNF on pharmacokinetics...Accrual completion is warranted. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts."

Clinical • P2 data • Biosimilar • CNS Disorders • Diffuse Large B Cell Lymphoma • Epilepsy • Gene Therapies • Hematological Disorders • Hematological Malignancies • Immunology • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma

Long-term survival outcomes of a placebo-controlled phase 3 trial with NGR-hTNF in combination with best investigator choice in relapsed malignant pleural mesothelioma (MPM). (ASCO 2018) - P3; " In the phase 3 trial NGR015 (ASCO 2015; abs 7501), 400 patients received single-agent gemcitabine, vinorelbine or doxorubicin NGR-hTNF as second-line therapy. Benefit with NGR-hTNF treatment in the short TFI subgroup was maintained after a 3-year follow-up, deserving a confirmatory randomized trial as these MPM patients have a poor prognosis."

Clinical • Combination therapy • P3 data • Mesothelioma

Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour (clinicaltrials.gov) - P1; N=48; Completed; Sponsor: MolMed S.p.A.; Active, not recruiting ➔ Completed; Trial completion date: Jun 2016 ➔ Feb 2017; Trial primary completion date: Jun 2016 ➔ Feb 2017

Clinical • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastric Cancer • Hepatocellular Cancer • Non Small Cell Lung Cancer • Renal Cell Carcinoma • MRI

NGR007: Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Metastatic Small Cell Lung Carcinoma (clinicaltrials.gov) - P2; N=28; Active, not recruiting; Sponsor: MolMed S.p.A.; Trial primary completion date: Jan 2013 ➔ Dec 2015

Clinical • Combination therapy • Trial primary completion date • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour (clinicaltrials.gov) - P1; N=48; Active, not recruiting; Sponsor: MolMed S.p.A.; Trial primary completion date: Jun 2013 ➔ Dec 2015

Clinical • Trial primary completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • MRI

NGR007: Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Metastatic Small Cell Lung Carcinoma (clinicaltrials.gov) - P2; N=28; Completed; Sponsor: MolMed S.p.A.; Active, not recruiting ➔ Completed; Trial completion date: Jun 2016 ➔ Nov 2015; Trial primary completion date: Jun 2016 ➔ Nov 2015

Clinical • Combination therapy • Trial completion • Trial completion date • Trial primary completion date • Neuroendocrine Tumor • Small Cell Lung Cancer • MRI

NGR007: Study of NGR-hTNF in Combination With Doxorubicin in Patients Affected by Metastatic Small Cell Lung Carcinoma (clinicaltrials.gov) - P2; N=28; Active, not recruiting; Sponsor: MolMed S.p.A.; Trial primary completion date: Dec 2015 ➔ Jun 2016

Clinical • Combination therapy • Trial primary completion date • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • MRI

Study of NGR-hTNF as Single Agent in Patients Affected by Advanced or Metastatic Malignant Pleural Mesothelioma (clinicaltrials.gov) - P2; N=57; Completed; Sponsor: MolMed S.p.A.; Active, not recruiting ➔ Completed

Clinical • Trial completion • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • MRI

Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour (clinicaltrials.gov) - P1; N=48; Active, not recruiting; Sponsor: MolMed S.p.A.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • MRI

Study of NGR-hTNF Administered at High Doses in Patient With Advanced or Metastatic Solid Tumour (clinicaltrials.gov) - P1; N=48; Active, not recruiting; Sponsor: MolMed S.p.A.; Trial primary completion date: Dec 2015 ➔ Jun 2016

Clinical • Trial primary completion date • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • MRI

Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial. (PubMed, Blood Adv) - P2 | "Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL)...Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial...Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance)...Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11."

Clinical • Journal • P2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma

NGR-TNF engineering with an N-terminal serine reduces degradation and post-translational modifications and improves its tumor targeting activity. (PubMed, Mol Pharm) - "The SCNGRC peptide may represent a ligand for cytokine delivery to tumors more robust than conventional CNGRC. The S-NGR-TNF conjugate (more stable, homogeneous and active than NGR-TNF) could be rapidly developed for clinical trial."

Journal • TNFA

Phase II Study of NGR-hTNF in Combination With Doxorubicin in Platinum-resistant Ovarian Cancer (clinicaltrials.gov) - P2; N=124; Active, not recruiting; Sponsor: MolMed S.p.A.; Recruiting -> Active, not recruiting ; Trial primary completion date: Dec 2013 ->Jun 2016

Enrollment closed • Biosimilar • Oncology • Ovarian Cancer

NGR-hTNF Administered in Combination With a Standard Oxaliplatin Based Regimen in Patients With Metastatic Colorectal Cancer (clinicaltrials.gov) - P2; N=24; Completed; Sponsor: MolMed S.p.A.; Active, not recruiting -> Completed

Trial completion • Biosimilar • Colorectal Cancer • Oncology • Renal Cell Carcinoma

NGR019: Phase II Study of NGR-hTNF Versus Placebo as Maintenance Treatment in Patients With Advanced Malignant Pleural Mesothelioma (clinicaltrials.gov) - P2; N=100; Recruiting; Sponsor: MolMed S.p.A.; Trial primary completion date: Jun 2016 ➔ Dec 2016

Trial primary completion date • Biosimilar • Mesothelioma • Oncology

Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling. (PubMed, Int J Mol Sci) - "The reduced activation of the pro survival pathways induced by NGR-hTNF correlated with the increased caspases activation and reduced cell survival. This study demonstrates that the binding of the NGR-motif to CD13 determines not only the homing of NGR-hTNF to tumor vessels, but also the increase in its antiangiogenic activity."

Journal

R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma. (PubMed, Blood) - P2; "Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor...In conclusion, NGR-hTNF/R-CHOP was safe in these heavily-pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses."

Journal

Targeting tumor vasculature with TNF leads effector T cells to the tumor and enhances therapeutic efficacy of immune checkpoint blockers in combination with ACT. (PubMed, Clin Cancer Res) - "Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers."

Checkpoint inhibition • Clinical • Combination therapy • Journal

NGR-hTNF and Doxorubicin as Second-Line Treatment of Patients with Small Cell Lung Cancer. (PubMed, Oncologist) - "NGR-hTNF plus doxorubicin showed manageable toxicity and promising activity in patients with relapsed SCLC."

Clinical • Journal

R‐CHOP PRECEDED BY ENGINEERED TUMOR NECROSIS FACTOR (TNF) IN RELAPSED OR REFRACTORY PRIMARY DIFFUSE LARGE B‐CELL LYMPHOMA OF THE CNS (rPCNSL): FINAL RESULTS OF THE INGRID TRIAL (ICML 2019) - P2; "Background: Patients (pts) with PCNSL are usually treated with high-dose methotrexate-based combinations that are not currently used in other DLBCL and require hospitalization and extensive expertise to manage toxicity. NGR-hTNF/RCHOP is active and safe in pts with rPCNSL. CD13, the target of TNF, was expressed in tumor tissue and, consistently, NGR-hTNF enhanced vascular permeability specifically in tumor and perilesional areas. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts."

Clinical

Learning from the past to design better trials in second-line treatment for mesothelioma patients. (PubMed, Ecancermedicalscience) - "...The standard treatment remains platinum-based chemotherapy with pemetrexed. Recently, the addition of an antiangiogenic drug, bevacizumab, to first-line chemotherapy has been shown to improve overall survival...Despite encouraging data achieved in previous phase I and phase II studies, the NGR-hTNF drug failed to meet the primary endpoint of the study, although a signal of activity was observed in the group of patients who had a shorter treatment failure interval from the first-line treatment. Hereby, we start from this recent trial to highlight once more the importance of thoroughly investigating possible predictive factors during the early drug development phase to allow more efficient phase III trial design, thus avoiding the possibility of potentially effective molecules like NGR-hTNF, continuing to be wasted."

Clinical • Journal

Phase II Study of NGR-hTNF Versus Placebo as Maintenance Treatment in Patients With Advanced MPM (clinicaltrials.gov) - P2; N=137; Completed; Sponsor: MolMed S.p.A.; Active, not recruiting ➔ Completed; N=100 ➔ 137

Clinical • Enrollment change • Trial completion

NGR-hTNF in Combination With an Anthracycline in Platinum-resistant Ovarian Cancer (NGR018) (clinicaltrials.gov) - P2; N=14; Completed; Sponsor: MolMed S.p.A.

Clinical • Combination therapy • New P2 trial