Patients with primary CNS 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 could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor Necrosis Factor-a coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m²) afterwards. This trial included two phases: an "explorative phase" addressing the effect of NGR-hTNF on drugs pharmacokinetics and on vessel permeability, assessed by DCE-MRI and 99mTc-DTPA-SPECT, and the expression of CD13 on tumor tissue; and an "expansion phase" with ORR as primary endpoint, where the two-stage Simon Minimax design was used. At the first stage, if greater than or equal to4 responses were observed among 12 patients, the study accrual would have continued (sample size: 28). Herein, we report results of the explorative phase and the first-stage analysis (n=12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/CSF concentrations. NGR-hTNF/R-CHOP combination was well tolerated: there were only two SAEs and grade-4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with nine confirmed responses (75%; 95%CI=51-99%), eight of which were complete. 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.
R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma
Ferreri, Andrés J M;Ponzoni, Maurilio;Ciceri, Fabio;Bordignon, Claudio;Corti, Angelo;Anzalone, Nicoletta
2019-01-01
Abstract
Patients with primary CNS 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 could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor Necrosis Factor-a coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m²) afterwards. This trial included two phases: an "explorative phase" addressing the effect of NGR-hTNF on drugs pharmacokinetics and on vessel permeability, assessed by DCE-MRI and 99mTc-DTPA-SPECT, and the expression of CD13 on tumor tissue; and an "expansion phase" with ORR as primary endpoint, where the two-stage Simon Minimax design was used. At the first stage, if greater than or equal to4 responses were observed among 12 patients, the study accrual would have continued (sample size: 28). Herein, we report results of the explorative phase and the first-stage analysis (n=12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/CSF concentrations. NGR-hTNF/R-CHOP combination was well tolerated: there were only two SAEs and grade-4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with nine confirmed responses (75%; 95%CI=51-99%), eight of which were complete. 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
