BackgroundIn this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H)... Show moreBackgroundIn this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.Patients and methodsPatients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses.ResultsTwenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB.ConclusionDurvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Show less
Velden, D.L. van der; Hoes, L.R.; Wijngaart, H. van der; Henegouwen, J.M.V.; Werkhoven, E. van; Roepman, P.; ... ; Voest, E.E. 2019
Purpose To evaluate the safety and tolerability of LiPlaCis a liposomal formulated platinum compound in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous... Show morePurpose To evaluate the safety and tolerability of LiPlaCis a liposomal formulated platinum compound in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous v) LiPlaCis and to assess plasma and urine pharmacokinetics and plasma biomarkers Patients and methods Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3 weeks until RECIST progression or unacceptable toxicity Cohorts of 3-6 patients were treated at each dose level until MTD was reached Results Eighteen patients were enrolled and 64 cycles were delivered At the first dose level 3 patients experienced an infusion reaction Despite prophylactic pre medication and prolongation of the infusion to 2 h in further patients three other patients had mild acute infusion reactions Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients Peak plasma concentrations and AUC were dose proportional The interpatient variability in the clearance of total LiPlaCis derived platinum was 41% Platinum was excreted via the urine mainly during the first 24 h after administration Investigated plasma biomarkers sPLA(2) and SC5b 9 were related to but not predictive for acute infusion reactions Conclusion The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development (C) 2010 Elsevier Ltd All rights reserved Show less
