PMID- 33301375 OWN - NLM STAT- MEDLINE DCOM- 20210802 LR - 20240210 IS - 1527-7755 (Electronic) IS - 0732-183X (Print) IS - 0732-183X (Linking) VI - 39 IP - 2 DP - 2021 Jan 10 TI - First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors. PG - 145-154 LID - 10.1200/JCO.20.00596 [doi] AB - PURPOSE: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies. FAU - Baird, Richard D AU - Baird RD AD - University of Cambridge, Cambridge, United Kingdom. FAU - Linossi, Constanza AU - Linossi C AD - University of Cambridge, Cambridge, United Kingdom. FAU - Middleton, Mark AU - Middleton M AD - University of Oxford, Oxford, United Kingdom. FAU - Lord, Simon AU - Lord S AD - University of Oxford, Oxford, United Kingdom. FAU - Harris, Adrian AU - Harris A AD - University of Oxford, Oxford, United Kingdom. FAU - Rodon, Jordi AU - Rodon J AD - MD Anderson Cancer Center, Houston, TX. AD - Vall d'Hebron University Hospital, Vall d'Hebron, Spain. FAU - Zitt, Christof AU - Zitt C AD - Molecular Partners AG, Schlieren-Zurich, Switzerland. FAU - Fiedler, Ulrike AU - Fiedler U AD - Molecular Partners AG, Schlieren-Zurich, Switzerland. FAU - Dawson, Keith M AU - Dawson KM AD - Molecular Partners AG, Schlieren-Zurich, Switzerland. FAU - Leupin, Nicolas AU - Leupin N AD - Molecular Partners AG, Schlieren-Zurich, Switzerland. FAU - Stumpp, Michael T AU - Stumpp MT AD - Molecular Partners AG, Schlieren-Zurich, Switzerland. FAU - Harstrick, Andreas AU - Harstrick A AD - Molecular Partners AG, Schlieren-Zurich, Switzerland. FAU - Azaro, Analia AU - Azaro A AD - Vall d'Hebron University Hospital, Vall d'Hebron, Spain. FAU - Fischer, Stefanie AU - Fischer S AD - Manchester Cancer Research Centre, Manchester, United Kingdom. AD - Cantonal Hospital St Gallen, St Gallen, Switzerland. FAU - Omlin, Aurelius AU - Omlin A AD - Cantonal Hospital St Gallen, St Gallen, Switzerland. LA - eng SI - ClinicalTrials.gov/NCT02194426 GR - 18974/CRUK_/Cancer Research UK/United Kingdom GR - DH_/Department of Health/United Kingdom PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20201210 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Antineoplastic Agents) RN - 0 (HGF protein, human) RN - 0 (MP0250) RN - 0 (Recombinant Fusion Proteins) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 67256-21-7 (Hepatocyte Growth Factor) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/administration & dosage/adverse effects/pharmacokinetics MH - Cohort Studies MH - Dose-Response Relationship, Drug MH - Female MH - Hepatocyte Growth Factor/*antagonists & inhibitors/metabolism MH - Humans MH - Infusions, Intravenous MH - Male MH - Middle Aged MH - Molecular Targeted Therapy MH - Neoplasms/*drug therapy/metabolism/pathology MH - Recombinant Fusion Proteins/*administration & dosage/adverse effects/pharmacokinetics MH - Tumor Microenvironment MH - Vascular Endothelial Growth Factor A/*antagonists & inhibitors/metabolism MH - Young Adult PMC - PMC8196087 EDAT- 2020/12/11 06:00 MHDA- 2021/08/03 06:00 PMCR- 2022/01/10 CRDT- 2020/12/10 17:10 PHST- 2020/12/11 06:00 [pubmed] PHST- 2021/08/03 06:00 [medline] PHST- 2020/12/10 17:10 [entrez] PHST- 2022/01/10 00:00 [pmc-release] AID - JCO.20.00596 [pii] AID - 10.1200/JCO.20.00596 [doi] PST - ppublish SO - J Clin Oncol. 2021 Jan 10;39(2):145-154. doi: 10.1200/JCO.20.00596. Epub 2020 Dec 10.