BackgroundDose-limiting toxicity (DLT) due to systemic CD40 activation and peripheral target-mediated drug disposition are major challenges in clinical development of CD40 agonists. MP0317, a ...CD40-agonistic DARPin (designed ankyrin repeat protein), is exclusively active in the presence of fibroblast activation protein (FAP) expressed by cancer-associated fibroblasts in the tumor microenvironment (TME). This mode of action enables tumor-localized CD40 activation, while reducing systemic toxicity.MethodsThis ongoing Phase 1, multicenter, open-label, dose-escalation study aims to establish safety/tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of MP0317 monotherapy (NCT05098405). The dose-escalation scheme uses an adaptive Bayesian logistic regression model guided by the escalation with overdose control principle to determine the recommended dose. Eligible adult patients with selected advanced solid tumors (based on anticipated FAP expression) are enrolled into 9 sequentially-escalating dose cohorts of MP0317 (0.03–10 mg/kg), administered IV 3-weekly (Q3W) or 1-weekly (Q1W) until disease progression or unacceptable toxicity. The study was approved by the Dutch and French Ethics Boards.ResultsAs of data cut-off (02 May 2023), 36 patients received ≥1 MP0317 dose across 8 cohorts, including 19 women (53%) and 17 men (47%). The median age at enrollment was 63 years (range 35–79) and patients received a median number of 3.5 prior treatments (range 1–13). Colorectal cancer was the most frequent tumor type (11 patients, 31%). One patient experienced a DLT (asymptomatic Grade 3 elevation of alanine and aspartate aminotransferases), at the highest planned dose of MP0317 (10 mg/kg Q3W). Grade 2 infusion-related reaction was the most frequently observed adverse reaction (7 patients, 19%), followed by Grade ≤2 fatigue, nausea and vomiting in 9, 6, and 4 patients, respectively. One patient achieved unconfirmed partial response, and stable disease was observed in 5 patients. Paired tumor biopsies confirmed colocalization of MP0317 with FAP and CD40. MP0317 detection in tumor biopsies was associated with an increase in abundance of antigen-presenting cells (dendritic cells, B cells and plasma cells) and IFNγ signature in the TME. Increases in CXCL10 serum levels post-MP0317 treatment support these findings.ConclusionsThese data of 36 patients, dosed across 8 dose levels (0.03–10 mg/kg, Q3W and Q1W schedules), confirmed a favorable safety profile of MP0317 monotherapy with limited systemic inflammation compared to other CD40 agonists. Analysis of paired tumor biopsies and peripheral biomarkers provided evidence of target occupancy and pharmacodynamic modulation in the TME, consistent with tumor-localized CD40 activation. These data support continued clinical evaluation of MP0317, including combination studies.Trial RegistrationThis study is registered at ClinicalTrials.gov: NCT05098405Ethics ApprovalThe study was approved by the Dutch and French Ethics Boards.
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Background: CD40 is a master switch for both innate and adaptive immune systems. The clinical development of CD40 agonists has been hampered by dose-limiting toxicity (DLT) due to systemic CD40 ...activation and peripheral target-mediated drug disposition (TMDD). MP0317 is a CD40-agonistic DARPin (designed ankyrin repeat protein), developed to reduce systemic toxicity. MP0317 is exclusively active in the presence of fibroblast activating protein (FAP) expressed by cancer associated fibroblasts in the tumor microenvironment. This allows reaching serum levels that overcome the TMDD and have the potential to deliver sustained and tumor-localized CD40 activation. Ongoing clinical testing aims at establishing its safety/tolerability profile, PK/PD characteristics, and a recommended dose for combination therapy. Methods: NCT05098405 is a Phase 1, multicenter, open label, dose escalation study followed by a safety expansion part in adult patients with advanced solid tumors. The dose escalation scheme uses an adaptive Bayesian logistic regression model with overdose control. Peripheral blood biomarkers are analyzed by immuno-assays and flow cytometry, and baseline and on-treatment tumor biopsies are characterized by RNA sequencing and immunofluorescence. Eligible patients are enrolled into 9 sequentially escalating dose cohorts of MP0317 (0.03-10 mg/kg), administered IV 3-weekly (Q3W) or 1-weekly (Q1W) until disease progression or unacceptable toxicity. Results: At submission, 23 patients across 6 cohorts completed the study, with no DLT observed. Patient enrolling in higher dose cohorts is ongoing. The most frequent AE was grade 2 infusion related reaction in 5 patients. The 23 patients received ≥2 (range 2-8) doses (range 0.03 – 3 mg/kg) of MP0317 across five Q3W and one Q1W cohorts and completed the 28-day DLT period. PK data confirmed all patients were exposed to MP0317 with broadly dose-dependent Cmax and no sign of accumulation. PD data was derived from patients dosed with 0.03 – 3 mg/kg. Soluble biomarkers (sFAP and sCD40) showed target engagement in periphery with signs of FAP saturation at ≥0.5 mg/kg. Colocalization of MP0317 with FAP and CD40 in the tumor was confirmed in 4 out of 8 evaluable paired tumor biopsies. Whole transcriptome and gene set enrichment analyses showed an upregulation of genes related to B-cell trafficking (CXCL3, CXCR5, CCR6, CCL20) upon treatment. Transient increase of IFNg-induced chemokines (CXCL9, CXCL10) was observed, whereas the pro-inflammatory cytokines (TNFa, IL-2, IL-6, IL-8) were not upregulated. Conclusions: Clinical data and the lack of pro-inflammatory circulating cytokines confirm MP0317 is safe and well-tolerated, while analysis of paired pre- and on-treatment tumor biopsies suggests early evidence of tumor-localized CD40 activation. The current data enables further evaluation in a combination setting. Clinical trial information: NCT05098405 .
