In an early-phase study reported in the Journal of Clinical Oncology, Liu et al evaluated the safety and preliminary efficacy of DEP-SN38, a polylysine-based dendrimer-nanoparticle delivery platform for the topoisomerase 1 inhibitor SN38, in patients with advanced solid tumors. SN38 is the active metabolite of irinotecan. By bypassing irinotecan’s variable hepatic conversion, DEP-SN38 aims to improve drug delivery, enhance tumor localization, and reduce gastrointestinal toxicity.
Study Details
The open-label, multicenter study enrolled 114 patients between September 2019 and September 2023 with advanced or metastatic solid tumors as confirmed via RECIST version 1.1. Median patient age was 60.5 years (interquartile range = 31–78 years) and almost two-thirds were female. Most of the participants had received a median of four prior treatment lines and nearly 60% had previous irinotecan exposure.
Patients were assigned to one of three regimens: DEP-SN38 monotherapy every 3 weeks, DEP-SN38 monotherapy every 2 weeks, or DEP-SN38 in combination with fluorouracil/leucovorin every 2 weeks. Dose escalation and expansion followed an accelerated phase I design, with 12.5 mg/m² ultimately established as the recommended dose for all three regimens. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal. The primary objectives of the study were to assess safety and tolerability, with secondary endpoints including efficacy and pharmacokinetics.
Key Results
Most treatment-related adverse events were mild or moderate in severity. Neutropenia emerged as the most frequent severe toxicity and the key dose-limiting factor, accounting for nearly half of all grade 3 or 4 events. Severe gastrointestinal events were rare, with grade 3 diarrhea and vomiting reported in fewer than 1% of patients and grade 3 nausea in fewer than 2%. No cholinergic symptoms were observed. Only 3.5% of patients discontinued therapy due to treatment-related adverse events, and many tolerated long-term treatment of 6 months or longer.
Efficacy outcomes varied by regimen and tumor type. Among evaluable patients, objective response rates were 1.8% and 21.4% for DEP-SN38 monotherapy every 3 or 2 weeks, respectively, and 12.5% with combination treatment. Disease control rates were 56.4%, 71.4%, and 81.3%, respectively. Patients with colorectal cancer saw an objective response rate of 42.9% (with monotherapy every 2 weeks), while those with platinum-resistant ovarian cancer saw an objective response rate of 42.9% with the combination. Long-term responses (progression-free survival ≥ 6 months) in the combination arm were also seen in one patient with pancreatic cancer (10.2 months), one with non–small cell lung cancer (8.4 months), and two with breast cancer (16.6 and 6 months).
The authors concluded: “DEP-SN38 was clinically well tolerated with minimal severe GI [treatment-related adverse events]. Preliminary antitumor activity in heavily pretreated patients with cancer demonstrates the potential clinical utility of DEP-SN38 monotherapy and combination regimens.”
Natalie Cook, PhD, MBChB, of the University of Manchester, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Starpharma Pty Ltd. and the NIHR Manchester Clinical Research Facility. For full disclosures of all study authors, visit ascopubs.org.
