Abstract B039: A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111/DEP irinotecan) in patients with advanced solid tumours
Authors: Liu Jia , Minchom Anna R , Greystoke Alastair , Evans Thomas R J , Sarker Debashis , Joshua Anthony M , Morton Cienne , Gaus Aisha , Yau Wing , Cosman Rasha , Chwialkowska Dominika , Paull Jeremy R A , Jean-Francois Bernadette M , Fairley Jacinth K , Main Nicola J , Edmondson Stephanie R , Cook Natalie 
Published: December 2023

Abstract
Background: Dendrimers are highly branched nanoparticles that achieve significant tumor targeting of cytotoxic drugs. DEP SN38 (or DEP irinotecan) is a highly optimised dendrimer conjugate of the irinotecan active metabolite, SN38. We report initial results of a phase 1/2 trial evaluating the safety, tolerability and preliminary efficacy of DEP SN38 in patients (pts) with advanced solid tumors, including colorectal (CRC) and platinum-resistant high-grade serous ovarian carcinoma (HGSOC).
Methods: Solid tumor pts who had exhausted standard therapy were enrolled (EudraCT2019-001318-40). DEP SN38 given IV 3-weekly (Q3W) was escalated to identify a recommended phase 2 dose (RP2D). Additional dose assessment/expansion cohorts followed at Q3W or Q2W (2-weekly) alone or in combination with 5-fluorouracil and leucovorin (5FU/LV). Efficacy was assessed via RECIST 1.1 criteria and serum tumor biomarkers.
Results: Dose escalation (N=7) confirmed a Q3W RP2D of 12.5 mg/m2 SN38 with 1 pt having a dose limiting toxicity (DLT) of grade 4 neutropenia for &gt;7d. Following successful dose expansion, additional dose exploration confirmed a Q2W RP2D of 12.5 mg/m2 SN38 alone or in combination with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens (N=101) with mostly mild/moderate treatment-related adverse events (TRAEs), with no new events compared to those observed with conventional irinotecan. Notably, there were no reports of severe (≥ grade 3) diarrhea with DEP SN38 and no reports of cholinergic symptoms, both being common with conventional irinotecan (~20% and 47% pts, respectively). Moreover, with DEP SN38, severe nausea (2.2% pts) and vomiting (1.1% pts) occurred less frequently than with irinotecan (both ~10% pts). While febrile neutropenia was observed as a DLT at 15 mg/m2 Q2W monotherapy (2 pts), neutropenia was otherwise uneventful and managed with G-CSF.CRC pts: 38 heavily pre-treated CRC pts were dosed (N=31 evaluable); pts had an average ~4 prior treatment lines with 97% having received at least 1 irinotecan containing line. DEP SN38 achieved a disease control rate (DCR) of 48%, with stable disease up to 72 weeks.HGSOC pts: 23 platinum-resistant HGSOC pts were dosed (N=18 evaluable); pts had received an average ~6 prior treatment lines. DCR for pts dosed Q2W was 100% with 33.3% objective response rate, and 72% DCR for all HGSOC pts. There were 3 partial responses (PR), for up to 27 wks with 1 pt achieving complete tumour and ascites resolution with pts ongoing. 75% of pts achieved CA-125 reductions of up to 98% vs baseline. For DEP SN38 in combination with 5FU/LV, in a cohort of mainly CRC pts (N=6), DCR is 100% including 1 PR, with pts ongoing.
Conclusions: DEP SN38 was very well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to conventional irinotecan. Encouraging anti-tumour activity, including prolonged disease control in heavily pre-treated CRC and HGSOC pts, demonstrates promising clinical utility of DEP SN38, both as a monotherapy and as a combination therapy. Recruitment is ongoing.
Citation Format: Jia Liu, Anna R Minchom, Alastair Greystoke, Thomas R J Evans, Debashis Sarker, Anthony M Joshua, Cienne Morton, Aisha Gaus, Wing Yau, Rasha Cosman, Dominika Chwialkowska, Jeremy R A Paull, Bernadette M Jean-Francois, Jacinth K Fairley, Nicola J Main, Stephanie R Edmondson, Natalie Cook. A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111/DEP irinotecan) in patients with advanced solid tumours [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B039.