Dendrimer-enhanced (DEP) SN38 (DEP irinotecan) in patients (pts) with advanced solid tumors: A phase 1/2 trial.
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article Abstract
Authors Jia (Jenny) Liu
The Kinghorn Cancer Centre, St. Vincent's Hospital, Darlinghurst, NSW, Australia
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Jia (Jenny) Liu, Anna Rachel Minchom, Alastair Greystoke, T.R. Jeffry Evans, Debashis Sarker, Anthony M. Joshua, Cienne Morton, Burak Y Aktas, Rasha Cosman, Dominika Chwialkowska, Jeremy Paull, Nicola Jane Main, Bernadette Marie Jean-Francois, Julia Le Meur, Stephanie Ruth Edmondson, Natalie Cook
Organizations
The Kinghorn Cancer Centre, St. Vincent's Hospital, Darlinghurst, NSW, Australia, Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, United Kingdom, Department of Medical Oncology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom, King's College London, London, United Kingdom, Kinghorn Cancer Centre, St. Vincent's Hospital, Sydney, NSW, Australia, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom, Freeman Hospital, Sir Bobby Robson Cancer Trial Research Centre, Newcastle, United Kingdom, Starpharma Pty Ltd., Melbourne, Australia, Starpharma, Melbourne, Australia, The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom
Backgroundendrimer nanoparticles enable prolonged cytotoxic drug targeting to tumors. DEP SN38 is a water-soluble version of SN38, the active metabolite of irinotecan, attached to a dendrimer, so avoiding usual metabolic pathways of conventional irinotecan (c-IRI). This phase 1/2 (P1/2) trial evaluated safety, tolerability and efficacy of DEP SN38 in pts with advanced solid tumors, including colorectal (CRC), platinum-resistant high-grade serous ovarian (HGSOC) and breast (BC).Methodsts who had exhausted standard therapy were enrolled in dose assessment (P1)/dose expansion (P2) cohorts of DEP SN38 given IV 3-weekly (Q3W) or Q2W alone or in combination with 5-fluorouracil & leucovorin (5FU/LV combo). Efficacy was evaluated by RECIST 1.1 and serum tumor markers. (EudraCT 2019-001318-40).Results:114 pts were enrolled. The Q3W Recommended Dose (RD) was 12.5 mg/m2 SN38 with dose limiting toxicity (DLT) in 1/7 pts (grade (G) 4 neutropenia > 7d). The Q2W RD was 12.5 mg/m2 for SN38 alone or with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens with mostly mild/moderate (G1/2) treatment-related adverse events (TRAEs) & no new events compared with c-IRI. TRAEs in ≥ 10% pts included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, diarrhea, constipation and alopecia. Of734 DEP SN38 cycles only 1 event of G3 diarrhea (0.9% pts) and no cholinergic symptoms have been observed, contrasting with c-IRI (~20% & 47% pts respectively). G3 nausea (1.8% pts) and vomiting (0.9% pts) occurred less frequently than with c-IRI (both ~10% pts). Febrile neutropenia was the DLT at 15 mg/m2 Q2W monotherapy (2/6 pts), with neutropenia otherwise essentially uneventful and managed with G-CSF. 38 CRC pts received DEP SN38 monotherapy (31 evaluable) and 17 received the 5FU/LV combo (14 evaluable). CRC pts had a mean 4 prior lines with 97% receiving ≥ 1 c-IRI containing line. The disease control rate (DCR) in monotherapy was 48% (stable disease (SD) up to 72 wks). The 5FU/LV combo cohort DCR was 85.7%, the objective response rate (ORR) was 14.3%, with disease control observed for at least 35 wks. Several CRC pts continue combo treatment. 23 HGSOC pts with a mean of 6 prior lines received DEP SN38 monotherapy (18 evaluable). The DCR for Q2W was 100% with 33.3% ORR, and 72% DCR for all HGSOC pts. 3 pts have PRs for at least 36 wks; with 1 pt achieving complete tumor & ascites resolution. Reduced CA-125 of up to 98% was observed in 75% pts. Several HGSOC pts continue DEP SN38 treatment. 8 BC pts with a mean of 7 prior lines received DEP SN38 monotherapy Q3W (5 evaluable). The DCR was 100% with SD up to 72 wks.ConclusionsEP SN38 shows promising clinical utility with encouraging antitumor activity including prolonged disease control & durable PRs in heavily pre-treated CRC, HGSOC & BC pts. DEP SN38 is well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to c-IRI, & warrants further clinical assessment. Clinical trial information: 2019-001318-40.
endrimer nanoparticles enable prolonged cytotoxic drug targeting to tumors. DEP SN38 is a water-soluble version of SN38, the active metabolite of irinotecan, attached to a dendrimer, so avoiding usual metabolic pathways of conventional irinotecan (c-IRI). This phase 1/2 (P1/2) trial evaluated safety, tolerability and efficacy of DEP SN38 in pts with advanced solid tumors, including colorectal (CRC), platinum-resistant high-grade serous ovarian (HGSOC) and breast (BC).Methods
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