Abstract CT166: First-in-human phase 1 study of a phosphatidylserine-targeting small molecule drug conjugate (T-1201) in patients with advanced solid tumors

Abstract Background Phosphatidylserine (PS), a phospholipid, is an essential component of bilayer cell membranes and is normally present in the inner cell membrane layer of the cells. In rapid proliferating cancer cells, PS externalizes to the outer cell membrane and has the potential to act as a tumor biomarker and therapeutic target. T-1201 is a small molecule drug conjugate comprised of a phosphatidylserine-targeting head, Zinc (II) bis-dipicolylamine (Zn-DPA), linked to bioactive topoisomerase I inhibitor SN-38. Once T-1201 via Zn-DPA targets tumor cells, then enzymatic cleavage releases the cytotoxic payload of SN38, the active metabolite of irinotecan. This leads to high accumulation of antineoplastic drug directly in the tumor microenvironment. Here, we describe a trial in progress of a first-in-human trial of T-1201 in patients with advanced solid tumors. Methods This first-in-human, open-label, multicenter, phase I trial (NCT04866641) is investigating the safety, tolerability, pharmacokinetics and antitumor activity of T-1201 administrated as monotherapy to subjects with advanced solid tumors. Eligible patients have ≥ 1 measurable lesion per RECIST v1. 1. and no effective standard therapy exists. T-1201 is administered intravenously once every 4 weeks (Q4W) in 28-day cycles with dose escalation guided by an accelerated titration design. The study started with 1 subject enrolled per cohort. With 100% dose increment for the next cohort. If 1 subject experiences any ≥ Grade 2 AE or DLT at any dose level during first cycle, the dose escalation will transit to 3+3 design where dose increment will follow a modified Fibonacci sequence. Starting with Cycle 2, the dosing interval can be adjusted to once every two weeks (Q2W) and the dose level after switching to Q2W schedule will be half of that at Q4W. Intra-subject dose escalation is permitted to maximize the likelihood of responses while keeping toxicity acceptable for individual subjects. The dose can be increased after subjects complete at least 2 treatment cycles at a particular dose level without experiencing any grade 2 drug-related toxicity. The primary endpoints are the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D) and adverse event rate as measured by CTCAE v5. 0. Secondary endpoints include objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR) and time to tumor progression. This study has begun enrolling patients and is continuing as planned in Taiwan. 77% of planned patients have been enrolled as of November 2023. Citation Format: Hui-Ching Wang, Yu-Min Yeh, Jeng-Shiun Du, Tsung-Jang Yeh, Jui-Hung Tsai, Yu-Chin Gau, Shang Yin Wu, Li-Tzong Chen, Hsiao-Fang Li, Wu-Chou Su. First-in-human phase 1 study of a phosphatidylserine-targeting small molecule drug conjugate (T-1201) in patients with advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT166.