Abstract CT050: A phase 2, multi-center, open-label, dose-finding study evaluating telomere targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC
Authors: Obrocea Mihail , Seidl Brenton , Joshi Rohit , Moore Melissa , Vitoc Vlad , Yao Bin , Gryaznov Sergei 
Published: April 2023

Abstract
Background: The modified nucleoside 6-thio-2'-deoxyguanosine (THIO) is a first-in-class direct telomere-targeting agent that is preferentially incorporated in telomeres of telomerase-positive cells, leading to telomere uncapping and cancer cell death. Preclinical evidence indicates that THIO pretreatment sensitizes non-small cell lung cancer (NSCLC) cells to cemiplimab, a PD-1 inhibitor approved as 1L treatment for patients with locally advanced/metastatic NSCLC with ≥50% PD-L1 expression. The THIO-101 trial is designed to evaluate safety and efficacy of THIO followed by cemiplimab in patients with advanced NSCLC who have developed resistance or relapsed after prior immune checkpoint inhibitor (ICI) therapy.
Trial Design: THIO-101 enrolls adult patients with stage 3/4 NSCLC, who have progressed or relapsed after treatment with an ICI alone or in combination with platinum-based therapy. Using a 3+3 design, the safety lead-in (Part A) is enrolling up to 6 patients in the first cohort to receive a total dose of THIO 360 mg IV (120 mg QD, D1-3) followed by a fixed dose of cemiplimab 350 mg on D5 Q3W. If ≥2 patients experience dose-limiting toxicities, a second cohort will receive a total dose of THIO 180 mg IV (60 mg QD, D1-3) followed by cemiplimab. In the dose- finding portion of the study (Part B), patients will be randomized 1:1:1 in a Simon 2-stage design (n=41 per arm) to receive THIO 360 mg [if cleared in Part A], 180 mg, or 60 mg followed by cemiplimab. Sequential THIO and cemiplimab treatment may be continued Q3W for up to 1 year, or until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoints are safety, objective response rate, and disease control rate (CR, PR, and SD). Secondary endpoints include duration of response, progression-free survival, and overall survival; exploratory endpoints include PK/PD parameters (type I IFN, IL-6, CRP) and assessment of tumor telomerase status by IHC. Investigators will assess disease progression per RECIST v1.1 and/or iRECIST, with radiographic scans performed on D1 of cycles 3 and 5 and every 9-12 weeks thereafter. Adverse events are evaluated according to NCI CTCAE v5.0. The trial is enrolling patients at sites in Europe and Australia. The trial has completed enrollment in Part A without DLTs and opened enrollment in Part B. NCT05208944; EUDRA CT Number, 2021-005136-34
Citation Format: Mihail Obrocea, Brenton Seidl, Rohit Joshi, Melissa Moore, Vlad Vitoc, Bin Yao, Sergei Gryaznov. A phase 2, multi-center, open-label, dose-finding study evaluating telomere targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT050.