Abstract CT252: transcendIT-101: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors
Authors: Davar Diwakar , Singel Stina M. , Nyamuswa Gil , Tran Tuan-Anh , Wu Yang , Grewal Jaspreet , Aghmesheh Morteza , Spira Alexander , Ganju Vinod , Rand Jamie , Frentzas Sophia , Bajor David , Gabrail Nashat 
Published: June 2022

Abstract
Background: Toll-like receptors (TLRs) play a key role in innate immune cell recognition of foreign pathogens, stimulating innate and adaptive immune responses. TLR agonists amplify tumor antigen-specific immune responses in the context of anti-PD-1 therapy. TransCon TLR7/8 Agonist is designed as a long-acting prodrug to provide localized delivery of resiquimod, a potent TLR7/8 agonist. TransCon TLR7/8 Agonist has the potential to improve on challenges of pattern recognition receptor agonist treatments by providing prolonged high local concentrations of resiquimod and promoting potent anti-tumoral responses while reducing systemic drug exposure and related adverse events. TransCon TLR7/8 Agonist comprises 3 main components: resiquimod, a polymeric hydrogel microparticle carrier, and a linker bound permanently to the hydrogel microparticle carrier on one end and transiently to resiquimod on the other. TLR-mediated T cell activation induces PD-1 expression on T cells, providing a clear rationale to study TransCon TLR7/8 Agonist alone and in combination with pembrolizumab (pembro). Intratumoral TransCon TLR7/8 Agonist is expected to stimulate innate and adaptive immune response in the tumor microenvironment and further enhance the activity of checkpoint inhibitors like pembro.
Methods: transcendIT-101 is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced, unresectable, recurrent, or metastatic solid tumors. All patients must have at least 2 measurable lesions by RECIST 1.1 that are predesignated as target-injected and target non-injected lesions, respectively. The primary objectives are to evaluate the safety, tolerability, define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon TLR7/8 Agonist alone or in combination with pembro. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of TransCon TLR7/8 Agonist alone (Part 1) or with 200 mg intravenous pembro in solid tumors where pembro monotherapy may have clinical activity (Part 2). Each part will enroll ≈20 patients. Part 3 Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon TLR7/8 Agonist at the RP2D determined in Part 2 combined with pembro. Currently planned expansion cohorts are 1) head and neck squamous cell carcinoma, 2) other HPV-associated tumors (anal, vulvar, cervical, penile, vaginal). Each cohort will be analyzed using a Simon 2-stage design and will enroll ≈50 patients. Secondary objectives are TransCon TLR7/8 Agonist pharmacokinetics and its antitumor activity using ORR, duration of response, time to response by RECIST 1.1 and itRECIST; progression-free survival; overall survival. Recruitment started March 2021 and is ongoing (NCT04799054).
Citation Format: Diwakar Davar, Stina M. Singel, Gil Nyamuswa, Tuan-Anh Tran, Yang Wu, Jaspreet Grewal, Morteza Aghmesheh, Alexander Spira, Vinod Ganju, Jamie Rand, Sophia Frentzas, David Bajor, Nashat Gabrail. transcendIT-101: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT252.