Abstract CT167: Trial in progress: Phase 1 dose escalation study of T-1101, a first-in-class oral Hec1/Nek2 inhibitor, in patients with advanced refractory solid tumors
Authors: Su Wu-Chou , Bai Li-Yuan , Hsiao Hui-Hua , Shiah Her-Shyong , Yeh Yu-Min , Chen Shang-Hung , Wu Shang-Yin , Wang Hui-Ching , Tsai Hui-Jen , Chang Kwang-Yu , Tsai Jui-Hung , Lee Chun-Hui , Lee Chieh Hua , Chao Yu-Sheng , Chen Li-Tzong 
Published: April 2024

Background: T-1101, a novel small molecule, is the first-in-class oral agent that specifically disrupts the interaction between two commonly overexpressed, critical mitotic regulators, Hec1 and Nek2, within cancer cells. Such disruption leads to abnormal mitosis followed by apoptosis of cancer cells and provides a potential therapeutic strategy for cancer treatment. T-1101, with growth inhibition concentrations (IC50) ranging from14 to 74 nM across various human cancer cell lines, exhibited potent anti-liver and breastcancer activities in vivo, and highly active (IC50 7-19 nM) in MDR (multiple drugresistance) expressing cell lines. The effective inhibitory dose of T-1101 was determined to be between 10 and 25 mg/kg twice a day in xenograft animal models. Moreover, T-1101 has synergistic activity when combined with other anticancer drugs such as doxorubicin, topotecan and paclitaxel etc. Clinically, oral powder for constitution (OPC) form was first used in the initial study. To improve better patient compliance, the capsule (CAP) form is then deployed in current T-1101’s phase 1 study.

Methods: Two T-1101 oral formulations (OPC and CAP) have been designed for the first-in-human, multi-center, open-label, dose-escalation studies to evaluate the safety, tolerability and establish the Recommended Phase 2 Dose (RP2D) in subjects with advanced refractory solid tumors. The secondary objectives are to assess the pharmacokinetics (PK) and therapeutic response after receiving treatment. DLT was determined within the first treatment cycle. Patients showing clinical benefit after first 2cycles of T-1101may enter extension cohort to continue the treatment. In OPC 3+3 escalation study (NCT03195764, NCT03349073), T-1101 was administered orally once daily, days 1 to 14 every 21 days per cycle with 8 planned dose levels at dose of 9, 18, 36, 54, 72, 90, 108 to 126 mg/m2. The OPC study was terminated at 36 mg/m2 before the primary endpoint (determination of maximum tolerated dose; MTD) was reached and subsequent dosing level will be evaluated with the CAP formulation. Based on the 52% of relative oral bioavailability (%F) of CAP versus OPC in preclinical Beagle dogs’ PK study, the starting dose of CAP form of T-1101 was determined at 100 mg daily forconsecutive 28-day per cycle for 2 cycles with dose levels of 100, 200, 225, 250, 300 and 350 mg/day. The accelerated titration and Bayesian Optimal Interval (BOIN) designs are used for the T-1101 capsule dose escalation study (NCT04685473), in which one subject will be enrolled per dose level until one subject have DLT or two subjects experience ≥ Grade 2 drug-related AE during Cycle 1 at any dose level, then the dose escalation will follow the BOIN design. Cohorts 1 (100 mg/day) 2 (200 mg/day) and 3 (225 mg/day) have been completed without DLT. As of November 2023, the trial remains open to enrollment.

Citation Format: Wu-Chou Su, Li-Yuan Bai, Hui-Hua Hsiao, Her-Shyong Shiah, Yu-Min Yeh, Shang-Hung Chen, Shang-Yin Wu, Hui-Ching Wang, Hui-Jen Tsai, Kwang-Yu Chang, Jui-Hung Tsai, Chun-Hui Lee, Chieh Hua Lee, Yu-Sheng Chao, Li-Tzong Chen. Trial in progress: Phase 1 dose escalation study of T-1101, a first-in-class oral Hec1/Nek2 inhibitor, in patients with advanced refractory 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(7_Suppl):Abstract nr CT167.