TT125-802, a highly selective, well-tolerated bromodomain inhibitor of CBP/p300 with anti-tumor activity in patients with advanced solid tumors: An update on the ongoing phase I study.

Abstract

e15105 Background: Transcriptional mechanisms of resistance undermine the long-term efficacy of targeted cancer therapies. TT125-802 is a small molecule that inhibits the bromodomain of CBP/p300, a regulator of epigenetic mechanisms of drug resistance. The safety, tolerability, PK/PD, and preliminary anti-tumor activity of TT125-802 is currently being investigated in a FIH study (NCT06403436). Ultimately it will be developed in combination with targeted cancer treatments to offer durable clinical benefit. Methods: Patients with advanced solid tumors relapsed/refractory to SOC are enrolled into the Phase 1 dose escalation component of the study which uses the Bayesian Logistics Regression Model design. Each dose cohort includes 3 to 6 patients, with a DLT period of 21 days. TT125-802 is administered orally in fasting condition once or twice daily until disease progression, unacceptable toxicity, or consent withdrawal. The effect of food is being assessed in separate cohorts. Single-cell RNA-seq of paired (baseline and on-treatment) PBMCs and optional tumor biopsies, as well as bulk RNA-seq of hair follicles, are being performed to evaluate changes in PD biomarkers of CBP/p300 inhibition. ctDNA samples are collected to measure molecular response and investigate putative predictive biomarkers. Results: To date, 26 patients with adenoid cystic carcinoma (4), ampullary carcinoma (1), anal cancer (2), breast cancer (2), CRC (3), dedifferentiated liposarcoma (1), enteroid adenocarcinoma (1), malignant cylindroma (1), CRPC (2), NSCLC (5), NUT carcinoma (1), PDAC (1), thymic cancer (1) and UPS (1) have been administered TT125-802 from 15 mg QD to 100 mg QD, and 60 mg BID fasted and 30 mg QD with food. TT125-802 has been well tolerated, with one DLT (G3 hyperglycemia) at 60 mg BID. The safety profile is characterized by dysgeusia, hyperglycemia, anemia, transient elevation in liver and pancreatic enzymes, stomatitis, fatigue and decreased appetite. 98% of related events have been Grade 1/2, and reversible. Notably, no thrombocytopenia has been observed. TT125-802 exposures increased with doses up to 60 mg QD and reached predicted efficacious ranges. PD assessments on surrogate tissues showed suppression of CBP/p300-regulated gene expression signatures, supporting target engagement. So far, seven patients demonstrated clinical benefit lasting over 6 months, including one (NSCLC) who achieved a deep and durable, confirmed partial response as per RECISTv1.1. Conclusions: TT125-802 has a well tolerated and differentiated safety profile from other CBP/p300 targeting drugs with no thrombocytopenia and has shown encouraging signs of anti-tumor activity in advanced solid tumors. Updated clinical data, including food effect on drug exposure, additional dose cohorts, PK/PD, and ctDNA changes will be presented at the meeting. Clinical trial information: NCT06403436 .