Phase 1 Trial of TTI-101, a First-in-Class Oral Inhibitor of STAT3 in Patients with Advanced Solid Tumors

Purpose: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase 1 study of TTI‑101, a first-in-class, selective small-molecule inhibitor of STAT3, in patients with advanced metastatic cancer. Patients and Methods: Patients were treated with TTI-101 orally twice daily in 28-day cycles at 4 dose levels (DLs): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/d (“3+3” design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699). Results: Sixty-four patients were treated (median age, 63 years; male sex, 52%; median number of prior therapies, 3). No dose-limiting toxicities or fatal treatment-related adverse events (TRAEs) were observed. Diarrhea (mostly grade 1/2) was the only TRAE observed in ≥30% of subjects. Five patients had grade 3 TRAEs that resolved. TTI-101 showed linear pharmacokinetics from DL1 to DL3, with plateauing at DL3. The recommended phase 2 dose is 12.8 mg/kg/d (DL3). Of the 41 patients who were evaluable for response, 5 (12%) had confirmed partial responses (cPRs) and 17 (41%) had stable disease. Three (18%) of the 17 patients with HCC had a cPR (median time to treatment failure, 10.6 months). Two other cPRs were noted in one patient with ovarian cancer and one with gastric cancer. Conclusions: TTI-101 was well-tolerated. cPRs were observed across tumor types. The anti-tumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase 2 study of TTI-101 in HCC is currently underway.