cPRs to TTI-101 monotherapy in patients with ovarian and gastric cancers. A, The patient with ovarian cancer (76-year-old female) achieved a 61% decrease in the sum of target tumor diameter with a TTF of 8 months. The patient with gastric cancer (73-year-old male) experienced a 38% reduction in the sum of target tumor size with a TTF of 7 months. PET/CT scans demonstrate sample target tumor regression from baseline to on-treatment. B, cPRs in patients with HCC treated with TTI-101 monotherapy. Patient A (56-year-old male) achieved a 42% reduction in the sum of target tumor size as BOR with an 11-month TTF, patient B (61-year-old male) experienced a 66% reduction with a TTF of 14 months, and patient C (40-year-old female) showed a 45% reduction with a TTF of 4 months. These responses illustrate the potential efficacy of TTI-101 in heavily pretreated patients with HCC.
Funding
Cancer Prevention and Research Institute of Texas (CPRIT)
V Foundation for Cancer Research (VFCR)
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...ARTICLE ABSTRACT
Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer.
Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day (“3+3” design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699).
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 (TRAE) were observed. Diarrhea (mostly grade 1/2) was the only TRAE observed in ≥30% of subjects. Five patients experienced grade 3 TRAEs that resolved. TTI-101 showed linear pharmacokinetics from DL1 to DL3, with the pharmacokinetics plateauing at DL3. The recommended phase II dose is 12.8 mg/kg/day (DL3). Of the 41 patients who were evaluable for response, five (12%) had confirmed partial responses (cPR) and 17 (41%) had stable disease. Three (18%) of the 17 patients with hepatocellular carcinoma had a cPR (median time to treatment failure, 10.6 months). Two other cPRs were noted in one patient with ovarian cancer and one patient with gastric cancer.
TTI-101 was well tolerated. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase II study of TTI-101 in hepatocellular carcinoma is currently underway.
