Imran Alibhai

Supplementary Table S1. Representativeness of Study Participants.

Supplementary File S1. Patient Eligibility.

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.

Best response to TTI-101 treatment per RECIST v1.1.

Summary of TRAEs reported in >10% of patients treated with TTI-101 monotherapy.

Study design and tumor response to TTI-101 monotherapy. A, Study design outlining the dose-escalation and dose-expansion phases. The dose-escalation phase involved advanced solid tumors across four DLs (DL1–DL4), with dose expansion at the RP2D for HCC and other solid tumors. Different TTI-101 formulations (F1, F2, and F3) were used to optimize delivery and tolerability. B, Spider plots depicting individual tumor responses to TTI-101 treatment over time. Each line represents a patient’s sum of target tumor response, with changes in tumor size from baseline measured at various time points. The plot illustrates the variability in response across patients and DLs. C, Waterfall plot showing the best response by RECIST criteria for patients treated with TTI-101 monotherapy. Bars represent the maximum reduction in the sum of target tumor size for each patient, categorized as a PR, SD, or progressive disease. Tumor types are indicated, highlighting the distribution of responses across HCC and other solid tumors.

Purpose: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 and Methods: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).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 (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.Conclusions: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.

PK parameters of TTI-101 in plasma.

Supplementary Table S1. Representativeness of Study Participants.

Supplementary File S1. Patient Eligibility.