Novel STAT3 Inhibitor TT1-101 Is Safe and Shows Antitumor Activity in R/R HCC and Other Solid Tumors

Novel STAT3 Inhibitor TT1-101 in R/R HCC

and Other Solid Tumors | Image Credit:

© Sebastian Kaulitzki – stock.adobe.com

Treatment with TT1-101, was well tolerated and showed clinically meaningful antitumor activity, including confirmed partial responses (cPRs), in patients with advanced metastatic hepatocellular carcinoma (HCC) and other solid tumors that were relapsed or refractory to standard treatment, according to findings from a phase 1 study (NCT03195699) published in Clinical Cancer Research.1,2

Among response-evaluable patients who received TT1-101 (n = 41)— a first-in-class, selective small-molecule inhibitor of STAT3—the best overall responses included cPRs (12%) and stable disease (SD; 41%; median time to treatment failure [TTF], 3.9 months ([range, 1.4–11.3]), resulting in a clinical benefit rate (CBR) of 54%.

Of the evaluable patients with HCC (n = 17), 18% experienced a cPR with a median TTF of 10.6 months, and 35% had SD. Notably, all patients with HCC who achieved cPRs were also refractory to prior immunotherapy and antiangiogenic therapy, and each responded during the first restaging scan.

Confirmed responses were also observed in 1 patient with ovarian cancer (61% tumor reduction; TTF, 7.1 months) and 1 patient with gastric cancer (38% tumor reduction; TTF, 7 months). Moreover, 1 patient with melanoma maintained SD with more than 20 months of disease control. CBRs were comparable between the HCC (53%) and non-HCC (54%) cohorts.

No dose-limiting toxicities (DLTs) were observed at any dose level. Although the frequency and severity of treatment-related adverse effects (TRAEs) increased at dose level 4 (DL4), dose-normalized exposure was lower than at DL3, and pharmacokinetics were linear from DL1 through DL3. Given the favorable safety and exposure profile at DL3, 12.8 mg/kg per day was selected as the recommended phase 2 dose (RP2D) for both the HCC and non-HCC solid tumor cohorts.

“In this first-in-human phase 1 study, TTI-101 was well tolerated and demonstrated clinically meaningful antitumor,” the study authors wrote in the publication. “STAT3 is distinct from the currently established targets in HCC. By targeting both intrinsic tumorigenesis and extrinsic immune suppression, TTI-101 showed promising antitumor activity in patients with HCC refractory to immune checkpoint inhibitors and antiangiogenic agents.”

Study Background and Rationale

STAT3 is a key oncogenic driver implicated in numerous cancer hallmarks—including cell proliferation, apoptosis resistance, immune evasion, angiogenesis, and cancer stem cell maintenance—and high STAT3 activity is associated with poor prognosis. Its aberrant activation is observed in approximately half of cancers, including renal, lung, breast, colorectal, and hepatocellular carcinomas, making it a viable target for therapeutic development.

TTI-101 is a first-in-class, orally bioavailable, selective small molecule that binds to STAT3 and prevents STAT3-mediated transcriptional activity. Preclinical studies have demonstrated the agent’s strong pharmacokinetic properties and minimal toxicity in rats and monkeys.

Based on this favorable profile, a first-in-human, phase 1, multicenter dose-escalation and -expansion study of TTI-101 was initiated in patients with advanced metastatic solid tumors to evaluate the agent’s safety and preliminary efficacy.

To be eligible for the study, patients must have been at least 18 years of age; have a histologically confirmed diagnosis of a solid tumor and advanced metastatic disease; and have experienced disease progression following standard treatment. An ECOG performance status of 0 or 1 with measurable disease per RECIST 1.1 criteria was also necessary. Notably, eligible patients with HCC were also required to have a histologically or radiologically confirmed diagnosis of locally advanced, inoperable, or unresectable disease and a Child-Pugh score of A. Those who had received previous anticancer therapy within 28 days of day 1 of the study drug treatment, had known active metastases in the central nervous system, or had chronic hepatitis B virus infection were excluded from the study.

Upon enrollment onto the dose-escalation phase, patients received oral TTI-101 twice daily at the following escalating daily dose levels: 3.2 mg/kg (DL1), 6.4 mg/kg (DL2), 12.8 mg/kg (DL3), and 25.6 mg/kg (DL4). Eligible patients who proceeded to the dose-expansion portion received the RP2D, DL3.

Notably, 3 different TTI-101 formulations (F1, F2, and F3) were administered to optimize delivery and tolerability. Patients were originally treated with F1 and F2 during dose escalation and then received either F2 or F3 in the dose-expansion phase.

The study’s primary end points were the maximum tolerated dose (MTD) or rRP2D, DLTs, and tolerability of TTI-101, as well as the pharmacokinetic profile of the agent. Pharmacodynamics before and during treatment, and clinical outcomes with TTI-101 served as secondary end points. Exploratory end points included the association between biomarkers and antitumor efficacy and survival outcomes; clinical outcomes related to liver fibrosis in patients with HCC; and the effects of food on TTI-101 bioavailability in select subgroups. An additional exploratory retrospective analysis was performed in evaluable patients in the HCC subgroup with an available tumor molecular profile to compare molecular markers.

Baseline Characteristics

A total of 64 patients were identified and recruited from The University of Texas MD Anderson Cancer Center in Houston and The University of Texas Health Science Center at San Antonio and enrolled onto the study between December 5, 2017, and August 15, 2022. The mean age among all patients was 61 years. Most patients were male (52%) and had an ECOG performance status of 1 (89%).

HCC was the most frequently represented tumor type (n = 22), followed by breast and colorectal cancers (n = 7 each); neuroendocrine carcinoma (n = 3); melanoma, non–small cell lung cancer, pancreatic cancer, and ovarian cancer (n = 2 each); and other (n = 27; 1 patient each). At diagnosis, most patients had stage III (38%) disease followed by stage IV (30%), II (6%), I (3%), and 0 (2%). Stage IV disease was most prevalent at the time of treatment (83%). Patients were heavily pretreated, with a median of 3.5 prior systemic therapies (range, 1-9).

By the data cutoff of May 1, 2024, 63 patients had discontinued study treatment. The most common reason for discontinuation was disease progression (65%), followed by treatment-related or unrelated AEs (16%) and withdrawal of consent (16%). Among those who withdrew consent, 6 cited poor tolerance of the study drug, 2 experienced AEs unrelated to the study drug, and 2 discontinued for logistical or performance-related reasons.

One patient remained on therapy under an open-label extension protocol. These discontinuation patterns, particularly the low incidence of discontinuation due to toxicity, further support the tolerability profile of TTI-101 in this diverse, heavily pretreated patient population, investigators noted.

Safety and Pharmacokinetic Data

Among the 64 patients treated with TTI-101, 98% experienced at least 1 AE, with the most common AEs being diarrhea (52%), fatigue (41%), and nausea (31%). TRAEs occurred in 70% of patients, with 25% of patients experiencing grade 3 or greater TRAEs. No DLTs or fatal TRAEs were reported.

Diarrhea, predominantly grade 1/2, was the only TRAE observed in at least 30% of patients. One case of transient grade 4 hyperglycemia resolved with standard glucose-lowering therapy. Five patients experienced grade 3 TRAEs that resolved, whereas 10 patients (15%) had grade 3 or higher TRAEs that led to treatment interruption or discontinuation. The frequency and severity of TRAEs were higher at DL4, and the F3 formulation (n = 7) appeared better tolerated than F1 (n = 15) and F2 (n = 47).

Pharmacokinetic data showed that TTI-101 exhibited linear pharmacokinetics from DL1 to DL3; however, the increase in exposure was less than proportional at DL4. At DL3, minimum plasma concentrations exceeded the in vitro STAT3 IC50 threshold for cell growth inhibition, indicating potentially therapeutically relevant exposure. A 77% increase in drug exposure (area under the curve/dose × body weight) was observed when switching from the F1 to F2 formulation at the RP2D. No significant differences in systemic exposure were noted between fed and fasting patients receiving the F2 formulation on cycle 1, day 1 and cycle 2, day 1.

Additionally, an intrapatient crossover analysis comparing the F2 and F3 formulations on consecutive days demonstrated equivalent exposure levels between the formulations, supporting the use of the more tolerable F3 formulation without compromising drug bioavailability. Overall, TTI-101 was well tolerated across multiple dose levels and formulations, with a manageable safety profile and consistent pharmacokinetics supportive of continued clinical development.

Paired tumor biopsies demonstrated decreased levels of phosphorylated STAT3 (pY-STAT3) in all cases where pY-STAT3 was elevated at baseline, with the most substantial reductions (mean H-score decrease of 79%) observed in the 3 patients who derived clinical benefit.

Responses by Disease Etiology and Tumor Molecular Profiling Analysis

In an exploratory analysis of disease etiology, among the evaluable patients with HCC (n = 17), 59% and 41% displayed viral vs nonviral etiology, respectively. Within the nonviral subgroup, 3 patients experienced cPR and 1 had SD, yielding an ORR of 43% and a DCR of 57%. In contrast, 5 patients with viral HCC achieved SD but no ORRs were observed, resulting in a CBR of 50%.

A total of 44 patients had retrospective tumor molecular profiling data available. Notably, a potential correlation betweenp53 mutations and TTI-101 response was observed in response-evaluable patients with HCC (n = 10). Among the 7 patients with p53-mutant tumors, 86% experienced clinical benefit, comprising 2 PRs and 4 SDs, whereas all 3 patients with p53 wild-typetumors had progressive disease. Investigators said that these findings are supported by prior preclinical evidence showing that mutant p53 can drive tumorigenesis and invasiveness via sustained STAT3 activation, with constitutive STAT3 activity observed in multiple p53-mutant cancer cell lines, including ovarian, breast, and prostate.

These findings further support the ongoing evaluation of TTI-101 in patients with locally advanced or metastatic, unresectable HCC in a phase 1/2 trial (NCT05440708). The study comprises 3 arms: TTI-101 in combination with atezolizumab (Tecentriq) plus bevacizumab (Avastin) in the first-line setting; TTI-101 in combination with pembrolizumab (Keytruda) in the second-line setting; and TTI-101 as monotherapy in the third-line setting.

Reference

Tsimberidou AM, Vining DJ, Arora SP, et al. Phase I trial of TTI-101, a first-in-class oral inhibitor of STAT3, in patients with advanced solid tumors. Clin Cancer Res. 2025;31(6):965-974. doi:10.1158/1078-0432.CCR-24-2920