TDI01 Demonstrates Preliminary Efficacy and Tolerability in Moderate-to-Severe cGVHD

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Treatment with TDI01—an oral, highly selective ROCK2 inhibitor—led to clinical activity and tolerability in patients with moderate-to-severe chronic graft-vs-host disease (cGVHD), according to findings from a phase 1b/2 study (NCT06169722) presented at the 51st Annual EBMT Meeting.

Findings showed that at week 24, the best overall response rate (ORR) was 67.9% (95% CI, 47.6%-84.1%) in patients treated with TDI01 at 200 mg once daily (n = 30) and 86.2% (95% CI, 68.3%-96.1%) in those treated at 400 mg once per day (n = 30). The 24-week ORR was 50.0% (95% CI, 30.6%-69.4%) and 55.2% (95% CI, 35.7%-73.6%) in the 200-mg and 400-mg groups, respectively. The median time to response was 44.0 days (range, 29-169) and 31.0 days (range, 28-115) in the 200-mg and 400-mg arms, respectively. Across both arms, 67.4% of responders achieved a response within 8 weeks of treatment initiation.

At the time of analysis, the median failure-free survival (FFS) had not been reached in either cohort. The estimated FFS rate at week 24 was 78.6% (95% CI, 58.4%-89.8%) in the 200-mg arm and 89.2% (95% CI, 70.1%-96.4%) in the 400-mg arm.

“TDI01 [showed] encouraging efficacy in [patients with] cGVHD with a 24-week best ORR of 67.9% and 87.2% in [the] 200-mg and 400-mg cohorts, respectively. High responses were observed across all the subgroups, including patients [who previously progressed on] ruxolitinib [Rituxan],” lead study author Xiaodong Mo, MD, of Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease in China, explained in the presentation.

Phase 1b/2 Trial Design

The multicenter, open-label phase 1b/2 trial enrolled patients at least 18 years of age with moderate-to-severe cGVHD who had received between 1 to 5 prior lines of systemic therapy. Eligible participants were required to have active cGVHD at study entry, an estimated survival of at least 6 months, and a clinical indication for further systemic therapy.

The treatment phase utilized a dose-escalation design, beginning with cohort 1 (n = 30), in which patients received TDI01 at 200 mg once daily. In cohort 2 (n = 30), additional patients were enrolled to receive an escalated dose of 400 mg once per day.

The study’s co-primary end points were best ORR at week 24 and safety. Secondary end points included ORR at week 24, duration of response (DOR), FFS, organ-specific response rates, and pharmacokinetics (PK).

Baseline Patient Demographics

The phase 1b study enrolled a total of 60 patients; the median age across cohorts was 37 years (range, 19-55), and 70% of patients were male. Most patients had an ECOG performance status of 1 (70%), with fewer patients enrolling with a performance status of 0 (18.3%) or 2 (11.7%).

The most common primary underlying malignancy was acute myeloid leukemia (41.7%), followed by myelodysplastic syndromes (16.7%) and acute lymphoblastic leukemia (13.3%). Other primary diagnoses included chronic myeloid leukemia (8.3%), aplastic anemia (5.0%), acute promyelocytic leukemia (3.3%), and other hematologic malignancies (11.7%).

Regarding cGVHD disease characteristics, 38.3% of patients presented with moderate disease, and 61.7% had severe disease. Patients had received a median of 3 prior systemic lines of therapy (range, 1-5). Patients had a median of 4 organs affected (range, 1-7), and 60% of patients had involvement of 4 or more organs at baseline.

Prior to enrollment, nearly all patients (98.3%) had been treated with glucocorticoids, and 88.3% had received calcineurin inhibitors, including cyclosporine and tacrolimus. Ruxolitinib had been administered to 73.3% of patients, and 28.3% received other immunosuppressive agents such as methotrexate, azathioprine, or thalidomide.

Safety and PK Analysis

All patients in both the 200-mg and 400-mg once-daily cohorts experienced at least 1 adverse effect (AE); treatment-related AEs (TRAEs) were reported in 100% and 93.3% of patients, respectively. Grade 3 or higher AEs were observed in 53.3% and 43.3% of patients, respectively. Grade 3 or higher TRAEs occurred at respective rates of 40.0% and 33.3%.

Serious AEs (SAEs) were reported in 25% of the total study population (n = 15), including 33.3% in the 200-mg group and 16.7% in the 400-mg group. Drug-related SAEs occurred in 16.7% of patients receiving 200 mg of TDI01; none were reported in the 400-mg cohort. One patient (1.7%) in the 400 mg group experienced a fatal AE; however, no deaths were attributed to treatment.

Discontinuation due to AEs occurred in 6.7% of patients overall, with TRAE-related discontinuation reported in 2 patients (6.7%) in the 200-mg cohort and 1 patient (3.3%) in the 400-mg cohort.

The most common TRAE occurring in more than 20% of patients was increased bilirubin levels, reported in 80% of patients overall (73.3% in the 200-mg cohort and 86.7% in the 400-mg cohort). An increase in unconjugated bilirubin levels was also observed in 55.5% of all patients. Headache as a TRAE was reported in 18.3% of patients.

The PK analysis demonstrated that TDI01 exhibited a favorable and predictable profile. Across both dose levels evaluated, mean systemic exposure, as assessed by maximum concentration and area under the curve, increased proportionally with dose escalation.

The concentration-time profiles were comparable between the 2 cohorts, indicating uniform drug exposure over time. The median time to peak plasma concentration after the initial administration was 4.48 hours in the 200-mg group and 4.08 hours in the 400-mg group, suggesting similar absorption kinetics between the dosing regimens.

Reference

Mo X, Zhang X, Guo R, et al. TDI01 in the treatment of moderate to severe chronic graft-versus-host disease: Results from a multicenter, open-label phase Ib/II study. Presented at: 51th Annual EBMT Meeting; March 30-April 2, 2025. Florence, Italy. Abstract GS2-8.