Abstract 1043P
Background
TU2218 is a highly potent, oral dual inhibitor against TGFβ type I receptor (TGFβRI /ALK5) and VEGFR2. VEGF and TGF-β pathways play important roles in the function of TME, especially in immune tolerance inextricably related with poor outcomes of anti-PD-(L)1 therapy. This is a first-in-human study to investigate the safety and tolerability of TU2218 mono- and combination therapy with pembrolizumab.
Methods
This non-randomized, multinational, open-label study has been evaluating the safety, tolerability, PK, and preliminary efficacy of TU2218 mono- and combination therapy with pembrolizumab in advanced solid tumors. The eligible patients were aged ≥ 18 years, ECOG (0 or 1), and had measurable tumors per RECIST 1.1. TU2218 monotherapy was planned at 6 dose levels (30, 60, 105, 150, 195, 270 mg/day) with 2 weeks on and 1 week off in 3-week cycles according to the BOIN method. The starting dose of TU2218 given with pembrolizumab was determined after yielding TRAEs of at least Grade 2 in severity during monotherapy using the traditional 3+3 design.
Results
Seventeen patients with advanced solid tumors received 5 different dose levels of monotherapy. Major demographics, treatment-related adverse events (TRAEs) and PK parameters are summarized in the table.
Table: 1043P
Cohort | 1 | 2 | 3 | 4 | 5 |
Total Daily Dose (mg) | 30 | 60 | 105 | 150 | 195 |
N | 3 | 4 | 4 | 3 | 3 |
Median age (Range) | 54 (48-56) | 61 (46-78) | 70 (52-77) | 72 (56-72) | 65 (37-75) |
Male/ Female | 0/3 | 2/2 | 1/3 | 1/2 | 1/2 |
TRAE, n (Grade) | 0 | 3 (G2) | 2 (G2) | 1 (G2) | 6 (G2) |
* G2 TRAEs were reported from 2 patients of Nausea, Dehydration, Fatigue in Cohort 2, 2 patients of Itching & Platelet Count Decreased in Cohort 3, 1 patient of Nausea in Cohort 4, and 3 patients of Itching, Skin Rash, Myalgia, Anorexia, Arthralgia & Mucositis oral in Cohort 5. | |||||
Mean PK Parameters | |||||
tmax (h) | 1 | 0.7 | 1.6 | 1.2 | |
Cmax (ng/mL) | 95 | 162 | 374 | 781 | 1875 |
AUClast (ng·h/mL) | 200 | 257 | 819 | 1854 | 3664 |
t1/2 (h) | 2.1 | 1.7 | 1.7 | 2.6 | |
* For cohort 5, simulated data |
No TRAEs of Grade 3 or higher were reported while all Grade 2 TRAEs were tolerable in TU2218 monotherapy. Systemic exposure to TU2218 increased over-proportionally with the dose-escalation. The starting dose of TU2218 for the combination therapy with pembrolizumab was 105mg/day, with subsequent incremental doses of 150mg/day and 195mg/day. To date, clinical studies of TU2218 are ongoing.
Conclusions
TU2218, a first-in-class oral dual inhibitor against TGFβRI and VEGFR2, was well-tolerated in the monotherapy.
Clinical trial identification
NCT05204862.
Editorial acknowledgement
Legal entity responsible for the study
TiumBio Co., Ltd.
Funding
TiumBio Co., Ltd.
Disclosure
All authors have declared no conflicts of interest.
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