78P - First-in-human phase I study of TT-00434, an orally available FGFR (1-3) inhibitor in patients with advanced solid tumors

Background

TT-00434 is an irreversible, highly selective inhibitor of FGFR1, 2, and 3 with potent preclinical activity against tumors harboring FGFR aberrations. We present initial results from the first-in-human phase 1 study of TT-00434 orally administrated in patients (pts) with solid tumors.

Methods

This phase 1, multicenter, open-label, dose-escalation study enrolled pts with advanced solid tumors who had exhausted all available standard treatments. An accelerated titration design followed by a standard 3 + 3 scheme was used. Pts received a single daily dose of TT-00434 continuously for 28-day cycles. Key objectives included determining the recommended phase 2 dose (RP2D), safety, PK, pharmacodynamics (PD) and preliminary antitumor activity.

Results

As of 7 Aug 2023, 11 eligible pts received TT-00434 40 mg (n = 1), 80 mg (n = 6), and 160 mg (n = 4). One pt in 160 mg experienced Grade (G) 2 fatigue, vomiting and dizziness, resulting in dose interruption for 13 days (≥7 days) in Cycle 1 which was qualified as DLTs. The most frequently reported treatment-related adverse events included hyperphosphatemia (91%), fatigue (45%), hypercalcemia (36%), dry mouth (36%) and decreased appetite (36%). Two G3 events of fatigue and hyponatremia (each n=1) were observed. No G4 or G5 AEs were reported. The exposure (AUC and C_max) was dose proportional from 80 to 160 mg. The maximum serum phosphate concentration as PD biomarker reached plateau (6.1∼8.9 mg/mL) at 80 mg. Stable diseases were observed in 2 pts with bladder cancer and endometrial cancer. One cholangiocarcinoma pt with FGFR alteration (FGFR2(17)-ARHGAP24(3) fusion) treated at 80 mg achieved partial response. The treatment lasts 203+ days and is still ongoing. Based on safety, efficacy and PK/PD assessments, the RP2D was determined as 80 mg QD.

Conclusions

This first-in-human study of TT-00434 showed a manageable and well-tolerated safety profile. The preliminary antitumor activity was observed in pt with FGFR2 altered cholangiocarcinoma. Further evaluation of the efficacy and safety of TT-00434 in solid tumors with FGFR1-3 alterations is encouraged.

Clinical trial identification

NCT04830501.

Editorial acknowledgement

Legal entity responsible for the study

TransThera Sciences (Nanjing), Inc.

Funding

TransThera Sciences (Nanjing), Inc.

Disclosure

All authors have declared no conflicts of interest.