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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors
Toshihiko Doi1, Nobuaki Matsubara2, Akira Kawai3
1Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.
Abstract:
TAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5 days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200-800 mg SID administered to 21 patients), systemic exposure after single administration increased almost dose-proportionally. Three dose-limiting toxicities (DLTs) were observed in three patients: grade 3 rash (650 mg), thrombocytopenia with bleeding, and rash (800 mg). The maximum tolerated dose (MTD) was determined as 650 mg SID. In part 2, the 5-on/2-off schedule was evaluated at the MTD to improve treatment exposure. No DLTs were observed and no patients required treatment interruption in cycle 1. During part 2 and the expansion part (N = 61), grade ≥3 treatment-related adverse events were reported in 47 patients, with neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each), and leukocytopenia (11.5%) occurring in ≥10% of patients. The best overall response was stable disease in 31 of 82 patients (37.8%). An apparent reduction in fluorodesoxyglucose-uptake and bone scan index was observed in some patients. TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed.
Insights
TAS-115, a novel tyrosine kinase inhibitor, demonstrated manageable toxicity and promising antitumor activity in patients with solid tumors. The recommended Phase II dose is 650 mg once daily on a 5-days on/2-days off schedule.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- TAS-115 is a novel inhibitor targeting MET, VEGFR, FMS, and PDGFR, designed for improved drug administration continuity.
- Its short half-life necessitates careful evaluation of dosing schedules and tolerability in cancer patients.
Purpose of the Study:
- To assess the tolerability, safety, pharmacokinetics, pharmacodynamics, and efficacy of TAS-115 in patients with solid tumors.
- To determine the recommended Phase II dose and schedule for TAS-115.
Main Methods:
- An open-label, dose-escalation Phase I study involving oral administration of TAS-115.
- Part 1: Daily dosing (200-800 mg) to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD).
- Part 2 and expansion: 5-days on/2-days off schedule at the MTD (650 mg) to evaluate safety and efficacy in a larger cohort (N=61).
Main Results:
- The maximum tolerated dose (MTD) was established at 650 mg once daily (SID).
- The 5-on/2-off schedule at 650 mg SID showed improved tolerability with no DLTs in Cycle 1.
- Common grade ≥3 treatment-related adverse events included neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each).
- Best overall response was stable disease in 37.8% of patients (31/82), with observed reductions in metabolic activity in some cases.
Conclusions:
- TAS-115 is generally well-tolerated with manageable toxicities.
- The recommended Phase II dose is 650 mg SID on a 5-on/2-off schedule.
- TAS-115 exhibits promising antitumor activity, warranting further investigation in solid tumors.
