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Ref Type abstract
PMID
Authors J. Rodon, H. Arkenau, P. Funchain, A. Hervieu, L. Gao, M. Liu, A. Halim, M. Mina, O. Takahashi, K. Benhadji, S. Delaloge
Title 467P - Dose escalation of TAS-117 in patients with advanced solid tumors
Journal Vol Issue Date Pages Journal Short Title
Ann Oncol 33 suppl_7 2022
URL https://www.annalsofoncology.org/article/S0923-7534(22)02447-4/fulltext
Abstract Text Background TAS-117, a non–ATP-competitive allosteric AKT inhibitor, was previously explored in a Japanese phase I study. We report preliminary results in a phase II study (NCT04770246) of TAS-117 in Western patients (pts) with advanced solid tumors harboring germline PTEN-inactivating mutations. Methods In the dose escalation portion of this open-label, single-arm, 2-part study, the primary objectives were to evaluate safety/tolerability and determine maximum tolerated dose/recommended phase II dose (RP2D). Pts had advanced/metastatic solid tumors with germline PTEN-inactivating mutations and progression on standard therapy. A 3+3 design was used to determine RP2D for once daily (QD) and intermittent dosing (ID; 4 days on/3 days off). Starting dosage was 16 mg/day (QD) or 24 mg/day (ID); dosages were increased by 4 mg/day up to 24 mg/day and 32 mg/day, respectively. Toxicities were graded using CTCAE v5.0. In addition to pharmacokinetics, AKT/pAKT and PRAS/pPRAS were assessed in circulating platelets via immunofluorescence assays as pharmacodynamic (PD) biomarkers. Results Eligible pts (N=16; median age, 54 y; range, 23–82 y) received either the QD (n=9; 16 mg, n=3 and 20 mg, n=6) or ID (n=7; 24 mg, n=4 and 28 mg, n=3). Dose-limiting toxicities were observed (n=3): 1 at 20 mg QD (febrile neutropenia) and 2 at 28 mg ID (grade 3 oral mucositis). Twelve pts (75%) had treatment-related adverse events (TRAEs; none grade 5). The most frequent TRAEs (>10%) were rash (56%), fatigue (38%), hyperglycemia, pruritus (31%), diarrhea, stomatitis, decreased appetite (19%), nausea, hypophosphatemia, dry skin, and maculopapular rash (13%). Grade 3–4 serious TRAEs were neutropenic infection, hyperglycemia, and type 2 diabetes (6%). Unconfirmed partial response was observed in 1 pt with breast cancer; 6 pts had stable disease. A pt with breast cancer had stable disease of >8 months associated with a target lesion tumor shrinkage of ≈15%. Approximate dose-proportional exposure increase was observed within the studied dose range. Preliminary PD analysis showed pAKT decrease >50% in 7 of 8 pts and pPRAS decrease >50% in 5 of 7 pts. RP2D was defined as 16 mg QD. Conclusions TAS-117 showed tolerable toxicity; durable clinical benefit associated with tumor shrinkage was observed in 1 pt. This phase II study is ongoing.

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