Reference Detail

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN inact mut	breast cancer	predicted - sensitive	TAS-117	Case Reports/Case Series	Actionable	In a Phase II trial, TAS-117 treatment demonstrated tolerability in patients with advanced solid tumors harboring germline inactivating PTEN mutations, and resulted in an unconfirmed partial response in one patient with breast cancer and target tumor lesion shrinkage of approximately 15% and stable disease lasting more than 8 months in another breast cancer patient (Ann Oncol (2022) 33 (suppl_7): S754-S755; NCT04770246).	detail...