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Ref Type abstract
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
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...