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A Phase I, Dose Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of TAS-115 in Patients with Advanced Solid Tumors.

Phase I Study of TAS-115 in Patients with Advanced Solid Tumors

84

A total of 84 patients were enrolled. [Step 1] The median age of the population was 64 years, and approximately 70% of the patients were male. [Step 2 + Expand cohort] The median age of the population was 51 years, and approximately two-thirds of the patients were male.

[Step 1] Enrolled: 23 Treated: 21 Completed: 21 [Step 2] Enrolled: 6 Treated: 6 Completed: 6 [Expand cohort] Enrolled: 55 Treated: 55 Completed: 55

Analysis Population: As-treated population The most common TRAEs included laboratory abnormalities, gastrointestinal symptoms, general disorders, and skin disorders. [Step 1: 21 patients] All the patients developed some kind of TRAE. The incidence of Grade 3 or higher TRAEs was 61.9%. TRAEs (>= 40%) - AST increased (71.4%) - Rash (57.1%) - ALT increased (52.4%) - Fatigue (47.6%) Grade 3 or higher TRAEs (>= 10%) - Lipase increased and hypophosphataemia (23.8%) - Amylase increased and neutropenia (14.3%) [Step 2 + Expand cohort: 61 patients] Sixty patients developed some kind of TRAE. The incidence of Grade 3 or higher TRAEs was 77.0%. TRAEs (>= 30%) - AST increased (50.8%) - Fatigue (44.3%) - Nausea and decreased appetite (42.6%) - ALT increased (37.7%) - Neutropenia and anemia (34.4%) - Hypophosphataemia (32.8%) - Vomiting and thrombocytopenia (31.1%) Grade 3 or higher TRAEs (>= 10%) - Neutropenia (24.6%) - Hypophosphataemia (21.3%) - Thrombocytopenia and anemia (14.8%) - Leukopenia (11.5%) Serious TEAEs were reported in 40 patients (Step 1:7, Step 2:2, Expand cohort:31). Serious TRAEs - Part 1: tumor hemorrhage and decreased appetite (1 patient each; 650 mg), thrombocytopenia (1 patient; 800 mg) - Part 2: peritonitis (1 patient) - Expansion part: Decreased appetite (3 patients), nausea (2 patients), interstitial lung disease, rash, enterocolitis, fatigue, thrombocytopenia, and pyrexia (1 patient each) AEs resulting in death were hepatic failure, disease progression, and respiratory failure in 1 patient each in the expansion part (650 mg); these were not considered related to TAS-115.

Primary outcome measures (Analysis population: DLT Evaluable Patients) Development of DLT: In Step 1, the MTD was determined to be 650 mg/day. In Step 2 and the Expand cohort, TAS-115 was administered at 650 mg/day or 450 mg/day SID in CRPC patients with 5-day on and 2-day off, and both doses were shown to be safe and tolerable. For solid tumors excluding prostate cancer, the recommended dose and dosing method of TAS-115 were determined to be 650 mg/day SID with 5-day on and 2-day off administration (between meals).

Secondary outcome measures 1. Safety (Analysis population: All Treated Patients) The incidence of adverse events is described in the Adverse events section. 2. Efficacy (Analysis population: PPS 82 patients) Overall Response: No patients showed partial response (PR) or complete response (CR) as the best overall response, while 31 patients exhibited stable disease (SD). Among them, 17 patients maintained SD for more than 12 weeks. Four patients who were determined to have progressive disease (PD) showed minor tumor shrinkage of target lesions. BSI Response Rate in Patients with Bone Lesions: 14 patients (56.0%) showed a BSI response. The primary cancer types of the responders were osteosarcoma (6 patients), prostate cancer (5 patients), epithelioid sarcoma (1 patient), clear cell sarcoma (1 patient), and breast cancer (1 patient). 3. Pharmacokinetic (Analysis population: Step 1:21 patients, Step 2:6 patients) TAS-115 was quickly absorbed after oral administration, reaching Tmax within 1.0 to 2.0 hours. After a single dose, AUC0-24 increased proportionally with doses ranging from 200 mg to 650 mg, but no further increase was observed between 650 mg and 800 mg due to significant inter-patient variability and the small difference in doses. Cmax and AUC0-24 were compared between the first day of the repeated-dose period and the time during the repeated-dose period at Step 1 and Step 2, which suggested that the repeated doses of 450, 650, and 800 mg/day would not markedly affect the pharmacokinetic parameters. Effect of Food (Analysis population: the first 6 patients in Expand) The estimated geometric mean ratios (90% CI) of Cmax and AUC0-24 under fed conditions compared to empty stomach conditions was 0.545 (0.243-1.224) and 0.812 (0.414-1.593), respectively, indicating no statistically significant difference.

The tolerability of TAS-115 administered once daily at 200-650 mg, and the safety and tolerability of 650 mg in a 5-day on, 2-day off schedule, were confirmed in patients with solid tumors. The MTD was determined to be 650 mg/day. To improve treatment continuity, the safety and efficacy of 650 mg/day (450 mg/day in CRPC patients) were further confirmed using the once-daily 5-on/2-off regimen from Step 2 in the Expand cohort. Consequently, the recommended dose for solid tumors (excluding prostate cancer) was

Dec. 10, 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC7340670/pdf/10637_2019_Article_859.pdf

No

Data will not be shared according to the Sponsor policy on data sharing. Taiho policy on data sharing may be found at https://www.taiho.co.jp/en/science/policy/clinical_trial_information_disclosure_policy/index.html.

Motoo Yoshiharu

Fukui-ken Saiseikai Hospital

Funabashi 7-1, Wadanaka-cho, Fukui City, Fukui

toiawaseCD1@taiho.co.jp

Taiho Pharmaceutical Co., Ltd.

1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo

+81-3-3293-2113

toiawase@taiho.co.jp

completed

Dec. 03, 2013

Interventional

Open-label, multi-center, phase I study

treatment purpose

1

- Signed, written informed consent.
- Histologically or cytologically confirmed solid tumor.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

- Investigational drug therapy within 28 days prior to enrollment.
- Radiotherapy within 21 days prior to enrollment.
- Received extensive radiotherapy on more than 30% of bone marrow within one year.
- Females who are pregnant or breastfeeding.
- Serious complications.

Both

Patients with advanced solid tumor

investigational material(s)
Generic name etc : TAS-115
INN of investigational material : pamufetinib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : The starting dose of TAS-115 will be 200 mg/body/day given orally, either once daily or 5 days on 2 days off, in patients with advanced solid tumors.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

safety
Safety
CTCAE (ver.4.03)

efficacy
pharmacokinetics
Pharmacokinetics, Efficacy
RECIST (ver.1.1)

Oct. 23, 2013