臨床研究等提出・公開システム

A Phase I, Dose Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of TAS-116 in Patients with Advanced Solid Tumors.

Phase I Study of TAS-116 in Patients with Advanced Solid Tumors

61

The median age was 55.5 years (range, 34 to 74) in step 1 dose escalation, 61.0 years (range, 40 to 73) in step 1 expansion, 54.5 years (range, 34 to 72) in step 2 dose escalation, and 56.0 years (range, 40 to 75) in step 2 expansion. The main type of cancer of the enrolled patients were non-small cell lung cancer, gastrointestinal stromal tumor, pancreas cancer, biliary tract cancer, thymic cancer, and cancer of unknown primary.

Between March 31, 2014 and February 7, 2017, 61 patients were enrolled into the dose escalation (n = 36) and expansion (n = 25) phases and received at least one dose of TAS-116. Sixty patients were evaluable for efficacy; 1 patient was excluded from the efficacy analysis due to prohibited concomitant medication usage. Six UK patients were enrolled in the step 1 expansion phase.

The most frequently reported treatment-related Adverse events (AEs) (25% or more) were diarrhea (83.6%), creatinine increased (55.7%), anorexia (50.8%), nausea (42.6%), eye disorders (32.8%), aspartate aminotransferase (AST) increased (32.8%), alanine aminotransferase (ALT) increased (29.5%), and fatigue (29.5%). Eye disorders were mainly night blindness (n = 13), blurred vision (n = 3), and visual impairment (n = 3). Eye disorders grade 2 or more, the AE of special interest in this study, occurred in the dose escalation phases at the maximum tolerated dose (MTD) and maximum administered dose (MAD) on the once daily (QD) schedule, and maximum administered dose (MAD) on the every other day (QOD) schedule. However, with modified QD (5 days on/2 days off per week, QD x 5) and at the MTD in the QOD schedule, eye disorders were limited to grade 1. Except for macular edema found on ophthalmological examination in 1 patient, eye disorders were found on physical examination by the investigators. All eye disorders were reversible with interruption or discontinuation of TAS-116 treatment. Thirteen treatment-related serious AEs (SAE) were observed in 6 patients (9.8%). Those observed in step 1 were pulmonary embolism (n = 1) and interstitial lung disease (n = 1) at level 5 (76.8 mg/m2), and AST/ALT/gamma-glutamyltransferase (gamma-GTP) increased (n = 1) and visual impairment (n = 1) at level 7 (150.5 mg/m2). Those observed in step 2 were septic shock, respiratory failure, pneumonia, neutrophil count decrease, and PLT count decrease in 1 patient at level 4 (295.0 mg/m2), and dehydration and enterocolitis infectious in 1 patient in the expansion phase (340 mg/body). All treatment-related SAEs recovered or resolved after interruption, dose reduction, or discontinuation of TAS-116 treatment. No treatment-related deaths were reported.

TAS-116 was escalated from 4.8 to 150.5 mg/m2/day once daily (QD) in step 1, and from 107.5 to 295.0 mg/m2/day QOD in step 2. The MTDs were 107.5 mg/m2/day for QD and 210.7 mg/m2/day for QOD. The doses of the expansion phases were determined to be a flat-dose of the MTD, that is, 160 mg/body/day for QD x 5 in step 1 and 340 mg/body/day for QOD in step 2. In step 1 (QD), Dose limiting toxicities (DLTs) were observed in 3 patients at level 7 (150.5 mg/m2) with grade 3 night blindness, grade 3 visual impairment, and grade 3 AST/ALT/gamma-GTP increased and in 1 patient at level 6 (107.5 mg/m2) with grade 3 anorexia. In step 2 (QOD), DLTs were observed in 2 patients at level 4 (295.0 mg/m2). Grade 3 PLT count decreased was observed in 1 patient. Grade 4 septic shock, grade 4 respiratory failure, grade 4 pneumonia, and grade 3 febrile neutropenia were observed in another patient. As a result, the MTD was determined at 107.5 mg/m2/day (level 6) for QD and 210.7 mg/m2/day (level 3) for QOD.

Confirmed durable partial responses (PR) by RECIST were observed in 3 patients [two patients with non-small cell lung cancer (NSCLC) and one patient with gastrointestinal stromal tumor]. Disease control rate (DCR) including PR and stable disease (SD) 12 weeks or more were 27% (16/60 patients). Response durations of three patients with PR were 173 days in NSCLC without detectable EGFR and ALK mutations (107.5 mg/m2 QD), 463 days (at the time of data cutoff) in NSCLC with an EGFR exon 19 deletion mutation (150.5 mg/m2 QOD), and 239 days in gastrointestinal stromal tumor without a detectable KIT mutation (150.5 mg/m2 QD, one dose level higher than the MTD, who continued on TAS-116 treatment for more than 6 months after dose reduction to the MTD).

Three oral dosing schedules, QD, QD x 5, and QOD of TAS-116 were evaluated in this first in human phase 1 study, and dosing regimens were identified for further development with promising preliminary clinical activities and safety profiles.

Jan. 24, 2019

https://mct.aacrjournals.org/content/18/3/531.long

Undecided

https://www.clinicaltrials.jp/file/keRxcJUXc

Taiho Pharmaceutical Co., Ltd.

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toiawaseCD1@taiho.co.jp

Taiho Pharmaceutical Co., Ltd.

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toiawase@taiho.co.jp

completed

Mar. 31, 2014

Interventional

Open-label, 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 21 days prior to enrollment.
- Radiotherapy within 21 days prior to enrollment.
- Received extensive prior radiotherapy on more than 30% of bone marrow.
- Females who are pregnant or breastfeeding.
- Serious complications.

Both

Patients with advanced solid tumor

investigational material(s)
Generic name etc : TAS-116
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : The starting dose of TAS-116 will be 4.8 mg/m2 given orally, either once or other, in patients with advanced solid tumors.

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

safety
Safety
CTCAE (ver.4.03)

efficacy
pharmacokinetics
Pharmacokinetics, Efficacy
RECIST (ver.1.1)

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Sept. 09, 2015