TO-TAS-102-302

Taiho Oncology, Inc

101 Carnegie Center, Suite 101, Princeton, New Jersey, United States, NJ 08540

Simon Ruini, Associate Director, Regulatory Affairs, Taiho Pharma Europe, Ltd, +01 609 750 5300, SRuini@taiho.eu

Simon Ruini, Associate Director, Regulatory Affairs, Taiho Pharma Europe, Ltd, +01 609 750 5300, SRuini@taiho.eu

No

No

No

Final

28 Sep 2018

Yes

30 Apr 2018

Yes

19 Dec 2019

No

Overall survival (OS)

This study was designed and conducted in accordance with the Sponsor procedures, which comply with the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities and in accordance with the Declaration of Helsinki, ICH E6 Guideline for GCP, and local regulations. The protocol and amendments, Informed Consent Form (ICF), and the Investigator’s Brochure (IB) provided to the Investigators, and any other documents that pertained to patient information (eg, patient diaries), recruitment methods, and advertisements received Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval before the first patient was enrolled at the investigational site. When necessary, all protocol amendments and changes to the ICF were submitted by the Investigator to the IRB/IEC for approval. The Investigators notified the IRB/IEC of deviations from the protocol or serious adverse events occurring at the site according to local policies and IRB/IEC requirements, as well as other adverse event reports, in accordance with local procedures. The Investigator or a designee under the Investigator’s responsibility (according to applicable regulatory requirements) fully informed patients of all pertinent aspects of the clinical study. All participants were informed to the fullest extent possible about the study in a language and in terms they were able to understand. Prior to participation in the trial, the written ICF was signed and personally dated by the patient or by the patient’s legal representative and by the person who conducted the informed consent discussion. A copy of the signed and dated ICF was provided to the patient.

11 Feb 2016

Yes

Yes

Italy: 66

United States: 26

Turkey: 43

France: 24

Japan: 73

Israel: 12

Russian Federation: 46

Belarus: 30

Poland: 14

Portugal: 39

Romania: 8

Spain: 40

United Kingdom: 45

Belgium: 13

Czech Republic: 9

Germany: 11

Ireland: 8

507

277

0

0

0

0

0

0

279

159

69

Screening - Confirmation of Eligibility: 507

Baseline Period

Not applicable

TAS-102

FTD, F3TdR, F3dThd

5-TRIFLUOROTHYMIDINE

Film-coated tablet

Oral use

TAS-102 is formulated as an immediate-release film-coated tablet, which is supplied in 2 strengths: • The 15 mg white, round tablet • The 20 mg pale-red, round tablet The total dose is 70 mg/m2 milligram(s)/square meter, per day within 1 hour after completion of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest. This treatment cycle will be repeated every 4 weeks.

Treatment Period

Randomised - controlled

Eligible patients who met all of the inclusion and none of the exclusion criteria were centrally randomized (2:1) to TAS-102 plus BSC (experimental arm) or placebo plus BSC (control arm) using a dynamic allocation method (biased coin) via an Interactive Voice/Web Response System (IXRS). Randomization was stratified by: region (Rest of World (ROW) vs Japan); ECOG performance status (0 vs 1); and prior treatment with ramucirumab (yes vs no).

Yes

TAS-102

FTD, F3TdR, F3dThd

5-TRIFLUOROTHYMIDINE

Film-coated tablet

Oral use

TAS-102 is formulated as an immediate-release film-coated tablet, which is supplied in 2 strengths: • The 15 mg white, round tablet • The 20 mg pale-red, round tablet The total dose is 70 mg/m2 milligram(s)/square meter, per day within 1 hour after completion of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest. This treatment cycle will be repeated every 4 weeks.

TAS-102

FTD, F3TdR, F3dThd

5-TRIFLUOROTHYMIDINE

Film-coated tablet

Oral use

TAS-102 is formulated as an immediate-release film-coated tablet, which is supplied in 2 strengths: • The 15 mg white, round tablet • The 20 mg pale-red, round tablet The total dose is 70 mg/m2 milligram(s)/square meter, per day within 1 hour after completion of morning and evening meals, for 5 days a week with 2 days rest for 2 weeks, followed by a 14-day rest. This treatment cycle will be repeated every 4 weeks.

End of Treatment Period

Not applicable

No investigational medicinal product assigned in this arm

Baseline Period

Intention to treat (ITT)

ITT population - patients who were randomized

As Treated (AT) - TAS-102 + BSC

As Treated (AT) population for the TAS-102 + BSC group

As Treated (AT) - Placebo + BSC

As Treated population for the Placebo + BSC group

Baseline

TAS-102 plus BSC

Placebo plus BSC

End of Study

Intention to treat (ITT)

ITT population - patients who were randomized

As Treated (AT) - TAS-102 + BSC

As Treated (AT) population for the TAS-102 + BSC group

As Treated (AT) - Placebo + BSC

As Treated population for the Placebo + BSC group

Overall Survival (OS) was the primary endpoint of this study and was defined as the time from the date of randomization to the death date. In the absence of death confirmation or for patients alive on the survival cut-off date, survival was censored at the date of last study follow-up or the cut-off date, whichever was earlier.

Primary

The overall survival (OS) cut-off date used for the primary analysis was based on the survival data obtained through the date of the 384th death observed in the study (27 Mar 2018).

Overall Survival (OS) in the Intent to Treat (ITT) population will be compared between the 2 treatment groups using the stratified log-rank test.

TAS-102 plus BSC v Placebo plus BSC

507

Pre-specified

0.6917

2-sided

Standard deviation

Progression free survival was defined as the time from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause. Patients who were alive with no disease progression as of the analysis cut-off date were censored at the date of the last tumor assessment. Patients who received non-study cancer treatment before disease progression, or patients with clinical but not radiological evidence of progression was censored at the date of the last evaluable tumor assessment before the non-study cancer treatment was initiated.

Secondary

PFS was defined as the time from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause as of the pre-specified cut-off date of 31 Mar 2018 for non-survival data.

Progression-free survival (PFS) was defined as the time from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause as of the pre-specified cut-off date of 31 Mar 2018 for non-survival data.

TAS-102 plus BSC v Placebo plus BSC

507

Pre-specified

0.5723

2-sided

Standard deviation

Adverse Events (AE) were reported from the first dose of study medication through the period of patient follow-up (30 days after the last dose of study medication or until the start of new anti-tumor therapy, whichever was earlier).

All adverse event reporting were performed using the as-treated (AT) analysis population. The Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) terms was used to assess severity/provide the grade for each adverse event (AE) that was reported.

4.03

TAS-120 Population

Placebo Population