Study of TAS-102 or Placebo Plus BSC in Patients With Metastatic Gastric Cancer

• ClinicalTrials.gov Identifier: NCT02500043
• Recruitment Status: Completed
• First Posted: July 16, 2015
• Results First Posted: September 16, 2021
• Last Update Posted: September 16, 2021
• Sponsor: Taiho Oncology, Inc.
• Information provided by (Responsible Party): Taiho Oncology, Inc.

Tracking Information

• First Submitted Date: July 13, 2015
• First Posted Date: July 16, 2015
• Results First Submitted Date: July 2, 2021
• Results First Posted Date: September 16, 2021
• Last Update Posted Date: September 16, 2021
• Actual Study Start Date: February 24, 2016
• Actual Primary Completion Date: April 30, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2021)

Overall Survival (OS) [ Time Frame: From the date of randomization to the data cut-off date (maximum duration: up to approximately 46 months) ]

OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death were censored at last follow-up or cut-off date, whichever comes first. OS was estimated by Kaplan-Meier method.

Original Primary Outcome Measures (submitted: July 14, 2015)

Overall Survival [ Time Frame: Up to 3 years ]

OS is defined as the time from the date of randomization to the date of death.

Current Secondary Outcome Measures (submitted: August 19, 2021)

• Progression-Free Survival (PFS) [ Time Frame: From the date of randomization to the cut-off date (maximum duration: up to approximately 46 months) ]
  PFS was defined as the time from randomization until the date of first occurrence of investigator-assessed radiological disease progression or death due to any cause, whichever came first. Disease progression as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) for target lesions were defined as target lesions with at least 20 % relative increase in the sum of diameters with reference to the smallest sum on study, including the baseline sum and this sum demonstrated an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions or Unequivocal progression of existing non-target lesions. All alive participants with no disease progression as of the analysis cut-off date were censored at the last tumor assessment. PFS was estimated by Kaplan-Meier method.
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE) [ Time Frame: From the first dose of study treatment until 30 days after the last dose of study treatment (maximum duration: up to approximately 46 months) ]
  Any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study medication was considered an adverse event (AE). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs/TESAEs were defined as events that started on or after treatment or started before treatment and worsened after the start of treatment through 30 days after the last dose of study treatment.

Original Secondary Outcome Measures (submitted: July 14, 2015)

• Progression-Free Survival (PFS) [ Time Frame: Up to 3 years ]
  PFS is defined as the time from the date of randomization until radiological disease progression or death due to any cause.
• Safety and Tolerability [ Time Frame: Up to 3 years ]
  Safety and Tolerability is defined as AEs graded using NCI criteria for AEs (CTCAE).

Current Other Pre-specified Outcome Measures (submitted: August 19, 2021)

• Overall Response Rate (ORR) [ Time Frame: From the date of randomization to the cut-off date (maximum duration: up to approximately 46 months), assessed every 8 weeks ]
  Overall response rate was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR). CR was defined as the disappearance of all target or non-target lesions. Any pathological lymph nodes for target lesions or all lymph nodes for non-target lesions were non-pathological morphologically that was reduced in size in short axis to < 10 mm. PR was defined as target lesions with at least 30% decrease in the sum of diameters, taking baseline sum diameters as reference.
• Disease Control Rate (DCR) [ Time Frame: From the date of randomization to the cut-off date (maximum duration: up to approximately 46 months), assessed every 8 weeks ]
  DCR was defined as the proportion of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD). The assessment of DCR was based on Investigator review of radiologic images and following RECIST criteria (version 1.1, 2009).
• Time to Deterioration of European Cooperative Oncology Group (ECOG) Performance Status Score From Baseline [ Time Frame: At the time of randomization (Day 1 Cycle 1) and within 24 hours prior to start of study treatment in every cycle (maximum duration: up to approximately 46 months) ]
  The ECOG performance status was used to evaluate participant's disease progression and the effect of the disease on the participant's activities of daily living. It ranges on the scale from 0-5 (0 = normal activity; 1= symptoms but ambulatory; 2= in bed for < 50% of the time; 3= in bed for > 50% of the time; 4= 100% bedridden; 5= dead). Time to definitive deterioration in ECOG performance status score from baseline was defined as a change from 0, 1 to >=2, or from 2 to >=3.
• Change From Baseline in Quality of Life European Organization for Research and Treatment for Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30 Score): Global Health Status [ Time Frame: Baseline, Day 1 Cycle 2 up to end of treatment (EOT) (within 30 days of last study treatment) and 30-Day safety follow-up visit (maximum duration: up to approximately 46 months) ]
  EORTC-QLQ-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. First 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical,role,emotional,cognitive,social), 3 symptom scales (fatigue,nausea/vomiting,pain) and other single items. For each item,high score represented high level of symptomatology/problem. Last 2 questions represented participant's assessment of overall health and QoL, coded on 7-point scale (1=very poor to 7=excellent). EORTC QLQ-C30 observed values and change from baseline for global health status (scoring of questions 29 and 30) and 5 functional scales, 3 symptom scales and other single items (scoring of questions 1 to 28). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best QoL for participant.
• EORTC Quality of Life Questionnaire - Gastric-specific Module (EORTC QLQ-STO22): Percentage of Participants With Overall Compliance [ Time Frame: Baseline, Cycle 1 Day 1 up to end of treatment (EOT) (within 30 days of last study treatment) (maximum duration: up to approximately 46 months) ]
  The Quality of Life Questionnaire Stomach Cancer Module 22 (QLQ-STO22) assessed symptoms and treatment-related side effects commonly reported in participants. There are 22 questions which comprise 5 scales (dysphagia, dietary restrictions, pain QS22, reflux, and anxiety) and 4 single items (dry mouth, hair loss, taste problems, body image). Most questions use 4-point scale (1='Not at all', 2=a little, 3=quite a bit and 4='Very much'). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100, where higher score=better level of functioning or greater degree of symptoms.

Original Other Pre-specified Outcome Measures (submitted: July 14, 2015)

• Overall Response Rate (ORR) [ Time Frame: Up to 3 years ]
  ORR is defined as the proportion of patients with objective evidence of complete response or partial response.
• Disease Control Rate (DCR) [ Time Frame: Up to 3 years ]
  DCR is defined as the proportion of patients with objective evidence of complete response, partial response or SD.
• Time to Deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status to Score of 2 or Higher [ Time Frame: Up to 3 years ]
  The time to deterioration of ECOG performance status is defined as the time from randomization to the first date on which an ECOG performance status score of 2 or higher is observed.
• Quality of Life [ Time Frame: Up to 3 years ]
  Quality of life is defined as an assessment for health-related quality of life of cancer patients.

Descriptive Information

• Brief Title: Study of TAS-102 or Placebo Plus BSC in Patients With Metastatic Gastric Cancer
• Official Title: Randomized, Double-blind, Phase 3 Study Evaluating TAS-102 Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Patients With Metastatic Gastric Cancer Refractory to Standard Treatments
• Brief Summary: The purpose of this trial is to compare the effects of TAS-102 and best supportive care (BSC) with Placebo (an inactive drug) and best supportive care on metastatic gastric cancer.
• Detailed Description: This is a multinational, double-blind, two-arm, parallel, randomized, Phase 3 study evaluating the efficacy and safety of TAS-102 plus BSC versus placebo plus BSC in participants with metastatic gastric cancer who have previously received at least 2 prior regimens for advanced disease. Eligible participants will be centrally randomized (2:1) to TAS-102 + BSC (experimental arm) or placebo + BSC (control arm).
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Refractory Metastatic Gastric Cancer

Intervention

• Drug: TAS-102
  35 mg/m2/dose of TAS-102 orally, twice daily on days 1-5 and days 8-12 of each 28-day cycle.
• Drug: Placebo
  35 mg/m2/dose of placebo orally, twice daily on days 1-5 and days 8-12 of each 28-day cycle.

Study Arms

• Experimental: TAS-102+BSC
  Participants received 35 milligrams per meter square (mg/m^2) of TAS-102 tablets orally twice daily (BID) for 5 days per week (i.e., from Days 1 to 5 and Days 8 to 12) for 2 weeks followed by 14 days rest in each 28-day cycle along with BSC until a discontinuation criterion (participant withdrawal, disease progression, irreversible treatment-related Grade 4 non-hematologic event, physician's decision, pregnancy or death) was met.
  Intervention: Drug: TAS-102
• Experimental: Placebo+BSC
  Participants received 35 mg/m^2 of matching placebo for TAS-102 tablets orally BID for 5 days per week (i.e., from Days 1 to 5 and Days 8 to 12) for 2 weeks followed by 14 days rest in each 28-day cycle along with BSC until discontinuation criterion (participant withdrawal, disease progression, irreversible treatment-related Grade 4 non-hematologic event, physician's decision, pregnancy or death) was met.
  Intervention: Drug: Placebo

Publications *

• Tabernero J, Alsina M, Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Ando T, Yalcin S, Van Cutsem E, Sabater J, Skanji D, Leger C, Amellal N, Ilson DH. Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS. Gastric Cancer. 2020 Jul;23(4):689-698. doi: 10.1007/s10120-020-01053-9. Epub 2020 Mar 4.
• Ilson DH, Tabernero J, Prokharau A, Arkenau HT, Ghidini M, Fujitani K, Van Cutsem E, Thuss-Patience P, Beretta GD, Mansoor W, Zhavrid E, Alsina M, George B, Catenacci D, McGuigan S, Makris L, Doi T, Shitara K. Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy: Subgroup Analyses of a Randomized Clinical Trial. JAMA Oncol. 2020 Jan 1;6(1):e193531. doi: 10.1001/jamaoncol.2019.3531. Epub 2020 Jan 9.
• Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalcin S, Fujitani K, Beretta GD, Cutsem EV, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1437-1448. doi: 10.1016/S1470-2045(18)30739-3. Epub 2018 Oct 21. Erratum In: Lancet Oncol. 2018 Dec;19(12):e668.
• Bando H, Doi T, Muro K, Yasui H, Nishina T, Yamaguchi K, Takahashi S, Nomura S, Kuno H, Shitara K, Sato A, Ohtsu A. A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201). Eur J Cancer. 2016 Jul;62:46-53. doi: 10.1016/j.ejca.2016.04.009. Epub 2016 May 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 19, 2021): 507
• Original Estimated Enrollment (submitted: July 14, 2015): 500
• Actual Study Completion Date: December 19, 2019
• Actual Primary Completion Date: April 30, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Has histologically confirmed non-resectable, metastatic gastric adenocarcinoma including adenocarcinoma of the gastroesophageal junction.
2. Has previously received at least 2 prior regimens for advanced disease and were refractory to or unable to tolerate their last prior therapy.
3. Has measureable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
4. Is able to take medications orally (ie, no feeding tube).
5. Has an Eastern Cooperative Oncology Group performance status of 0 or 1.
6. Has adequate organ function as defined by protocol defined labs.
7. Women of childbearing potential must have a negative pregnancy test and must agree to adequate birth control if conception is possible. Males must agree to adequate birth control.

Exclusion Criteria:

1. Has certain serious illnesses or medical conditions
2. Has had certain other recent treatment e.g. major surgery, anticancer therapy, extended field radiation, received investigational agent within the specified time frames prior to study drug administration.
3. Has previously received TAS-102.
4. Has unresolved toxicity of greater than or equal to Common Terminology Criteria for Adverse Events Grade 2 attributed to any prior therapies.
5. Is a pregnant or lactating female.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, Belgium, Canada, Czechia, France, Germany, Ireland, Israel, Italy, Japan, Poland, Portugal, Romania, Russian Federation, Spain, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02500043
• Other Study ID Numbers: TO-TAS-102-302; 2015-002683-16 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Taiho Oncology, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Taiho Oncology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Taiho Oncology, Inc.
• Verification Date: August 2021