ToGA Study - A Study of Herceptin (Trastuzumab) in Combination With Chemotherapy Compared With Chemotherapy Alone in Patients With HER2-Positive Advanced Gastric Cancer

A Randomized, Open-label Study of the Effect of First-line Herceptin in Combination With a Fluoropyrimidine and Cisplatin Versus Chemotherapy Alone on Overall Survival in Patients With HER2-positive Advanced Gastric Cancer

This parallel, randomized, open-label, multi-centre study will evaluate the effect on overall survival of trastuzumab (Herceptin) in combination with a chemotherapy compared to the chemotherapy alone in patients with HER2-positive advanced gastric cancer. Trastuzumab (Herceptin) will be administered as intravenous infusion of 6 mg/kg (loading dose 8 mg/kg) every 3 weeks. The chemotherapy consists of a combination of 6 cycles of fluorouracil (800 mg/m2/day intravenous infusion every 3 weeks) and cisplatin (80 mg/m2 intravenous infusion every 3 weeks), or capecitabine (Xeloda, 1000 mg/m2 po twice daily for 14 days every 3 weeks) and cisplatin (80 mg/m2 intravenous infusion every 3 weeks). Treatment with trastuzumab (Herceptin) will continue until disease progression. The target sample size is 300-600 patients.

Study Overview

• Status: Completed
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: Trastuzumab; Drug: Fluorouracil; Drug: Cisplatin; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Actual): 584
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5011
  • Kurralta Park, Australia, 5037
  • Melbourne, Australia, 3128
  • Milton, Australia, 4064
  • Perth, Australia, 6008
  • Sydney, Australia, 2217
• Belgium
  • Leuven, Belgium, 3000
• Brazil
  • Barretos, Brazil, 14784-400
  • Rio de Janeiro, Brazil, 20231-050
  • Sao Paulo, Brazil, 05403-010
  • Sao Paulo, Brazil, 04023-900
• China
  • Beijing, China, 100021
  • Beijing, China, 100071
  • Beijing, China, 100853
  • Beijing, China, 100036
  • Guangdong, China, 510515
  • Guangzhou, China, 510060
  • Jiangsu, China, 210009
  • Nanjing, China, 210002
  • Shanghai, China, 200032
  • Shanghai, China, 200025
  • Shanghai, China, 200433
  • Shanghai, China, 200080
  • Shanghai, China, 200003
  • Shanghai, China, 200092
  • Suzhou, China, 215006
  • Wuhan, China, 430030
• Costa Rica
  • San Jose, Costa Rica, 10103
  • San José, Costa Rica
• Denmark
  • Herlev, Denmark, 2730
  • Odense, Denmark, 5000
• Finland
  • Tampere, Finland, 33520
• France
  • Brest, France, 29609
  • Caen, France, 14076
  • Colmar, France, 68024
  • Lille, France, 59020
  • Marseille, France, 13273
  • Reims, France, 51092
  • Rouen, France, 76031
  • Strasbourg, France, 67098
• Germany
  • Heidelberg, Germany, 69120
  • Mainz, Germany, 55101
  • München, Germany, 81675
  • Trier, Germany, 54290
  • Witten, Germany, 58455
• Guatemala
  • Guatemala City, Guatemala, 01015
• India
  • Hyderabad, India, 500 033
  • Kochi, India, 682304
  • Mumbai, India, 400026
  • New Delhi, India, 110 029
• Italy
  • Ancona, Italy, 60121
  • Firenze, Italy, 50139
  • Napoli, Italy, 80131
  • Parma, Italy, 43100
  • Roma, Italy, 00168
  • Udine, Italy, 33100
• Japan
  • Aichi, Japan, 464-8681
  • Chiba, Japan, 277-8577
  • Ehime, Japan, 791-0280
  • Fukuoka, Japan, 812-8582
  • Hyogo, Japan, 650-0017
  • Nagano, Japan, 384-0392
  • Osaka, Japan, 569-8686
  • Osaka, Japan, 589-8511
  • Saitama, Japan, 350-1298
  • Saitama, Japan, 362-0806
  • Shizuoka, Japan, 411-8777
  • Tochigi, Japan, 320-0834
  • Tokyo, Japan, 113-8677
  • Tokyo, Japan, 135-8550
  • Tokyo, Japan, 135-8577
  • Yamagata, Japan, 990-8520
• Korea, Republic of
  • Buchun, Korea, Republic of, 420-021
  • Bundang City, Korea, Republic of, 463-802
  • Daegu, Korea, Republic of, 702-210
  • Goyang-si, Korea, Republic of, 410-769
  • Pusan, Korea, Republic of, 602-715
  • Seoul, Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
  • Seoul, Korea, Republic of, 110-744
  • Seoul, Korea, Republic of, 120-752
  • Seoul, Korea, Republic of, 135-720
  • Seoul, Korea, Republic of, 135-170
• Mexico
  • Guadalajara, Mexico, 44280
  • Merida, Mexico, 97500
  • Mexico City, Mexico, 14000
  • Mexico City, Mexico, 06760
  • Monterrey, Mexico, 64020
• Panama
  • Panama City, Panama
• Peru
  • Callao, Peru
  • Lima, Peru, 11
  • Lima, Peru, 18
• Portugal
  • Braga, Portugal, 4700
  • Coimbra, Portugal, 3000-075
  • Faro, Portugal, 8000
  • Guimaraes, Portugal, 4810-055
  • Lisboa, Portugal, 1649-035
  • Lisboa, Portugal, 1099-023
  • Porto, Portugal, 4200-319
  • Porto, Portugal, 4099-001
  • Porto, Portugal, 4200-072
• Russian Federation
  • Chelyabinsk, Russian Federation, 454 087
  • Ekaterinburg, Russian Federation, 620905
  • Ivanovo, Russian Federation, 153040
  • Kazan, Russian Federation, 420029
  • Moscow, Russian Federation, 125284
  • Moscow, Russian Federation, 115478
  • Moscow, Russian Federation, 129128
  • Moscow, Russian Federation, 117837
  • Ryazan, Russian Federation, 390011
  • Samara, Russian Federation, 443031
  • St Petersburg, Russian Federation, 197022
  • St Petersburg, Russian Federation, 195067
  • St Petersburg, Russian Federation, 197758
  • UFA, Russian Federation, 450054
  • Yaroslavl, Russian Federation, 150054
• South Africa
  • Cape Town, South Africa, 1925
  • Cape Town, South Africa, 7506
  • Durban, South Africa, 4091
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08907
  • Barcelona, Spain, 08041
  • Girona, Spain, 17007
  • Madrid, Spain, 28041
  • Valencia, Spain, 46009
  • Valencia, Spain, 41014
• Taiwan
  • Changhua, Taiwan, 500
  • Kaohsiung, Taiwan, 807
  • Taipei, Taiwan, 00112
• Turkey
  • Istanbul, Turkey
  • Istanbul, Turkey, 34300
  • Izmir, Turkey, 35100
  • Izmir, Turkey, 35340
  • Shhiye, Ankara, Turkey, 06100
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
  • Denbigh, United Kingdom, LL18 5UJ
  • Dundee, United Kingdom, DD1 9SY
  • Glasgow, United Kingdom, G12 0YN
  • Manchester, United Kingdom, M2O 4BX
  • Weston Super Mare, United Kingdom, BS23 4TQ
  • Wirral, United Kingdom, CH63 4JY
  • Wolverhampton, United Kingdom, WV10 0QP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients >=18 years of age
• Inoperable locally advanced, recurrent, and/or metastatic cancer of the stomach or gastro-esophageal junction
• Adenocarcinoma
• HER2-positive tumors

Exclusion Criteria:

• Previous chemotherapy for advanced/metastatic disease
• Lack of physical integrity of the upper gastrointestinal tract, or malabsorption syndrome
• History of cardiac disease
• Dyspnoea at rest, due to complications of advanced malignancy or other disease, or patients who require supportive oxygen therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab, Fluoropyrimidine, Cisplatin; Participants received an initial loading dose of 8 milligrams per kilogram (mg/kg) trastuzumab i.v. on Day 1 of cycle, followed by 6 mg/kg i.v. every 3 weeks until disease progression; 800 mg/m2 fluorouracil i.v. on Days 1 through 5 of cycle every 3 weeks for 6 cycles; 80 mg/m2 cisplatin i.v. on Day 1 of cycle every 3 weeks for 6 cycles; and 1000 mg/m2 capecitabine p.o. twice daily on Days 1 through 15 of cycle every 3 weeks for 6 cycles.	Drug: Trastuzumab; Initial loading dose 8 mg/kg i.v. infusion on Day 1 of cycle, followed by 6 mg/kg i.v. infusion every 3 weeks until disease progression; Other Names: Herceptin; Drug: Fluorouracil; 800 mg/m2 i.v. infusion on Days 1 through 5 of cycle every 3 weeks for 6 cycles; Other Names: 5-FU; Drug: Cisplatin; 80 mg/m2 i.v. infusion on Day 1 of cycle every 3 weeks for 6 cycles; Drug: Capecitabine; 1000 mg/m2 p.o. twice daily on Days 1 through 15 of cycle every 3 weeks for 6 cycles; Other Names: Xeloda
Active Comparator: Fluoropyrimidine, Cisplatin; Participants received 800 milligrams per square meter (mg/m2) fluorouracil intravenous (i.v.) on Days 1 through 5 of cycle every 3 weeks for 6 cycles; 80 mg/m2 cisplatin i.v. on Day 1 of cycle every 3 weeks for 6 cycles; and 1000 mg/m2 capecitabine orally (p.o.) twice daily on Days 1 through 15 of cycle every 3 weeks for 6 cycles.	Drug: Fluorouracil; 800 mg/m2 i.v. infusion on Days 1 through 5 of cycle every 3 weeks for 6 cycles; Other Names: 5-FU; Drug: Cisplatin; 80 mg/m2 i.v. infusion on Day 1 of cycle every 3 weeks for 6 cycles; Drug: Capecitabine; 1000 mg/m2 p.o. twice daily on Days 1 through 15 of cycle every 3 weeks for 6 cycles; Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) - Percentage of Participants With an Event	OS was defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up.	Baseline (BL), Days 1, 8, 15, 22, 43, 64, 85, 106, 127, and every 21 days until the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Overall Survival - Time to Event	The median time, in months, from the date of randomization to the date of an OS event. Participants were censored at the last date tumor measurement, the last date in the study drug log, or the date of last follow-up.	BL, Days 1, 8, 15, 22, 43, 64, 85, 106, 127, and every 21 days until the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) - Percentage of Participants With an Event	PFS was defined as the time from the date of randomization to the date of the first documentation of progressive disease (PD) or date of death, whichever occurs first. For target lesions (TL), PD was defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD) of TLs, taking as a reference the smallest SLD recorded since the treatment started, or the appearance of one or more lesions. For non-target lesions (NTL), PD was defined as an unequivocal progression of existing NTLs. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Progression-Free Survival - Time to Event	The median time, in months, from the date of randomization to the date of a PFS event. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Time to Progression (TTP) - Percentage of Participants With an Event	TTP was defined as the time from the date of randomization and the date of the first occurrence of PD. Participants were censored at the last date of tumor assessment, the last date in the study drug log, or the last date of follow-up.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Time to Progression - Time to Event	The median time, in months, from the date of randomized to the date of a TTP event. Participants were censored at the last date of tumor assessment, the last date in the study drug log, or the last date of follow-up.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Percentage of Participants With Confirmed Complete Response (CR) or Partial Response (PR) Determined by Response Evaluation Criteria in Solid Tumors (RECIST)	For TLs, a CR was defined as the disappearance of all TLs and a PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD. For NTLs, a CR was defined as the disappearance of all NTLs and normalization of tumor marker levels.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Duration of Response - Percentage of Participants With an Event	Duration of response was defined for responders as the time from the date on which the CR or PR was first recorded to the date on which PD is first noted. Participants were censored on the date of death, the date of last tumor measurement, the last date in study drug log, or the date of last follow-up.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Duration of Response	The median time, in months, of the duration of response. Participants were censored at the date of death, the date of last tumor measurement, the last date in study drug log, or the date of last follow-up.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Percentage of Participants With Clinical Benefit	Clinical benefit was defined as stable disease (SD), CR, or PR for 6 weeks or longer as determined by RECIST. For TLs, SD was defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, taking as a reference the smallest SLD recorded since treatment had started. For NTLs, SD was defined as a persistence of one or more NTLs and/or maintenance of tumor marker levels above the normal limits.	BL, Days 43, 85, and 127, and every 21 days thereafter until disease progression or the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
European Organisation For the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ C-30) Questionnaire Scores	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score equals (=) better level of functioning or greater degree of symptoms.	BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
EORTC Quality of Life Questionnaire-Stomach Cancer Specific (QLQ STO22) Questionnaire Scores	The QLQ-STO22 is a gastric cancer quality of life questionnaire. There are 22 questions concerning disease, treatment related symptoms, side effects, dysphagia, nutritional aspects, and questions about the emotional problems of gastric cancer (dysphagia, pain, reflux, eating restrictions, anxiety, dry mouth, body image, and hair loss). The questions are grouped into five scales and 4 single items which are related to the symptoms of the disease. Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms.	BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Pain Intensity Scores as Assessed By Visual Analog Scale (VAS)	The participant assessed their pain on a 0 to 100 millimeter (mm) horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". A negative change indicated improvement.	BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Percentage of Participants With a Change in Analgesic Medication During the Study	Analgesic medications were recorded throughout the study until disease progression.	BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Body Weight (Kilograms [kg]) at BL		BL
Percentage of Participants With Change From Baseline in Body Weight by Percentage Change in Weight	Change in body weight was categorized as an increase of greater than (>)5 percent (%), no change (plus or minus [±]5%), decrease of >5-10%, or a decrease of >10% from BL to the end of study. Time windows were applied in order to assign visits to weight measurements, and the lowest post-screening value recorded was used for the analysis. The percentage change in weight from screening was summarized over time.	BL, Days 1, 22, 43, 64, 85, 106, 127, and every 21 days until disease progression of the end of study, 1 year after the cut-off date for the 2nd interim efficacy analysis
Steady State Trastuzumab Area Under the Concentration (AUC)	Individual steady state predicted exposure, as assessed by median AUC (measured as mg multiplied by [*] day per liter [L]) calculated for all treated participants using the nominal dosage schedule administered as an IV infusion. Individual steady state AUC was calculated using all available PK samples from all timepoints.	Predose and end of infusion on Days 1, 8, 15, and 64, and predose on Days 22 and 106
Trastuzumab Minimum Serum Concentration (Cmin)	Median Cmin (measured as milligrams per liter [mg/L]) calculated for all treated participants using the nominal dosage schedule administered as an IV infusion.	Predose and end of infusion on Days 1, 8, 15, and 64, and predose on Days 22 and 106
Trastuzumab Maximum Serum Concentration (Cmax)	Median Cmax (measured as mg/L) calculated for all treated participants using the nominal dosage schedule administered as an IV infusion.	Predose and end of infusion on Days 1, 8, 15, and 64, and predose on Days 22 and 106

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Chugai Pharmaceutical

Publications and helpful links

General Publications

• Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, Chong JL, Lopez-Sanchez RI, Price T, Gladkov O, Stoss O, Hill J, Ng V, Lehle M, Thomas M, Kiermaier A, Ruschoff J. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015 Jul;18(3):476-84. doi: 10.1007/s10120-014-0402-y. Epub 2014 Jul 20.
• Satoh T, Bang YJ, Gotovkin EA, Hamamoto Y, Kang YK, Moiseyenko VM, Ohtsu A, Van Cutsem E, Al-Sakaff N, Urspruch A, Hill J, Weber HA, Chung HC; ToGA Trial Investigators. Quality of life in the trastuzumab for gastric cancer trial. Oncologist. 2014 Jul;19(7):712-9. doi: 10.1634/theoncologist.2014-0058. Epub 2014 Jun 20.
• Satoh T, Omuro Y, Sasaki Y, Hamamoto Y, Boku N, Tamura T, Ohtsu A. Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer. Cancer Chemother Pharmacol. 2012 Apr;69(4):949-55. doi: 10.1007/s00280-011-1783-9. Epub 2011 Nov 25.
• Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97. doi: 10.1016/S0140-6736(10)61121-X. Epub 2010 Aug 19. Erratum In: Lancet. 2010 Oct 16;376(9749):1302.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: December 29, 2009
• First Submitted That Met QC Criteria: December 29, 2009
• First Posted (Estimate): December 31, 2009

Study Record Updates

• Last Update Posted (Estimate): November 5, 2014
• Last Update Submitted That Met QC Criteria: October 31, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Trastuzumab; Fluorouracil; Capecitabine
• Other Study ID Numbers: BO18255