Clinical trial NCT01671449: S-1 and Cisplatin (3 Weekly) Versus S-1 and Oxaliplatin Combination Chemotherapy for Advanced Gastric Cancer
Official title: Phase III Trial of S-1 and Cisplatin (3 Weekly) Versus S-1 and Oxaliplatin Combination Chemotherapy for First Line Treatment of Advanced Gastric Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastric Cancer
Keywords: Gastric cancer
S-1
Cisplatin
Oxaliplatin
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
First posted: 2012-08-23
Enrollment: 338
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A multicenter, randomized, open-label, phase III trial of S-1 plus cisplatin (3 weekly) versus S-1 plus oxaliplatin chemotherapy for the first-line treatment of advanced gastric cancer


Eligibility criteria: Inclusion Criteria:

1. Written informed consent before the enrollment
2. Age ≥18 years old
3. Histologically/cytologically confirmed recurrent or metastatic gastric or esophagogastric junctional adenocarcinoma
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
5. Patients able to swallow food and drugs
6. At least one measurable or evaluable lesion according to RECIST criteria version 1.1
7. Adequate bone, hepatic, and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to first administration of study drugs

   * Absolute neutrophil count (ANC) ≥ 1,500/ uL, platelet ≥ 100,000/ uL, haemoglobin (Hb) ≥ 9.0 g/dl,
   * Serum creatinine ≤ 1.5 mg/dL (If serum creatinine is greater than 1.5 mg/dL, creatinine clearance \[Ccr\] should be 60 mL/min or greater. Ccr is calculated by Cockcroft-Gault formula or 24hr urine collection)
   * Total bilirubin ≤ 1.5 x upper limit of normal (ULN), AST/ALT levels ≤ 3.0 x ULN (AST/ALT levels ≤ 5.0 x ULN for patients with liver involvement of their cancer)
8. In patients who received adjuvant or neoadjuvant chemotherapy, completion of systemic chemotherapy 6 months before the study enrollment, and no previous administration of platinum derivatives
9. Estimated life expectancy of more than 3 months

Exclusion Criteria:

1. Other histologic types than adenocarcinoma
2. Recurrence within 24 weeks following completion of adjuvant chemotherapy
3. R1 gastrectomy (i.e., microscopic residual disease)
4. History of another malignancy within the last five years from the day of written informed consent except cured basal cell carcinoma of skin and cured carcinoma in situ of uterine cervix
5. Radiotherapy within 4 weeks after randomization
6. History of significant neurologic or psychiatric disorders, and presence or history of CNS metastasis
7. Major surgery within 4 weeks before study entry, or insufficient recovery from major surgery (except the patients who received only open and closure or biopsy)
8. Other serious illness or medical conditions as follows;

   * Any following conditions occurred within 6 months before study entry: myocardial infarction, severe/unstable angina, bypass surgery for coronary artery/peripheral artery, congestive heart failure (NYHA class III or IV), cerebral infarction or transient ischemic attack
   * Conduction abnormality such as 2nd degree or greater AV block or severe arrhythmia that requires medical treatments (right bundle branch block (RBBB) is eligible, but left bundle branch block (LBBB) is not.)
   * Uncontrolled hypertension
   * Liver cirrhosis (Child Pugh Class B or greater)
   * Interstitial pneumonia, pulmonary fibrosis
   * Active viral hepatitis B
   * Uncontrolled diabetes mellitus
   * Uncontrolled ascites or pleural effusion
   * Uncontrolled active infection or sepsis
9. Administration of medications which may have potentially pharmacokinetic interaction with S-1, cisplatin, and oxaliplatin

   * Flucytosine, a fluorinated pyrimidine antifungal agent
   * Anti-viral agents, such as sorivudine, and brivudine, or chemical similar drugs
   * Warfarin (except, low dose warfarin for the purpose of prophylaxis), phenprocoumon
   * Phenytoin
   * Allopurinol
10. Participation to other clinical trials or administration of other investigational drugs within 30 days before the randomisation
11. Pregnant or lactating women
12. Women or men of child bearing potential not employing adequate contraception during study treatments or until the 3 months after the end of study treatments
13. Ineligible for the study at the discretion of investigators

Primary outcomes:
measure: Progression-free survival
timeFrame: From date of randomization to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
Secondary outcomes:
measure: Overall survival
timeFrame: From date of randomization to death from any cause, assessed up to 3 years
measure: Response rate
timeFrame: Every 6 weeks
measure: Quality of life
timeFrame: Every 6 weeks
measure: Number of Adverse Events
timeFrame: Every 3 weeks
Other outcomes:
Locations:
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungcheongbuk-do
city: Bundang-gu, Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Ilsan
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggi-do
city: Hwasun-eup, Hwasun-gun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Busan
country: Korea, Republic of
facility: Dongnam Institute of Radiological and Medical Sciences
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Gangneung-si
country: Korea, Republic of
facility: Gangneung Asan Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's hospital of the Catholic University of Korea
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
Study officials:
affiliation: Asan Medical Center
name: Min-Hee Ryu, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: National Cancer Center, Seoul, Korea
name: Young-Iee Park, MD., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Chonnam National University Hospital
name: Ik-Joo Chung, MD., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ahn YO, Park BJ, Yoo KY, Kim NK, Heo DS, Lee JK, Ahn HS, Kang DH, Kim H, Lee MS, et al. Incidence estimation of stomach cancer among Koreans. J Korean Med Sci. 1991 Mar;6(1):7-14. doi: 10.3346/jkms.1991.6.1.7.
citation: Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer. 1995 Mar;71(3):587-91. doi: 10.1038/bjc.1995.114.
citation: Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, Enander LK, Linne T, Sellstrom H, Heuman R. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997 Feb;8(2):163-8. doi: 10.1023/a:1008243606668.
citation: Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer. 1993 Jul 1;72(1):37-41. doi: 10.1002/1097-0142(19930701)72:13.0.co;2-p.
citation: Scheithauer W, Kornek G, Zek B et al. Palliative chemotherapy versus supportive care in patients with metastatic gastric cancer: A randomized trial. Second Int Conf Biol, Prev, Treatm GI Malignancy, Koln, Germany 1995;68(Abstr)
citation: Comis RL, Carter SK. A review of chemotherapy in gastric cancer. Cancer. 1974 Nov;34(5):1576-86. doi: 10.1002/1097-0142(197411)34:53.0.co;2-0. No abstract available.
citation: Kaufman S. 5-Fluorouracil in the treatment of gastrointestinal neoplasia. N Engl J Med. 1973 Jan 25;288(4):199-201. doi: 10.1056/NEJM197301252880408. No abstract available.
citation: Schein PS, Macdonald JS, Hoth D, Wooley PV. Mitomycin C: experience in the United States, with emphasis on gastric cancer. Cancer Chemother Pharmacol. 1978;1(2):73-5. doi: 10.1007/BF00254039. No abstract available.
citation: Moertel CG, Lavin PT. Phase II-III chemotherapy studies in advanced gastric cancer. Eastern Cooperative Oncology Group. Cancer Treat Rep. 1979 Nov-Dec;63(11-12):1863-9.
citation: Lacave AJ, Wils J, Diaz-Rubio E, Clavel M, Planting A, Bleiberg H, Duez N, Dalesio O. cis-Platinum as second-line chemotherapy in advanced gastric adenocarcinoma. A phase II study of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Eur J Cancer Clin Oncol. 1985 Nov;21(11):1321-4. doi: 10.1016/0277-5379(85)90311-6.
citation: Kambe M, Wakui A, Nakao I, Futatsuki K, Sakata Y, Yoshino M, Shimada Y, Taguchi T. A late phase II study of irinotecan (CPT-11) in patients with advanced gastric cancers (abstr 584). Proc Am Soc Clin Oncol 1993;12;198
citation: Sulkes A, Smyth J, Sessa C, Dirix LY, Vermorken JB, Kaye S, Wanders J, Franklin H, LeBail N, Verweij J. Docetaxel (Taxotere) in advanced gastric cancer: results of a phase II clinical trial. EORTC Early Clinical Trials Group. Br J Cancer. 1994 Aug;70(2):380-3. doi: 10.1038/bjc.1994.310.
citation: Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006 Jun 20;24(18):2903-9. doi: 10.1200/JCO.2005.05.0245.
citation: Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. doi: 10.1056/NEJMoa073149.
citation: Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, Lichinitser M, Guan Z, Khasanov R, Zheng L, Philco-Salas M, Suarez T, Santamaria J, Forster G, McCloud PI. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr;20(4):666-73. doi: 10.1093/annonc/mdn717. Epub 2009 Jan 19.
citation: Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008 Mar;9(3):215-21. doi: 10.1016/S1470-2045(08)70035-4. Epub 2008 Feb 20.
citation: Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, Fukushima M. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996 Jul;7(5):548-57. doi: 10.1097/00001813-199607000-00010.
citation: Tatsumi K, Fukushima M, Shirasaka T, Fujii S. Inhibitory effects of pyrimidine, barbituric acid and pyridine derivatives on 5-fluorouracil degradation in rat liver extracts. Jpn J Cancer Res. 1987 Jul;78(7):748-55.
citation: Shirasaka T, Shimamoto Y, Fukushima M. Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res. 1993 Sep 1;53(17):4004-9.
citation: Yoshisue K, Masuda H, Matsushima E, Ikeda K, Nagayama S, Kawaguchi Y. Tissue distribution and biotransformation of potassium oxonate after oral administration of a novel antitumor agent (drug combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) to rats. Drug Metab Dispos. 2000 Oct;28(10):1162-7.
citation: Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T. Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer. 1998 Oct;34(11):1715-20. doi: 10.1016/s0959-8049(98)00211-1.
citation: Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology. 2000 Apr;58(3):191-7. doi: 10.1159/000012099.
citation: Fujii M; 0. Chemotherapy for advanced gastric cancer: ongoing phase III study of S-1 alone versus S-1 and docetaxel combination (JACCRO GC03 study). Int J Clin Oncol. 2008 Jun;13(3):201-5. doi: 10.1007/s10147-008-0775-1. Epub 2008 Jun 14.
citation: Jeung HC, Rha SY, Kim HK, Lim HY, Kim S, Kim SY, Gong SJ, Park CH, Ahn JB, Noh SH, Chung HC. Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations. Oncologist. 2007 May;12(5):543-54. doi: 10.1634/theoncologist.12-5-543.
citation: Van den Brande J, Schoffski P, Schellens JH, Roth AD, Duffaud F, Weigang-Kohler K, Reinke F, Wanders J, de Boer RF, Vermorken JB, Fumoleau P. EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer. Br J Cancer. 2003 Mar 10;88(5):648-53. doi: 10.1038/sj.bjc.6600781.
citation: Chollet P, Schoffski P, Weigang-Kohler K, Schellens JH, Cure H, Pavlidis N, Grunwald V, De Boer R, Wanders J, Fumoleau P; EORTC Early Clinical Studies Group. Phase II trial with S-1 in chemotherapy-naive patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG). Eur J Cancer. 2003 Jun;39(9):1264-70. doi: 10.1016/s0959-8049(03)00237-5.
citation: Koizumi W, Tanabe S, Saigenji K, Ohtsu A, Boku N, Nagashima F, Shirao K, Matsumura Y, Gotoh M. Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer. 2003 Dec 15;89(12):2207-12. doi: 10.1038/sj.bjc.6601413.
citation: Hyodo I, Nishina T, Moriwaki T, Endo S, Terao T, Hirao K, Nasu J, Hirasaki S, Endo H, Masumoto T, Tajiri H, Kurita A. A phase I study of S-1 combined with weekly cisplatin for metastatic gastric cancer in an outpatient setting. Eur J Cancer. 2003 Nov;39(16):2328-33. doi: 10.1016/s0959-8049(03)00626-9.
citation: Ajani JA, Lee FC, Singh DA, Haller DG, Lenz HJ, Benson AB 3rd, Yanagihara R, Phan AT, Yao JC, Strumberg D. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2006 Feb 1;24(4):663-7. doi: 10.1200/JCO.2005.04.2994.
citation: Lee JL, Kang HJ, Kang YK, Ryu MH, Chang HM, Kim TW, Sohn HJ, Kim H, Lee JS. Phase I/II study of 3-week combination of S-1 and cisplatin chemotherapy for metastatic or recurrent gastric cancer. Cancer Chemother Pharmacol. 2008 Apr;61(5):837-45. doi: 10.1007/s00280-007-0541-5. Epub 2007 Jun 20.
citation: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group Study (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003 Jan 1;21(1):54-9. doi: 10.1200/JCO.2003.04.130.
citation: Lee SS, Lee JL, Ryu MH, Chang HM, Kim TW, Kang HJ, Kim WK, Lee JS, Kang YK. Combination chemotherapy with capecitabine (X) and Cisplatin (P) as first line treatment in advanced gastric cancer: experience of 223 patients with prognostic factor analysis. Jpn J Clin Oncol. 2007 Jan;37(1):30-7. doi: 10.1093/jjco/hyl134.
citation: van Meerten E, Eskens FA, van Gameren EC, Doorn L, van der Gaast A. First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study. Br J Cancer. 2007 May 7;96(9):1348-52. doi: 10.1038/sj.bjc.6603750. Epub 2007 Apr 17.
citation: Louvet C, Andre T, Tigaud JM, Gamelin E, Douillard JY, Brunet R, Francois E, Jacob JH, Levoir D, Taamma A, Rougier P, Cvitkovic E, de Gramont A. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol. 2002 Dec 1;20(23):4543-8. doi: 10.1200/JCO.2002.02.021.
citation: Al-Batran SE, Atmaca A, Hegewisch-Becker S, Jaeger D, Hahnfeld S, Rummel MJ, Seipelt G, Rost A, Orth J, Knuth A, Jaeger E. Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol. 2004 Feb 15;22(4):658-63. doi: 10.1200/JCO.2004.07.042.
citation: Lordick F, Lorenzen S, Stollfuss J, Vehling-Kaiser U, Kullmann F, Hentrich M, Zumschlinge R, Dietzfelbinger H, Thoedtmann J, Hennig M, Seroneit T, Bredenkamp R, Duyster J, Peschel C. Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer. Br J Cancer. 2005 Jul 25;93(2):190-4. doi: 10.1038/sj.bjc.6602697.
citation: Park YH, Kim BS, Ryoo BY, Yang SH. A phase II study of capecitabine plus 3-weekly oxaliplatin as first-line therapy for patients with advanced gastric cancer. Br J Cancer. 2006 Apr 10;94(7):959-63. doi: 10.1038/sj.bjc.6603046.
citation: Neri B, Pantaleo P, Giommoni E, Grifoni R, Paoletti C, Rotella V, Pantalone D, Taddei A, Mercatelli A, Tonelli P. Oxaliplatin, 5-fluorouracil/leucovorin and epirubicin as first-line treatment in advanced gastric carcinoma: a phase II study. Br J Cancer. 2007 Apr 10;96(7):1043-6. doi: 10.1038/sj.bjc.6603644. Epub 2007 Mar 13.
citation: Lee J, Kang WK, Kwon JM, Oh SY, Lee HR, Kim HJ, Park BB, Lim HY, Han MJ, Park JO, Park YS. Phase II trial of irinotecan plus oxaliplatin and 5-fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma. Ann Oncol. 2007 Jan;18(1):88-92. doi: 10.1093/annonc/mdl317. Epub 2006 Sep 13.
citation: Zhang CX, Huang S, Xu N, Fang JW, Shen P, Bao YH, Mou BH, Shi MG, Zhong XL, Xiong PJ. Phase II study of epirubicin plus oxaliplatin and infusional 5-fluorouracil as first-line combination therapy in patients with metastatic or advanced gastric cancer. Anticancer Drugs. 2007 Jun;18(5):581-6. doi: 10.1097/CAD.0b013e3280146296.
citation: Di Lauro L, Nunziata C, Arena MG, Foggi P, Sperduti I, Lopez M. Irinotecan, docetaxel and oxaliplatin combination in metastatic gastric or gastroesophageal junction adenocarcinoma. Br J Cancer. 2007 Sep 3;97(5):593-7. doi: 10.1038/sj.bjc.6603917. Epub 2007 Jul 31.
citation: Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jager E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. doi: 10.1200/JCO.2007.13.9378.
citation: Lee JL, Kang YK, Kang HJ, Lee KH, Zang DY, Ryoo BY, Kim JG, Park SR, Kang WK, Shin DB, Ryu MH, Chang HM, Kim TW, Baek JH, Min YJ. A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. Br J Cancer. 2008 Aug 19;99(4):584-90. doi: 10.1038/sj.bjc.6604536. Epub 2008 Jul 29.
citation: Lee KW, Chung IJ, Ryu MH, Park YI, Nam BH, Oh HS, Lee KH, Han HS, Seo BG, Jo JC, Lee HR, Kim JW, Park SR, Cho SH, Kang YK; SOPP study investigators. Multicenter phase III trial of S-1 and cisplatin versus S-1 and oxaliplatin combination chemotherapy for first-line treatment of advanced gastric cancer (SOPP trial). Gastric Cancer. 2021 Jan;24(1):156-167. doi: 10.1007/s10120-020-01101-4. Epub 2020 Jun 28.