TS-1 in Combination With Calcium Folinate in Patients With Heavily Pre-treated mCRC

Metastatic Colorectal Cancer Clinical Trial

Official title:

A Phase II Study Assessing Efficacy and Safety of TS-1 in Combination With Calcium Folinate in Patients With Heavily Pre-treated Metastatic Colorectal Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03517618
• Other study ID #: TG1307
• Status: Completed
• Phase: Phase 2
• Start date: July 5, 2014
• Est. completion date: June 18, 2015

Study information

• Verified date: April 2018
• Source: TTY Biopharm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

To determine disease control rate (DCR) of TS-1® in patients with heavily pre-treated metastatic colorectal cancer

Secondary Objectives:

• To determine objective response rate (ORR)

• To determine time to progression (TTP)

• To determine overall survival (OS)

• To assess incidence of adverse events (AEs), serious adverse events (SAEs) [Safety and Tolerability]

Description:

Simon's optimal two-stage design will be used to determine the sample size for this study.

• Stage I: >1/9: The first 9 evaluable patients enrolled, >1 (or ≥2) responders are required in order to enter the second stage, otherwise the trial will be terminated at the first stage due to futility.

• Stage II: Total >8/34: For the total 34 evaluable patients, >8 (or ≥9) responders are required to conclude the effectiveness of the study regimen.

The primary endpoint will be disease control rate which will be presented in frequency tabulation with two-sided 95% confidence interval (using binomial estimation).

The secondary endpoints are described as follows:

• ORR will be presented in frequency tabulation with two-sided 95% confidence interval;

• TTP will be estimated by Kaplan-Meier method with two-sided 95% confidence interval;

• OS will be estimated by Kaplan-Meier method with two-sided 95% confidence interval;

• Incidence of adverse events (AEs), serious adverse events (SAEs) [Safety and Tolerability] : assessed by CTCAE v4.0. Safety parameters will only be analyzed on the safety analysis set and be presented in frequency tabulation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: June 18, 2015
• Est. primary completion date: June 18, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

1. histologically or cytologically confirmed colorectal adenocarcinoma;

2. metastatic and unresectable disease;

3. presence of at least one measurable tumor lesion which is defined as lesion that can be measured in at least one dimension (longest diameter) with a minimum size of:

1. 10mm by CT scan and MRI (no less than double the slice thickness and a minimum of 10mm);

2. 20mm by conventional techniques;

4. previously treatment to

1. fluoropyrimidine, oxaliplatin and irinotecan;

2. at least one targeted therapy

5. adequate hematopoietic function which is defined as below:

1. hemoglobin = 9 g/dL;

2. absolute neutrophil count (ANC) = 1,500/mm3;

3. platelet count = 100,000/mm3;

6. adequate hepatic function which is defined as below:

1. total bilirubin = 2 times upper limit of normal (ULN);

2. hepatic transaminases (ALT and AST) = 3 x ULN. If there are known liver metastases, ALT or AST must be = 5 x ULN;

7. adequate renal function which is defined as below:

a. serum creatinine = 1.5 x ULN;

8. age of 20 years or above;

9. ECOG performance status 0-2;

10. life expectancy of at least 12 weeks;

11. ability to take oral medication;

12. ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. history or known presence of brain metastasis;

2. presence of mental disease or psychotic manifestation;

3. significant medical conditions that is contraindicated to study medication or render patient at high risk from treatment complications based on investigator's discretion;

4. presence of diarrhea = grade 2 in common terminology criteria for adverse event version 4.0 (CTCAE v4.0);

5. other malignancy within the past 5 years (different site or histology) except for adequately treated basal or squamous cell skin cancer or cervical cancer in situ;

6. recent (within 30 days prior to study treatment) treatment of another investigational drug;

7. pregnant women or nursing mothers, or positive pregnancy test for women of childbearing potential. Patients with childbearing potential should have effective contraception for both the patient and his or her partner during the study.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• S-1+leucovorin
Eligible patients will receive TS-1 orally 40-60 mg (depending on patient's body surface area (BSA)) in combination with calcium folinate 30 mg twice a day for 7 days in a 2-week cycle. The treatment will be administered until disease progression, intolerable toxicity, or consent withdrawal during any time of the study.

Locations

Country	Name	City	State
Taiwan	Chang-Gung Memorial Hospital, Linkou	Linkou

Sponsors (2)

Lead Sponsor	Collaborator
TTY Biopharm	Chang Gung Memorial Hospital

Country where clinical trial is conducted

Taiwan, 

References & Publications (30)

Alberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, Levitt R, Rowland K, Nair S, Sargent DJ, Donohue JH. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol. 2005 Dec 20;23(36):9243-9. Epub 2005 Oct 17. — View Citation

André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, Gilles-Amar V, Krulik M, Carola E, Izrael V, de Gramont A. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999 Sep;35(9):1343-7. — View Citation

Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008 Apr 20;26(12):2006-12. doi: 10.1200/JCO.2007.14.9898. — View Citation

Cassidy J, Tabernero J, Twelves C, Brunet R, Butts C, Conroy T, Debraud F, Figer A, Grossmann J, Sawada N, Schöffski P, Sobrero A, Van Cutsem E, Díaz-Rubio E. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol. 2004 Jun 1;22(11):2084-91. — View Citation

Chibaudel B, Tournigand C, André T, de Gramont A. Therapeutic strategy in unresectable metastatic colorectal cancer. Ther Adv Med Oncol. 2012 Mar;4(2):75-89. doi: 10.1177/1758834011431592. Erratum in: Ther Adv Med Oncol. 2012 Nov; 4(6):347-8. — View Citation

Dawood O, Mahadevan A, Goodman KA. Stereotactic body radiation therapy for liver metastases. Eur J Cancer. 2009 Nov;45(17):2947-59. doi: 10.1016/j.ejca.2009.08.011. Epub 2009 Sep 19. Review. — View Citation

Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G; Gruppo Oncologico Nord Ovest. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007 May 1;25(13):1670-6. — View Citation

Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004 Apr 1;22(7):1209-14. — View Citation

Hong YS, Park YS, Lim HY, Lee J, Kim TW, Kim KP, Kim SY, Baek JY, Kim JH, Lee KW, Chung IJ, Cho SH, Lee KH, Shin SJ, Kang HJ, Shin DB, Jo SJ, Lee JW. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1125-32. doi: 10.1016/S1470-2045(12)70363-7. Epub 2012 Oct 10. — View Citation

Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, Michaelis J, Meyer zum Büschenfelde KH, Knuth A. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 1996 Aug;14(8):2274-9. — View Citation

Jeung HC, Rha SY, Cho BC, Yoo NC, Roh JK, Roh WJ, Chung HC, Ahn JB. A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens. Br J Cancer. 2006 Dec 18;95(12):1637-41. Epub 2006 Nov 14. — View Citation

Kemeny N. Management of liver metastases from colorectal cancer. Oncology (Williston Park). 2006 Sep;20(10):1161-76, 1179; discussion 1179-80, 1185-6. Review. — View Citation

Kim SY, Hong YS, Kim BC, Park JW, Choi HS, Jeong SY, Kim DY, Hong CW, Sohn DK, Jung KH. A phase II study of S-1 plus irinotecan and oxaliplatin in heavily-treated patients with metastatic colorectal cancer. Invest New Drugs. 2009 Jun;27(3):269-74. doi: 10.1007/s10637-008-9177-5. Epub 2008 Sep 25. — View Citation

Koizumi W, Boku N, Yamaguchi K, Miyata Y, Sawaki A, Kato T, Toh Y, Hyodo I, Nishina T, Furuhata T, Miyashita K, Okada Y. Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer. Ann Oncol. 2010 Apr;21(4):766-71. doi: 10.1093/annonc/mdp371. Epub 2009 Oct 14. — View Citation

Lee DJ, Lee J, Lee HY, Lim T, Lee SJ, Yi SY, Park SH, Park JO, Lim HY, Kang WK, Park YS. Salvage S-1 monotherapy in metastatic colorectal cancer patients who failed irinotecan-based or oxaliplatin-based chemotherapy. Med Oncol. 2011 Dec;28 Suppl 1:S291-4. doi: 10.1007/s12032-010-9755-1. Epub 2010 Nov 30. — View Citation

Lee WS, Yun SH, Chun HK, Lee WY, Yun HR, Kim J, Kim K, Shim YM. Pulmonary resection for metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis. 2007 Jun;22(6):699-704. Epub 2006 Nov 16. — View Citation

Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, André T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008 Jan 20;26(3):374-9. doi: 10.1200/JCO.2007.12.5906. — View Citation

Muratore A, Zorzi D, Bouzari H, Amisano M, Massucco P, Sperti E, Capussotti L. Asymptomatic colorectal cancer with un-resectable liver metastases: immediate colorectal resection or up-front systemic chemotherapy? Ann Surg Oncol. 2007 Feb;14(2):766-70. Epub 2006 Nov 14. — View Citation

Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, Satoh T, Denda T, Ina K, Nishina T, Yamaguchi K, Takiuchi H, Esaki T, Tokunaga S, Kuwano H, Komatsu Y, Watanabe M, Hyodo I, Morita S, Sugihara K. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol. 2010 Sep;11(9):853-60. doi: 10.1016/S1470-2045(10)70181-9. Epub 2010 Aug 12. — View Citation

Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, Taguchi T. Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer. 2000 Jul;83(2):141-5. — View Citation

Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol. 1987 Oct;5(10):1559-65. — View Citation

Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, Kretzschmar A, Graeven U, Grothey A, Hinke A, Schmiegel W, Schmoll HJ; AIO Colorectal Study Group. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007 Sep 20;25(27):4217-23. Epub 2007 Jun 4. — View Citation

Sargent DJ, Köhne CH, Sanoff HK, Bot BM, Seymour MT, de Gramont A, Porschen R, Saltz LB, Rougier P, Tournigand C, Douillard JY, Stephens RJ, Grothey A, Goldberg RM. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer. J Clin Oncol. 2009 Apr 20;27(12):1948-55. doi: 10.1200/JCO.2008.20.2879. Epub 2009 Mar 2. Erratum in: J Clin Oncol. 2009 Jul 10;27(20):3410-1. — View Citation

Shirao K, Ohtsu A, Takada H, Mitachi Y, Hirakawa K, Horikoshi N, Okamura T, Hirata K, Saitoh S, Isomoto H, Satoh A. Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer. 2004 Jun 1;100(11):2355-61. — View Citation

Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, Kakolyris S, Tsousis S, Kouroussis Ch, Vamvakas L, Kalykaki A, Samonis G, Mavroudis D, Georgoulias V. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer. 2006 Mar 27;94(6):798-805. — View Citation

Van Cutsem E, Nordlinger B, Adam R, Köhne CH, Pozzo C, Poston G, Ychou M, Rougier P; European Colorectal Metastases Treatment Group. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer. 2006 Sep;42(14):2212-21. Epub 2006 Aug 10. Review. — View Citation

Van den Brande J, Schöffski P, Schellens JH, Roth AD, Duffaud F, Weigang-Köhler 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. — View Citation

Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol. 1993 Oct;11(10):1879-87. — View Citation

Yamada Y, Tahara M, Miya T, Satoh T, Shirao K, Shimada Y, Ohtsu A, Sasaki Y, Tanigawara Y. Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer. Br J Cancer. 2008 Mar 25;98(6):1034-8. doi: 10.1038/sj.bjc.6604271. Epub 2008 Mar 4. — View Citation

Yoo PS, Lopez-Soler RI, Longo WE, Cha CH. Liver resection for metastatic colorectal cancer in the age of neoadjuvant chemotherapy and bevacizumab. Clin Colorectal Cancer. 2006 Sep;6(3):202-7. Review. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Control Rate (DCR)	Documented objective response (OR) (defined as partial response [PR] or complete response [CR]), assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at any time during trial participation by Investigator assessment	6 months(an expected average)
Secondary	Objective Response Rate (ORR)	the rate of completely response [CR] and partial response [PR] patients according to RECIST version 1.1. criteria	6 months(an expected average)
Secondary	Time to Progression (TTP)	Participants follow-up for disease progression occur. Maximum follow-up time is 12 months after the initial administration of the last subject	until disease progression, intolerable toxicity, 12 months(an expected average)
Secondary	Overall survival (OS)	median time between the start date of study treatment and the date of the death	at death or at the end of study, 24 months(an expected average)
Secondary	Incidence of adverse events (AEs), serious adverse events (SAEs) [Safety and Tolerability]	assessed by the NCI-CTCAE (Common Toxicity Criteria for Adverse Effects) v4.0 and within some subgroups of patients	From the date of study entry until 30 days after the last dose of study treatment