© 2005 Foundation for Promotion of Cancer Research
Clinical Trial Note |
Phase II Study of Oral S-1 Plus Irinotecan in Patients with Advanced Colorectal Cancer: Hokkaido Gastrointestinal Cancer Study Group HGCSG0302
1 Department of Gastroenterology and 2 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo and 3 Misawa City Hospital, Misawa, Aomori, Japan
For reprints and all correspondence: Yoshito Komatsu, Department of Gastroenterology, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan. Email: ykomatsu{at}med.hokudai.ac.jp
Received December 12, 2004; accepted December 23, 2004
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Abstract |
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 TOP Abstract PROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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We have previously reported on phase I/II studies of irinotecan plus S-1 therapy for advanced gastric cancer. Based on the safety and efficacy data that were obtained, this phase II study was planned to assess the efficacy of irinotecan plus S-1 for patients with advanced colorectral cancer. A total of 40 patients are enrolled at 13 medical institutions. The objective of this study was to establish a useful chemotherapy regimen for an out-patient setting.
Key Words: S-1 • irinotecan • phase II study • colorectal cancer
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PROTOCOL SUMMARY FOR STUDY HGCSG0302 |
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TOPAbstractPROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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INTRODUCTION
The usefulness of combination therapy with irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) for previously untreated colorectal cancer has been demonstrated mainly in Europe and the USA (1,2). The possible efficacy of combination therapy with S-1, a prodrug of 5-FU, and CPT-11 for colorectal cancer has thus been suggested. The safety and efficacy of this combination therapy was investigated by a phase I/II study in patients with gastric cancer [Hokkaido Gastrointestinal Cancer Study Group (HGCSG)] and its usefulness was confirmed (3). The above results suggested that this combination therapy is a promising new option for patients with inoperable colorectal cancer or with post-operative recurrence. Because S-1 is an oral formulation, out-patient treatment would also be possible. Therefore, we planned a phase II study of combination therapy with CPT-11 plus S-1 for patients with inoperable colorectal cancer or with post-operative recurrence.
PURPOSE
The study had various aims. The first was to assess the usefulness of irinotecan plus S-1 therapy by performing a phase II study of this combination in patients with inoperable colorectal cancer or with post-operative recurrence, using the recommended doses of irinotecan and S-1 determined previously in patients with progressive gastric cancer. A second aim was to assess the usefulness of irinotecan plus S-1 therapy based on the antitumor effect and survival period.
STUDY SETTING
This was an open-label, single-arm, phase II clinical trial. The protocol was approved by the protocol review committee of the HGCSG.
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END-POINTS |
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TOPAbstractPROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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PRIMARY END-POINT: OBJECTIVE TUMOR RESPONSE
The tumor response will be assessed objectively after each course according to the Response Evaluation Criteria in Solid Tumors (RECIST), and the maximum response rate will be taken as the antitumor effect for that subject.
SECONDARY END-POINT: SURVIVAL
Response duration, time to progression, overall survival and safety will also be assessed.
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ELIGIBILITY CRITERIA |
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TOPAbstractPROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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(i) A histological diagnosis of colorectral adenocarcinoma. (ii) Measurable or assessable lesions. (ii) Age: 18–75 years. (iv) Performance status (Eastern Cooperative Oncology Group): 0–2. (v) No prior chemotherapy or only one regimen of previous chemotherapy (with a washout period >4 weeks after the final day of the previous therapy). Adjuvant chemotherapy is not defined as previous therapy. (vi) No history of treatment with CPT-11 or S-1. (vii) No history of radiotherapy to the abdomen. (viii) Oral intake of S-1 is possible. (ix) Adequate function of major organs (bone marrow, heart, lungs, liver, etc.). White blood cell count
3500/mm3 and 
12 000/mm3; Hb 10.0 g/dl; platelet count 100 000/mm3; GOT and GPT 2.5 times the upper limit of normal (excluding liver transplantation); T-Bil 2.0 mg/dl; creatinine <1.5 mg/dl (but if it is 1.0–1.5 mg/dl, the dose of S-1 can be decreased according to the dose reduction criteria to allow registration in the trial); normal ECG (not considering clinically unimportant arrhythmias and ischemic changes). (x) Predicted survival for >3 months. (xi) Able to give written informed consent. |
EXCLUSION CRITERIA |
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TOPAbstractPROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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(i) Severe pleural effusion or ascites. (ii) Metastasis to the central nervous system (CNS). (iii) Active gastrointestinal bleeding. (iv) Active infection. (v) Diarrhea (watery stools). (vi) Uncontrolled ischemic heart disease. (vii) Serious complications (such as intestinal paralysis, intestinal obstruction, interstitial pneumonia or pulmonary fibrosis, uncontrolled diabetes mellitus, heart failure, renal failure or hepatic failure). (viii) Active multiple cancer. (ix) Severe mental disorder. (x) Pregnancy, possible pregnancy or breast-feeding. (xi) Flucytosine treatment. (xii) Gilbert's syndrome (4). (xiii) Judged to be ineligible for this protocol by the attending physician.
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TREATMENT METHODS |
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TOPAbstractPROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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Irinotecan (100 mg/m2) will be added to 500 ml of 0.9% sodium chloride or 5% glucose. The solution will be infused intravenously over 90 min on days 1 and 15. Capsules containing 20 or 25 mg of S-1 (Taiho Pharmaceutical Co. Ltd, Tokyo, Japan) are to be administered from day 1 to day 14, and the actual dose will be based on the body surface area.
Treatment will be followed by a 2-week washout period, and the regimen will be repeated every 4 weeks. There is no set maximum number of courses, but at least two courses should be given.
In the phase I study, grade 4 neutropenia occurred at the optimum dose of irinotecan (100 mg/m2), but severe non-hematological toxicity was not seen.
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REGISTRATION |
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The eligibility criteria checking report form will be sent by Fax to the HGCSG Data Center after confirmation of the above criteria.
FOLLOW-UP
All eligible subjects will be included in the assessment of efficacy. Unevaluable subjects will only be added into the efficacy assessment data set as ‘not evaluable (NE)’. The response duration, time to progression, overall survival and safety will be assessed as secondary end-points. The following dates will be recorded: (i) date of starting treatment (first dose of CPT-11); (ii) date of achieving tumor shrinkage by 30%; (iii) presumed date of achieving complete remission; (iv) date of an increase in lesion size by 20% or development of a new lesion; (v) final date of assessing survival; and (vi) date of death. The time to progression will also be determined by the ‘Efficacy Assessment Committee’. Items will be calculated by the following formulae: response duration, (iv) – (ii); time to progression, (iv) – (i); and overall survival, (vi) or (v) – (i).
SAMPLE SIZE
This study was designed to allow assessment of the treatment in 40 colorectral cancer patients. Threshold value, 40%; expected efficacy rate, 60%; 
= 0.05; and ß = 0.2. The duration of the registration period will be 2 years, starting in January 2004 and ending in December 2005. Subjects will be followed-up for 1 year.
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PARTICIPATING INSTITUTIONS |
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TOPAbstractPROTOCOL SUMMARY FOR STUDY...END-POINTSELIGIBILITY CRITERIAEXCLUSION CRITERIATREATMENT METHODSREGISTRATIONPARTICIPATING INSTITUTIONSReferences |
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Hokkaido University School of Medicine (Third Department of Internal Medicine), Abashiri-kousei General Hospital, Aiiku Hospital, Kitami Red Cross Hospital, Kushiro Rosai Hospital, National Nishi Sapporo Hospital, Sapporo Hokuyu Hospital, Sapporo City Hospital, Wakkanai City Hospital, Tomakomai-nissho Hospital, Hokkaido Gastroenterology Hospital, Hokkaido Social Insurance Hospital.
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References |
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1 Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905–14.
2 Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer. Lancet 2000;25:1041–7.
3 Komatsu Y, Takeda H, Takei M, Kato T, Tateyama M, Miyagishima T. A phase I and PK study of S-1 and irinotecan (CPT-11) in patients with advanced gastric cancer (AGC). Proc Am Soc Clin Oncol 2002;21:171 (abstract 683).
4 Wasserman E, Myara A, Lokiec F, Goldwasser F, Trivun F, Mahjoubi M. Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. Ann Oncol 1997;8:1049–51.
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