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A Phase II selection design trial was conducted to identify the most promising regimen for comparison with standard therapy in chemo-naive patients with unresectable or recurrent biliary tract cancer (JCOG0805). Gemcitabine plus S-1 therapy showed better efficacy than S-1 monotherapy with acceptable safety in JCOG0805 study. Based on this result, a randomized Phase III trial was started in May 2013 to confirm the non-inferiority of gemcitabine plus S-1 therapy relative to gemcitabine plus cisplatin therapy, which is the current standard treatment for chemo-naive patients with unresectable or recurrent biliary tract cancer. A total of 350 patients will be accrued from 32 Japanese institutions within 4 years. The primary endpoint is overall survival, while the secondary endpoints are progression-free survival, adverse events, serious adverse events, clinically significant adverse events, response rate and %planned dose. This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm) and the registration number is UMIN000010667.
Biliary tract cancer includes cancer of the intrahepatic bile ducts (IHBD), extrahepatic bile ducts (EHBD), gallbladder (GB) and ampulla of Vater (AV).
Surgical resection is the only curative treatment for biliary tract cancer, but the proportion of curative resection is only 68.3% for IHBD cancer, 46.7% for EHBD cancer, 47.3% for GB cancer and 86.6% for AV cancer (1,2). Since the disease is unresectable at initial diagnosis in many patients, more effective and tolerable chemotherapy is needed to improve their prognosis and quality of life.
Gemcitabine has been considered the de facto standard chemotherapy since it was approved for biliary tract cancer in 2006 in Japan. S-1 was also approved for biliary tract cancer in 2007, and it has mainly been used for second-line therapy since then. Both S-1 monotherapy and combination therapy with gemcitabine plus S-1 (GS therapy) have achieved promising response rates and median survival times (MSTs) in Phase II trials (3–5). In order to determine which regimen was more promising, a randomized Phase II trial was performed (JCOG0805) (6). It showed that GS therapy was better than S-1 monotherapy in terms of 1-year survival, which was the primary endpoint [the proportion of 1-year overall survival (OS): 52.9% vs. 40.0%, MST: 12.5 months vs. 9.0 months]. Although Grade 3 or 4 hematological toxicity was more frequent with GS therapy than S-1 alone, both treatments were tolerable. Therefore, GS therapy was chosen as the regimen to be compared with standard treatment in the next Phase III study (7).
In 2009, gemcitabine plus cisplatin (GC therapy) showed superiority to gemcitabine alone (MST: 11.7 months vs. 8.1 months) in the ABC-02 trial conducted in the UK. Based on the study, GC therapy became a new standard treatment for patients with unresectable biliary tract cancer (8). After initiation of the ABC-02 trial, a randomized Phase II trial comparing GC therapy with gemcitabine monotherapy was conducted in Japan (BT22 trial) to evaluate the efficacy and safety of the combined regimen (9). The result of this trial was consistent with that of ABC-02 (MST: 11.2 months vs. 7.7 months). Therefore, GC therapy also became a standard treatment for patients with unresectable or recurrent biliary tract cancer in Japan.
We designed the present study as a non-inferiority trial, considering that GS therapy may show less toxicity and convenience compared with GC therapy. The frequency of thrombocytopenia and gastrointestinal toxicity is expected to be lower with GS therapy than GC therapy. Also, GS therapy can be continued until disease progression, although GC therapy should be terminated before progression if cumulative toxicity of cisplatin is observed such as peripheral neuropathy or renal damage. With regard to convenience, patients in the GS arm receive oral S-1 and hydration is not required. On the other hand, patients in the GC arm need 3 h or more of hydration and antiemetic therapy. Furthermore, we expected that GS therapy would achieve better OS than GC therapy based on the results of previous studies. Therefore, we decided to evaluate the non-inferiority and/or superiority of GS therapy versus GC therapy based on OS in a randomized Phase III trial.
The JCOG Protocol Review Committee approved this study protocol in March 2013 and patient enrollment began in May 2013 (10). Approval was obtained from the Institutional Review Board prior to starting patient accrual at each institution. This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm) and the registration number is UMIN000010667.
The primary objective of this study is to confirm the non-inferiority of GS therapy (gemcitabine/S-1) relative to GC therapy (gemcitabine/cisplatin) for unresectable or recurrent biliary tract cancer. If the non-inferiority of GS therapy relative to GC therapy is confirmed, we will also evaluate whether GS therapy is superior to GC therapy.
Multicenter, two-arm, open-label, randomized Phase III study.
The primary endpoint is OS in all randomized patients. OS is defined as the number of days from randomization to death from any cause, and is censored at the last day when the patient is alive. The secondary endpoints are progression-free survival (PFS), adverse events, serious adverse events, clinically significant adverse events, response rate and %planned dose. PFS is defined as the number of days from randomization to disease progression or death from any cause, and is censored at the last day when the patient is alive without any evidence of progression. Clinically significant adverse events are defined as any of the following adverse events during the observation period in patients receiving assigned protocol treatment: Grade 2 or higher fatigue, anorexia, nausea, vomiting, oral mucositis or diarrhea. For patients whose protocol treatment is terminated within eight courses, the observation period is defined as the interval from initiation of treatment to termination of treatment. For patients completing at least eight courses of protocol treatment, the observation period is defined as the interval from initiation to the day of completing eight courses of protocol treatment or 24 weeks after initiation of treatment, whichever is later.
After confirming the eligibility criteria, registration with the JCOG Data Center is performed by telephone, fax or a web-based system. The minimization method is employed to randomly assign patients to either the GC arm or GS arm using the institution, primary tumor (GB/IHBD, EHBD or AV) and history of primary tumor resection (R0 or R1/none) as adjustment factors.
In the GC arm, gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) are infused on Days 1 and 8, with this regimen being repeated every 3 weeks. In the GS arm, gemcitabine (1000 mg/m2) is infused on Days 1 and 8, and S-1 is given orally twice a day [30 mg/m2: 60 mg/day for a body surface area (BSA) <1.25 m2; 80 mg/day for BSA from 1.25 to <1.50 m2; and 100 mg/day for BSA ≥1.50 m2] on Days 1–14, with this regimen being repeated every 3 weeks. Cisplatin is administered up to 16 times (400 mg/m2) unless patients meet the following termination criteria: elevation of creatinine (>1.2 mg/dl) for >7 days, Grade 2 peripheral sensory/motor neuropathy, tinnitus, impaired hearing or Grade 3 allergic reaction or anaphylaxis. If patients in the GC arm have a leucocyte count <2500/mm3, neutrophil count <1000/mm3, platelet count <75000/mm3, AST or ALT >150 IU/L, total bilirubin >3.0 mg/dl, creatinine >1.2 mg/dl, Grade 3 skin rash or Grade 1–3 infection, initiation of the next course is postponed until recovery. If patients in the GS arm have a leucocyte count <2500/mm3, neutrophil count <1000/mm3, platelet count <75,000/mm3, AST or ALT >150 IU/L, total bilirubin >3.0 mg/dl, creatinine >1.2 mg/dl, Grade 3 skin rash, Grade 2 or 3 diarrhea or Grade 2 or 3 oral mucositis, initiation of the next course is postponed until recovery.
In both arms, protocol treatment will be continued until disease progression, unacceptable, toxicity or patient refusal. There are no restrictions on subsequent treatment, except that exactly the same regimen as the assigned protocol treatment should not be used.
All randomized patients will be followed-up for at least 1 year after patient accrual is completed. Enhanced abdominal computed tomography (CT) or magnetic resonance imaging (MRI), chest CT or MRI, and tumor markers (CEA and CA19-9) will be evaluated at least every 6 weeks until disease progression or death. The tumor response will be assessed at 6, 12, 18 and 24 weeks according to RECIST version 1.1. The response rate is calculated without confirmation. Physical examination, laboratory tests and evaluation of adverse events according to CTCAE ver. 4.0 will be carried out at least on Days 1 and 8 of each course during protocol treatment.
This randomized trial is designed to confirm the non-inferiority of GS therapy relative to GC therapy in terms of the OS of patients with unresectable or recurrent biliary tract cancer. Clinically significant adverse events are taken into account to evaluate less toxicity of GS therapy. If non-inferiority of GS therapy relative to GC therapy is confirmed with respect to OS and clinically significant adverse events are less frequent with GS therapy than GC therapy, we will conclude that GS therapy is more suitable for standard treatment. Then, we will investigate whether GS therapy is superior to GC therapy. Stratified Cox regression analysis will be performed using the primary tumor (GB/IHBD, EHBD or AV) and primary tumor resection (R0 or R1/none) as the strata to test the non-inferiority and/or superiority of GS therapy relative to GC therapy.
We assumed that the MST with GC therapy was 11.2 months and that with GS therapy was 13.0 months based on previous studies (7–9). According to Schoenfeld and Richter's method (11), a sample size of 350 patients would achieve a power of 80% with a one-sided α of 0.05 and a non-inferiority margin of 1.155 (hazard ratio), corresponding to a difference of 1.5 months in the MST. The total number of expected deaths is 288 in the patients subjected to primary analysis. The planned accrual period is 4 years, and the follow-up period is 1 year. All statistical analyses will be conducted at the JCOG Data Center.
We plan to conduct one interim analysis, using the Lan-DeMets method with the O'Brien and Fleming type α spending function to take multiplicity into account (12). This interim analysis will be conducted after half of the planned patients have been enrolled. The Data and Safety Monitoring Committee (DSMC) of the JCOG will review the results of interim analysis independently from the investigators and the study group statistician. If both superiority and non-inferiority of GC therapy is demonstrated by stratified Cox regression analysis with an one-sided P value below the adjusted α level, the study will be terminated at that time. This trial will also be terminated if the specified termination criteria for futility are met at the interim analysis or if nine treatment-related deaths occur in either arm.
The JCOG Data Center and study coordinator will conduct central monitoring and will issue a monitoring report every 6 months to evaluate study progress and improve data integrity and patient safety. For quality assurance, site audits will be performed by the JCOG Audit Committee (not on a study-specific basis but for the study group).
Sapporo-Kosei General Hospital, Hokkaido University Hospital, Teine-Keijinkai Hospital, Tochigi Cancer Center, Jichi Medical University, Saitama Cancer Center, National Cancer Center Hospital East, Chiba Cancer Center, Chiba University, Graduate School of Medicine, National Cancer Center Hospital, Kyorin University Faculty of Medicine, National Center for Global Health and Medicine (NCGM), Tokyo Women's Medical University, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Teikyo University School of Medicine, Tokai University School of Medicine, Kanagawa Cancer Center, Kitasato University School of Medicine, Yokohama City University Medical Center, Niigata Cancer Center Hospital, Toyama University Hospital, Kanazawa University School of Medicine, Shizuoka Cancer Center, Aichi Cancer Center Hospital, Kinki University Faculty of Medicine, Osaka Prefectural Hospital Organization Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka National Hospital, Kansai Medical University, Hirakata Hospital, Kobe University Graduate School of Medicine, National Hospital Organization Shikoku Cancer Center, National Kyushu Cancer Center, Kyushu University Hospital.
This study is supported by the National Cancer Center Research and Development Fund (grants 23-A-16, 23-A-22 and 26-A-4) and by the Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and development, AMED (15Ack0106079h0002).
Junji Furuse received paid consulting from Taiho, Eli Lilly Japan, Yakult, Chugai, Pfizer, Nippon Kayaku, Mochida, Sandoz and Sawai. Chigusa Morizane received honoraria from Pfizer, Novartis, Yakult Honsha and Lilly and has advisory role AstraZeneca, Yakult Honsha and Novartis. Takuji Okusaka declared honoraria from Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Yakult Honsha Co., Ltd. and Nippon Kayaku Co., Ltd. He received fee for consulting or advisory role from Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. and research funding from Eli Lilly Japan K.K., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd. and Pfizer Japan, Inc.