Gemcitabine With or Without Cisplatin in Treating Patients With Unresectable Locally Advanced or Metastatic Cholangiocarcinoma or Other Biliary Tract Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether gemcitabine is more effective with or without cisplatin in treating cholangiocarcinoma or biliary tract tumors. PURPOSE: This randomized phase III trial is studying gemcitabine and cisplatin to see how well they work compared to gemcitabine alone in treating patients with unresectable locally advanced or metastatic cholangiocarcinoma or other biliary tract tumors.

Detailed Description
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OBJECTIVES: Primary Compare the overall survival of patients with unresectable locally advanced or metastatic cholangiocarcinoma or other biliary tract tumors treated with gemcitabine hydrochloride with vs without cisplatin. Secondary Compare the progression-free survival of patients treated with these regimens. Compare the toxic effects of these regimens in these patients. Compare quality of life of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, primary site of disease (gallbladder vs bile ducts vs ampulla), prior therapy (photodynamic therapy [PDT] vs non-PDT therapy vs none), ECOG performance status (0 vs 1 vs 2), and disease status (locally advanced vs metastatic). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 1½ hours on days 1 and 8. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, 12 weeks, and after finishing treatment. After completion of study treatment, patients are followed periodically for at least 3 years. Peer Reviewed and Funded or Endorsed by Cancer Research UK PROJECTED ACCRUAL: A total of 400 patients will be accrued for this study.

Official Title
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Gemcitabine, Alone or in Combination With Cisplatin, in Patients With Advanced or Metastatic Cholangiocarcinomas and Other Biliary Tract Tumors: A Multicentre, Randomized Phase III Study

Conditions
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Extrahepatic Bile Duct Cancer, Gallbladder Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed biliary tract, gallbladder, or ampullary carcinoma Intra- or extra-hepatic disease allowed Unresectable locally advanced, recurrent, or metastatic disease No brain metastases PATIENT CHARACTERISTICS: Performance status ECOG 0-2 Life expectancy At least 3 months Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL (transfusion allowed) WBC ≥ 3,000/mm^3 Hepatic AST and ALT ≤ 3 times upper limit of normal (ULN) (5 times ULN if liver metastases are present) Bilirubin ≤ 1.5 times ULN Alkaline phosphatase ≤ 3 times ULN (5 times ULN if liver metastases are present) Adequate biliary drainage No unresolved biliary tract obstruction Renal Creatinine < 1.5 times ULN Urea < 1.5 times ULN Glomerular filtration rate (GFR) ≥ 45 mL/min If GFR < 60 mL/min, isotope EDTA confirmation of adequate renal function is required Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation No active, uncontrolled infection No other severe or uncontrolled systemic disease No other malignancy within the past 5 years except nonmetastatic basal cell or squamous cell skin cancer or carcinoma in situ of the cervix treated by cone-biopsy or resection No psychiatric disorder that would preclude giving informed consent PRIOR CONCURRENT THERAPY: Chemotherapy At least 6 months since prior adjuvant chemotherapy No prior gemcitabine hydrochloride No prior cisplatin No prior systemic chemotherapy for locally advanced or metastatic disease except low-dose radiosensitizing chemotherapy in conjunction with radiotherapy Radiotherapy Prior radiotherapy for localized disease allowed provided there is clear evidence of disease progression afterwards Surgery Prior curative surgery allowed provided there is evidence of nonresectable disease relapse requiring systemic chemotherapy Other Recovered from all prior therapies Prior photodynamic therapy (PDT) allowed provided it was given for localized disease only (with no evidence of metastatic disease) and resulted in subsequent disease progression after completion of therapy OR to relieve biliary obstruction in the presence of metastatic disease PDT must have been completed ≥ 4 weeks ago At least 4 weeks since prior investigational agents No other concurrent, curative anticancer therapy

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A - Gemcitabine<br>Gemcitabine alone | Drug: gemcitabine hydrochloride<br>* 1000mg/m2 in 250-500mls 0.9% saline over 30 mins by intravenous infusions on day 1, 8 and 15 (Arm A only) of each 28 (Arm A) or 21 (Arm B) day cycle.<br>* Other names: Gemzar;|
| Experimental: B - Gemcitabine and Cisplatin<br>Gemcitabine and Cisplatin | Drug: cisplatin<br>* 25 mg/m2 in 1000 mls 0.9% saline given over 1 hour followed by 500 mls 0.9% saline over 90 mins<br>* Other names: cisplatinum;Drug: gemcitabine hydrochloride<br>* 1000mg/m2 in 250-500mls 0.9% saline over 30 mins by intravenous infusions on day 1, 8 and 15 (Arm A only) of each 28 (Arm A) or 21 (Arm B) day cycle.<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | From date of randomisation till date of death or last date of follow-up (up to 5 years) | From date of randomisation till date of death or last date of follow-up (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | From date of randomisation till date of death or last date of follow-up (up to 5 years) | From date of randomisation till date of death or last date of follow-up (up to 5 years) | 
| Quality of life | Quality of life as measured by EORTC Quality of Life Questionnaire Core 30 Items periodically | Before and 12 weeks after completion of treatment | 
| Toxicity | Toxicity as measured by NCI CTC periodically. The proportion of patients who experience a toxicity of grade 3 or 4 will be compared between the two arms of the trial. | During treatment and follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cholangiocarcinoma of the extrahepatic bile duct, recurrent extrahepatic bile duct cancer, unresectable extrahepatic bile duct cancer, cholangiocarcinoma of the gallbladder, recurrent gallbladder cancer, unresectable gallbladder cancer, metastatic extrahepatic bile duct cancer, metastatic gallbladder cancer