Chemotherapy Before & After Surgery in Patients With Resectable Gallbladder Cancer

Study Overview
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Brief Summary
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This phase III trial studies how well chemotherapy before and after surgery works in treating participants with gallbladder cancer that can be removed by surgery. Drugs used in chemotherapy, such as cisplatin, gemcitabine, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before and after surgery may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the difference in overall survival (OS) at 3 years for patients with incidental gallbladder cancer (IGBC) who receive neoadjuvant gemcitabine hydrochloride (gemcitabine) and cisplatin (gem/cis) prior to reoperation followed by adjuvant capecitabine compared to patients who receive only adjuvant capecitabine after reoperation. SECONDARY OBJECTIVES: I. To determine the difference in recurrence-free survival (RFS) at 1 year for patients with IGBC who receive perioperative chemotherapy prior to and after re-operation compared to patients who receive only adjuvant chemotherapy after reoperation. II. To assess the clinical effect of perioperative chemotherapy compared to only adjuvant chemotherapy after reoperation on resectability among 3 cohorts: all enrolled patients, all patients who undergo staging laparoscopy, and all patients who undergo laparotomy. III. To compare the incidence of residual disease at the time of re-resection between patients who receive perioperative chemotherapy and those who receive only adjuvant chemotherapy. OUTLINE: Participants are randomized to 1 of 2 arms. ARM I: Participants undergo re-resection (including partial liver resection and portal lymph node dissection) after incidental diagnosis of gallbladder cancer. Participants then receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. ARM II: Participants receive cisplatin intravenously (IV) over 1 hour and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Within 10 weeks of chemotherapy, participants undergo re-resection (including partial liver resection and portal lymph node dissection). Participants then receive capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up periodically for up to 3 years.

Official Title
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Perioperative Chemotherapy Prior To and After Reoperation for Incidental Gallbladder Cancer - An International, Randomized Phase III Trial

Conditions
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Stage I Gallbladder Cancer AJCC v8, Stage II Gallbladder Cancer AJCC v8, Stage IIA Gallbladder Cancer AJCC v8, Stage IIB Gallbladder Cancer AJCC v8, Stage III Gallbladder Cancer AJCC v8, Stage IIIA Gallbladder Cancer AJCC v8, Stage IIIB Gallbladder Cancer AJCC v8

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Cisplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed T1b, T2 or T3 gallbladder cancer discovered incidentally at the time of or following routine cholecystectomy for presumed benign disease Resectable disease at the time of enrollment based on high-quality, preoperative, cross-sectional imaging of the chest, abdomen, and pelvis (C/A/P) Enrollment and randomization within 12 weeks of initial cholecystectomy High-quality cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) performed within 4 weeks prior to enrollment Able to give informed consent Able to adhere to study visit schedule and other protocol requirements Eastern Cooperative Oncology Group (ECOG) performance status of < 2 Absolute neutrophil count ≥ 1500/mm³ Platelet count ≥ 100,000/mm³ Exclusion Criteria: Patients with histologically-confirmed Tis, T1a, or T4 tumors Unresectable gallbladder cancer at the time of enrollment based on high-quality, preoperative, cross-sectional imaging of the C/A/P Unable to sign informed consent Serum creatinine > 1.5 x upper limit of normal or estimated creatinine clearance (CrCl) < 45 ml/min Serum total bilirubin > 1.5 x upper limit of normal Presence of active infection Pregnant and/or breastfeeding Known dihydropyrimidine dehydrogenase deficiency

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Arm I (capecitabine)<br>Participants undergo re-resection (including partial liver resection and portal lymph node dissection). Participants then receive capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;|
| Experimental: Arm II (chemotherapy, capecitabine)<br>Participants receive cisplatin IV over 1 hour and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Within 10 weeks of chemotherapy, participants undergo re-resection (including partial liver resection and portal lymph node dissection). Participants then receive capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Cisplatin<br>* Given IV<br>* Other names: Platinol;Drug: Gemcitabine<br>* Given IV<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) is defined as time from randomization to death from any cause. | Up to 3 years after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival | Recurrence-free survival (RFS) at one year, defined as time from surgery to first observed disease recurrence or death from any cause, among only patients who undergo complete, curative-intent re-resection. Disease recurrence will be based on findings from surveillance cross-sectional imaging of the chest, abdomen, and pelvis (CT or MRI, and any other additional imaging necessary to confirm recurrence). Patients who do not undergo reoperation or re-resection, have incomplete resections (R2), or who have gross evidence of distant metastases and/or T4 disease will be excluded from the RFS analysis | From surgery to first observed disease recurrence or death from any cause, assessed at 1 year | 
| Overall resectability rate | Overall resectability rate is defined as the proportion of patients who successfully undergo a re-resection versus all enrolled patients. Patients who do not undergo reoperation or re-resection, have incomplete resections (R2), or who have gross evidence of distant metastases and/or T4 disease will be considered as unresectable for resectability analyses. | Up to 3 years after study start | 
| Resectability rate at diagnostic laparoscopy | Resectability rate at diagnostic laparoscopy is defined as the proportion of patients who successfully undergo a re-resection versus all patients who undergo staging laparoscopy. Patients who do not undergo reoperation or re-resection, have incomplete resections (R2), or who have gross evidence of distant metastases and/or T4 disease will be considered as unresectable for resectability analyses. | Up to 3 years after study start | 
| Resectability rate at laparotomy | Resectability rate at laparotomy is defined as the proportion of patients who successfully undergo a re-resection versus all patients who undergo laparotomy. Patients who do not undergo reoperation or re-resection, have incomplete resections (R2), or who have gross evidence of distant metastases and/or T4 disease will be considered as unresectable for resectability analyses. | Up to 3 years after study start | 
| Incidence of residual disease after or at the time of re-resection | Incidence of residual disease after or at the time of re-resection is defined as the presence of either microscopic or gross malignancy based on pathologic analysis. | Up to 3 years after study start |