Gemcitabine Hydrochloride, Cisplatin, and Nab-Paclitaxel in Treating Patients With Advanced or Metastatic Biliary Cancers

Study Overview
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Brief Summary
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This phase II trial studies how well gemcitabine hydrochloride, cisplatin, and nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) work in treating patients with biliary cancers (which includes the gallbladder and bile ducts inside and outside the liver) that have spread to other places in the body and usually cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as gemcitabine hydrochloride, cisplatin, and paclitaxel albumin-stabilized nanoparticle formulation, 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 more than one drug (combination chemotherapy) may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the progression-free survival (PFS) of gemcitabine hydrochloride (gemcitabine), cisplatin, and nab-paclitaxel in advanced, untreated biliary cancers (intrahepatic cholangiocarcinomas, extrahepatic cholangiocarcinomas, and gallbladder cancers). SECONDARY OBJECTIVES: I. Determine the response rate (RR) and disease control rate (partial response + complete response + stable disease) of gemcitabine, cisplatin, and nab-paclitaxel in advanced biliary cancers. II. Determine overall survival (OS) of gemcitabine, cisplatin, and nab-paclitaxel in advanced biliary cancers. III. Evaluate the toxicity of gemcitabine, cisplatin, and nab-paclitaxel in advanced biliary cancers. EXPLORATORY OBJECTIVES: I. Correlate the carbohydrate antigen (CA) 19-9 response (defined as >50% decrease from baseline) with tumor response, PFS and OS. II. Assess ribonucleotide reductase subunit MI (RRMI), excision repair cross-complementation group 1 (ERCC1) pre-treatment status and correlate with tumor response, PFS and OS on an exploratory basis. III. Collect optional blood and tissue at the start of treatment and at progression to explore mechanisms of resistance. OUTLINE: Patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Official Title
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A Phase II Study of Gemcitabine, Cisplatin, and Abraxane in Advanced Biliary Cancers

Conditions
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Stage III Intrahepatic Cholangiocarcinoma AJCC v7, Stage IIIA Gallbladder Cancer AJCC v7, Stage IIIB Gallbladder Cancer AJCC v7, Stage IVA Gallbladder Cancer AJCC v7, Stage IVA Intrahepatic Cholangiocarcinoma AJCC v7, Stage IVB Gallbladder Cancer AJCC v7, Stage IVB Intrahepatic Cholangiocarcinoma AJCC v7, Unresectable Extrahepatic Bile Duct Carcinoma, Unresectable Gallbladder Carcinoma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Gemcitabine Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have histologically or cytologically confirmed intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer or may undergo a repeat biopsy for histologic confirmation if pre-existing biopsy is not sufficient for diagnosis Metastatic or unresectable disease documented on diagnostic imaging studies May not have received prior chemotherapy; if patient has received prior adjuvant therapy, must be > 6 months from treatment Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 Platelets >= 100,000/ul Hemoglobin > 9.0 g/dL Total bilirubin =< 1.5 mg/dL (in patients with known Gilbert's syndrome direct bilirubin =< 1.5 x upper limit of normal [ULN] will be used as organ function criteria, instead of total bilirubin) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = < 5 x ULN Creatinine =< 1.5 gm/dL Negative serum or urine pregnancy test in women with childbearing potential (WOCBP) defined as not post-menopausal for 12 months or no previous surgical sterilization, within one week prior to initiation of treatment; WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of study drug to minimize the risk of pregnancy A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study and for up to 12 weeks after the last dose of study drug to minimize the risk of pregnancy; if the partner is pregnant or breastfeeding, the subject must use a condom Patients must sign an informed consent and authorization indicating that they are aware of the investigational nature of this study and the known risks involved Exclusion Criteria: Peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for Adverse Events (CTCAE) 4.0; in CTCAE version 4.0 grade 2 sensory neuropathy is defined as moderate symptoms; limiting instrumental activities of daily living (ADLs) Concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study such as unstable angina, myocardial infarction within 6 months, unstable symptomatic arrhythmia, uncontrolled diabetes, serious active or uncontrolled infection Pregnancy (positive pregnancy test) or lactation Known central nervous system (CNS) disease, except for treated brain metastasis; treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period; anticonvulsants (stable dose) are allowed; treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nab-paclitaxel, cisplatin, gemcitabine)<br>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: Protein-bound Paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | The Kaplan-Meier method was used to estimate OS, with surviving patients censored at the time of surgery or at last known follow-up. | up to 3 years | 
| Number of Participants With Treatment Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria(RECIST v1.1.14) for target lesions and assessed by MRI: Complete Response (CR),Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 2 years |