Gemcitabine Hydrochloride and Cisplatin With or Without Nab-Paclitaxel in Treating Patients With Newly Diagnosed Advanced Biliary Tract Cancers

Study Overview
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Brief Summary
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This phase III trial studies how well gemcitabine hydrochloride and cisplatin given with or without nab-paclitaxel work in treating patients with newly diagnosed biliary tract cancers that have spread to other places in the body. Drugs used in chemotherapy, such as gemcitabine hydrochloride, cisplatin, and nab-paclitaxel, 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. It is not known if giving gemcitabine hydrochloride and cisplatin with or without nab-paclitaxel may work better at treating biliary tract cancers.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare overall survival (OS) in patients with untreated, advanced biliary cancers treated with gemcitabine hydrochloride (gemcitabine) and cisplatin (GC) versus those treated with gemcitabine, cisplatin, and nab-Paclitaxel (GCN). SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS) in patients treated with GC versus GCN. II. To compare overall response rate (ORR), complete and partial, confirmed and unconfirmed, in the subset of patients with measurable disease treated with GC versus GCN. III. To compare disease control rate (confirmed and unconfirmed; complete response + partial response + stable disease) (DCR) in patients treated with GC versus GCN. IV. To evaluate the frequency and severity of toxicity associated with GC and GCN in the patient population. V. To explore the correlation between change in cancer antigen 19-9 (CA19-9) levels from baseline to post-treatment (after 3 cycles) and overall response rate, in each treatment arm separately and in the total cohort. ADDITIONAL OBJECTIVES: I. To bank tissue and blood for future translational medicine studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive nab-paclitaxel 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. ARM II: Patients receive 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 every 6 months for 2 years and then at the end of year 3.

Official Title
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A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers

Conditions
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Stage III Distal Bile Duct Cancer AJCC v8, Stage III Gallbladder Cancer AJCC v8, Stage III Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIA Distal Bile Duct Cancer AJCC v8, Stage IIIA Gallbladder Cancer AJCC v8, Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIB Distal Bile Duct Cancer AJCC v8, Stage IIIB Gallbladder Cancer AJCC v8, Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8, Stage IV Distal Bile Duct Cancer AJCC v8, Stage IV Gallbladder Cancer AJCC v8, Stage IV Intrahepatic Cholangiocarcinoma AJCC v8, Stage IVA Gallbladder Cancer AJCC v8, Stage IVB Gallbladder Cancer AJCC v8, Unresectable Extrahepatic Bile Duct Carcinoma, Unresectable Gallbladder Carcinoma, Unresectable Intrahepatic Cholangiocarcinoma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Gemcitabine Hydrochloride
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer NOTE: Pathology report must be uploaded in Rave. Histology report must be consistent with an adenocarcinoma with pancreaticobiliary primary assuming there are no pancreatic lesions and other primaries are ruled out per local standard Patients must have documented metastatic or locally advanced unresectable disease on computed tomography (CT) or magnetic resonance (MR) imaging CT scans or MRIs used to assess measurable disease. Must have been completed within 28 days prior to registration. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form Patient must not have a current diagnosis of ampullary cancer Patients must not have received prior systemic therapy for the current metastatic or locally advanced biliary cancer Patient must not have received adjuvant therapy within 6 months prior to registration Patients must have a complete medical history and physical exam within 28 days prior to registration Patients must have a Zubrod performance status of 0 or 1 Patients must not have a history of peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. In CTCAE version 5.0 grade 2 sensory neuropathy is defined as ?moderate symptoms; limiting instrumental activities of daily living (ADLs)? Absolute neutrophil count (ANC) >= 1,500/mcL (obtained within 28 days prior to registration) Platelets >= 100,000/mcL (obtained within 28 days prior to registration) Hemoglobin >= 8 g/dL (obtained within 28 days prior to registration) Serum albumin >= 2.8 g/dL (obtained within 28 days prior to registration) Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert?s syndrome, who must have a direct bilirubin < 1.5 mg/dL) (obtained within 28 days prior to registration) Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 8 x IULN (obtained within 28 days prior to registration) Serum creatinine =< IULN OR calculated creatinine clearance >= 60 mL/min (obtained within 28 days prior to registration) Patients must have CA19-9 obtained within 42 days prior to registration Patients must have sodium, potassium, bicarbonate, chloride, blood urea nitrogen (BUN), calcium, total protein, magnesium, and alkaline phosphatase obtained within 28 days prior to registration Patients must not have an active infection requiring systemic therapy No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years Patients must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures Sites must seek additional patient consent for the future use of specimens Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

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 |
| --- | --- |
| Experimental: Arm I (nab-paclitaxel, cisplatin, gemcitabine hydrochloride)<br>Patients receive nab-paclitaxel 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;Drug: Nab-paclitaxel<br>* Given IV<br>* Other names: Protein-bound Paclitaxel;|
| Experimental: Arm II (cisplatin, gemcitabine hydrochloride)<br>Patients receive 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;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS will be determined using the log-rank test with stratification by disease site (gallbladder adenocarcinoma versus [vs.] intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma), disease stage (locally advanced vs. metastatic), and Zubrod performance status (0 vs. 1). Distributions of overall survival by treatment arm will be estimated using the method of Kaplan-Meier. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | Rates of serious toxicities will be compared between arms. | Up to 3 years | 
| Progression-free survival (PFS) | Distributions of PFS will be described using cumulative incidence estimates with differences in these estimates between treatment arms assessed by a stratified Cox regression model. | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years | 
| Overall response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | ORR is defined as confirmed and unconfirmed; complete response + partial response + stable disease. The chi-square test will be used to compare ORR, disease control rate (DCR), and rates of toxicity events across arms. ORR will be assessed in the subset of patients with measurable disease. | Up to 3 years | 
| Disease control rate as measured by RECIST 1.1 criteria | The chi-square test will be used to compare ORR, DCR, and rates of toxicity events across arms. Disease control includes confirmed and unconfirmed complete response, confirmed and unconfirmed partial response, and stable disease. In patients with non-measurable disease, disease control will be defined as those who are alive without disease progression. | Up to 3 years | 
| Changes in carbohydrate antigen 19-9 (CA 19-9) levels | Correlations between changes in CA19-9 levels from baseline to post-treatment and ORR will be estimated via logistic regression models, both within each treatment arm and in the overall cohort. Analyses will explore the prognostic and predictive values of CA19-9 for disease response. | Baseline up to course 3 |