Gemcitabine + Oxaliplatin +Nab-paclitaxel in Subjects With Advanced Biliary Tract Cancer

Study Overview
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Brief Summary
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The objective of the study is to determine a new combination of drug that improves the outcome in patients with advanced (unresectable or metastatic) BTC. The primary objective of the phase I part of the study is to determine the maximum tolerated dose (MTD) of the combination gemcitabine plus oxaliplatin plus nab-paclitaxel, established in the first cycle of therapy, in order to determine the recommended phase II dose (RP2D). The primary objective of the phase II is to determine activity of GEMOX plus nab-paclitaxel. The secondary objectives of the study consist in to better define the safety profile and the outcome of the study treated population.

Detailed Description
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Systemic chemotherapy is increasingly being applied in cases of biliary tract cancers. A benefit for chemotherapy over best supportive care alone was suggested in a trial that randomly assigned 90 patients with advanced pancreatic or biliary cancer (37 with bile duct cancer) to fluorouracil (FU)-based systemic chemotherapy or best supportive care alone (median survival 6 versus 2.5 months, respectively) (1). The literature regarding treatment results with specific regimens is limited because most series are small, and many reports consist of a mix of bile duct cancers, gallbladder cancer, ampullary cancer, and either pancreatic or hepatocellular cancers. Although they arise in similar locations, these cancers all have a unique natural history and response to chemotherapy. In general, no single drug or combination has consistently increased median survival beyond the expected six to eight months.

Official Title
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A Multicenter, Phase I-II Trial of Gemcitabine Plus Oxaliplatin and Nab-paclitaxel in Subjects With Advanced (Unresectable or Metastatic) Biliary Tract Cancer

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Drug: nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written, signed informed consent Male or female aged 18 years or older Histologically or citologically-confirmed advanced (unresectable or metastatic) BTC (gallbladder cancer, cancer of the extrahepatic bile duct, intrahepatic cholangiocarcinoma and ampullary carcinoma) Measurable or evaluable but non-measurable disease according to RECIST v. 1.1 Chemotherapy-naïve (prior chemotherapy in the adjuvant setting completed more than 6 months before the trial entry is accepted) Adequate bone marrow, liver, and renal function ECOG PS 0-1 Life expectancy of at least 12 weeks Negative serum pregnancy test for women of childbearing potential; Adoption of adequate contraceptive methods when applicable Women of child-bearing potential must use the following adequate contraceptive methods during all the study and for 1 month after completion of study treatment: abstinence, tubal ligation, oral contraception or transdermal contraceptives, copper intrauterine device, vasectomy of the partner. For male patients with female partners of childbearing potential, agreement to use a barrier method of contraception from the first dose of treatment and for 6 months after completion of study treatment. Male patients mustn't donate sperm during the treatment with nab-paclitexel and for 6 months after completion of study treatment. Agreement not to donate blood during the study. 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) Previous systemic treatment for advanced disease Known symptomatic brain metastases or carcinomatous meningitis Severe or uncontrolled systemic disease and/or active or uncontrolled infection Women who are currently pregnant or breast feeding Previous or current malignancies of other histologies within the last 3 years, with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin Known hypersensitivity to nab-paclitaxel, gemcitabine, oxaliplatin or any of the excipients

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: gemcitabine oxaliplatin nab-paclitaxel<br>combination at different dose of gemcitabine, oxaliplatin and nab-paclitaxel | Drug: nab-paclitaxel<br>* Phase I dosing regimens: The dose of treatment will be assigned at the time of enrolment in one of these 3 subsequent dose-levels: - 1° level: gemcitabine 800 mg/m2 + oxaliplatin 80 mg/m2 + nab-paclitaxel 80 mg/m2 0° level: gemcitabine 1000 mg/m2 + oxaliplatin 80 mg/m2 + nab-paclitaxel 100 mg/m2 level: gemcitabine 1000 mg/m2 + oxaliplatin 80 mg/m2 + nab-paclitaxel 125 mg/m2 level: gemcitabine 1000 mg/m2 + oxaliplatin 80 mg/m2 + nab-paclitaxel 150 mg/m2 each administered on day 1, every 14 day Phase II: Gemcitabine plus oxaliplatin plus nab-paclitaxel according to RP2D.<br>* Other names: Oxaliplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose | Determination of the maximum tolerated dose for phase I | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | The secondary objectives of the study consist in to better define the safety profile as assessed by CTCAE V4.0 | 16 weeks | 
| Number of responder (in term of CR, PR, SD) to GEMOX plus nab-paclitaxel as assessed by RECIST 1.1 | Determination of activity of GEMOX plus nab-paclitaxel as assessed by RECIST 1.1 | Maximum of 24 weeks |