Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Cholangiocarcinoma

Study Overview
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Brief Summary
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Patients with advanced or metastatic cholangiocarcinoma (CCA) who are not eligible for curative surgery, transplantation, or ablative therapies will receive nab-paclitaxel and gemcitabine chemotherapy. The purpose of this study is to evaluate the effectiveness and safety of the combination of nab-paclitaxel and gemcitabine. The effectiveness will be determined by improvement in the length of time during and after treatment, that the CCA does not get worse.

Detailed Description
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Advanced cholangiocarcinomas (CCAs) are aggressive tumors with median survival time after diagnosis of less than 12 months, and five-year overall survival (OS) of  5% with systemic chemotherapy. Currently available systemic therapies for CCA are largely ineffective, thus the rationale for the proposed research is to investigate targeted delivery of chemotherapy. The goal of this study is to evaluate the efficacy of gemcitabine plus nab-paclitaxel in patients with advanced CCA. This is based on the premise that nab-paclitaxel binds to SPARC (secreted protein acidic and rich in cysteine) through its interaction with albumin, leading to an increase in intra-tumoral concentration of gemcitabine through decreased deoxycytidine deaminase (CDA) enzyme. We hope to improve on the OS of patients with advanced CCA through the use of the synergistic combination of nab-paclitaxel and gemcitabine to specifically target the SPARC protein in the peri-tumoral stroma. We aim to provide critical data to further develop pharmacologic strategies to target the desmoplastic stroma in order to increase chemotherapy responsiveness of CCAs. We will also examine whether circulating tumor cell (CTC) levels with targeted gene expression analysis and stromal SPARC levels correlate with patient outcome and thus serve as prognostic biomarkers. We will evaluate the role of Human Equilibrative Nucleoside Transporter 1 (hENT1), CDA and tumor fibrosis as additional prognostic and predictive biomarkers in CCA. This clinical trial hopes to improve on the poor prognosis of patients with advanced CCA by establishing the activity of a platinum-free doublet, nab-paclitaxel plus gemcitabine that has shown clear clinical benefit in pancreatic cancer which has close biological parallels to CCA. A maximum of 70 patients will be enrolled to attain 67 eligible/evaluable patients. Stage I will enroll 37 patients. If 21 or more patients are alive and progression-free at 6 months, the study will proceed to Stage II and an additional 33 patients will be enrolled. Procurement of archived tissue, if available, from a previous diagnostic biopsy is mandatory for enrollment. If not available, this will not preclude participation in the trial, nor will additional biopsies be performed for research purposes only. Optional blood samples will be requested.

Official Title
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A Multi-Institutional, Single Arm, Two-Stage Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Drug: Nab-Paclitaxel and Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have histologically-confirmed diagnosis of cholangiocarcinoma Stage II, III, or IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed. Must have radiographically measurable disease in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures; a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable. May have received prior radiation, chemoembolization, radioembolization, or other local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 1 toxicity. NOTE: Measurable disease (as required above) must still be present. May have received prior radiation for bone or brain metastases if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2 weeks prior to registration. Age ≥ 18 years. Child-Pugh score of A or B with ≤ 7 points. Eastern Cooperative Oncology Group performance status of 0-1. Willing to provide archived tissue, if available, from a previous diagnostic biopsy. Must be able to tolerate CT and/or MRI with contrast. Adequate organ function obtained ≤ 2 weeks prior to registration: Absolute Neutrophil Count ≥ 1500/mm³ Hemoglobin ˃9.0 g/dL Platelets ˃100,000/mm³ Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN) Creatinine Clearance ≥ 50 mL/min Albumin ≥ 2.8 g/dL Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN Aspartate Aminotransaminase (AST)/Alanine Aminotransaminase (ALT) ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases) International Normalized Ratio (INR) <1.5x the ULN [INR ≥ 1.5 is allowed if anticoagulation is used.] Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine may harm the fetus or child. Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for this cancer. Must not be receiving treatment with other investigational agents. Must not have a pre-existing >grade 2 peripheral neuropathy. Must not be receiving immunosuppressive medications, including systemic corticosteroids, aside from the following exceptions: used for adrenal replacement, appetite stimulation, therapy for asthma, bronchitis exacerbation (≤ 2 weeks), anti-emesis, or pre-medication for procedures (i.e. CT scan). No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) seropositivity. Must not have undergone liver transplantation. Must not have serious non-healing wound, ulcer, bone fracture, or abscess. Must not have undergone a major surgical procedure <4 weeks prior to registration. Must not have possible histories of pneumonitis or pneumonitis risk factors. Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. Must have no ongoing or active, uncontrolled infections. Must have no evidence of significant, uncontrolled concomitant diseases including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months, uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, connective tissue disease including lupus. Must not have any history of allergic reaction(s) attributed to compounds of similar composition to nab-paclitaxel or gemcitabine.

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: Nab-Paclitaxel and Gemcitabine<br>Nab-Paclitaxel 125 mg/m² IV and Gemcitabine 1000 mg/m² on days 1, 8 and 15 every 28 days until progression or unacceptable toxicity. | Drug: Nab-Paclitaxel and Gemcitabine<br>* Nab-Paclitaxel will be administered first, at a dose of 125 mg/m² IV over a period of 30 minutes; gemcitabine will be administered second, at a dose of 1000 mg/m² over a period of 30 minutes.<br>* Other names: Pyrimidine Antimetabolite;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months) | Progression-free survival is defined as the time from the date of first study treatment to either the date of documented disease progression or death from any cause, whichever occurred first. Progression-free survival rate at 6 months is defined as the proportion of patients who were disease progression-free and alive at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameter/axes of target lesions, taking as reference the smallest sum on study, or unequivocal progression of existing non-target lesions, or the appearance of new lesions. | Assessed at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from enrollment until death or last patient contact. | Every 3-6 months for up to 3 years | 
| Progression-free Survival (PFS) | Progression-free survival is defined as the time from the date of first study treatment to either the date of documented disease progression or death from any cause, whichever occurred first. | Every 3-6 months for up to 3 years | 
| Time To Progression (TTP) | TTP was defined as the time from date of first dose of study therapy to date of removal from study for progression. Patients who have not experienced progression were censored at the date of last disease evaluation. Progression is evaluated using Solid Tumor Response Criteria (RECIST) Version 1.1. Progression is defined as at least a 20% increase in the sum of the diameters/axes of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm over the nadir. The appearance of new lesions or unequivocal progression of existing non-target lesions also constitutes disease progression. | Every 3-6 months for up to 3 years | 
| Overall Response Rate (ORR) | Overall response rate is defined as the proportion of patients with complete response or partial response per RECIST version 1.1. Complete response is defined as disappearance of all lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters/axes of target lesions and the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker levels above the normal limits. A confirmation assessment performed >=4 weeks after the criteria for response is met is required. | Every 3-6 months for up to 3 years | 
| Disease Control Rate (DCR) | Disease control rate is the proportion of patients achieved complete response, partial response or stable disease per RECIST version 1.1. Complete response is defined as disappearance of all lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters/axes of target lesions and the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker levels above the normal limits. Stable disease is defined as neither sufficient shrinkage to qualify for complete or partial response nor sufficient increase to qualify for progression. A confirmation assessment performed >=4 weeks after the criteria for response is met is required. | Every 3-6 months for up to 3 years | 
| Association Between PFS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline | Patients were dichotomized into maximum CA 19-9 decline >=50% and maximum CA 19-9 decline <50%. Cox proportional hazards model was used to evaluate the association between PFS and maximum change in CA 19-9. | CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment | 
| Association Between OS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline | Patients were dichotomized into maximum CA 19-9 decline >=50% and maximum CA 19-9 decline <50%. Cox proportional hazards model was used to evaluate the association between OS and maximum change in CA 19-9. | CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CCA, Gemzar®, Advanced Cholangiocarcinoma, Metastatic Cholangiocarcinoma, Bile Duct Cancer, Nab-Paclitaxel, Abraxane®, Gemcitabine