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

Phase 2

Completed

Conditions: Cholangiocarcinoma

Interventions: Drug: Nab-Paclitaxel and Gemcitabine

Registration Number: NCT02181634

Lead Sponsor: PrECOG, LLC.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 74

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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nab-Paclitaxel and Gemcitabine	Nab-Paclitaxel and Gemcitabine	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.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months)	Assessed 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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Every 3-6 months for up to 3 years	OS is defined as the time from enrollment until death or last patient contact.
Progression-free Survival (PFS)	Every 3-6 months for up to 3 years	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.
Overall Response Rate (ORR)	Every 3-6 months for up to 3 years	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.
Time To Progression (TTP)	Every 3-6 months for up to 3 years	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.
Disease Control Rate (DCR)	Every 3-6 months for up to 3 years	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.
Association Between PFS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline	CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment	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.
Association Between OS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline	CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment	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.

Trial Locations

Locations (25): University of Texas Southwestern Medical Center
🇺🇸
Dallas, Texas, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Advocate Christ Medical Center
🇺🇸
Oak Lawn, Illinois, United States
Siouxland Hematology-Oncology Associates
🇺🇸
Sioux City, Iowa, United States
Tufts Medical Center
🇺🇸
Boston, Massachusetts, United States
University Massachusetts Memorial Medical Center
🇺🇸
Worcester, Massachusetts, United States
Metro Minnesota CCOP
🇺🇸
Saint Louis Park, Minnesota, United States
Rutgers Cancer Institute of New Jersey
🇺🇸
New Brunswick, New Jersey, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
University of Pennsylvania, Abramson Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
University of Pennsylvania; Abramson Cancer Center at Presbyterian Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Gundersen Health System
🇺🇸
La Crosse, Wisconsin, United States
University of Wisconsin-Madison
🇺🇸
Madison, Wisconsin, United States
Aurora Cancer Care
🇺🇸
Wauwatosa, Wisconsin, United States
Ochsner Medical Center
🇺🇸
New Orleans, Louisiana, United States
University of Tennessee Medical Center
🇺🇸
Knoxville, Tennessee, United States
Medical University of Vienna
🇦🇹
Vienna, Austria
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
University of Michigan Health System
🇺🇸
Ann Arbor, Michigan, United States
Colorado Cancer Research Program
🇺🇸
Denver, Colorado, United States
St. Joseph Mercy Health System
🇺🇸
Ann Arbor, Michigan, United States
University of Michigan Medical Center
🇺🇸
Ann Arbor, Michigan, United States
Montefiore Medical Center
🇺🇸
Bronx, New York, United States