Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Cholangiocarcinoma (PrE0204)

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

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.

Study Overview

• Status: Completed
• Conditions: Cholangiocarcinoma
• Intervention / Treatment: Drug: Nab-Paclitaxel and Gemcitabine

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.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
• United States
  • Colorado
    • Denver, Colorado, United States, 80222
      • Colorado Cancer Research Program
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University Massachusetts Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Ann Arbor, Michigan, United States, 48106-0995
      • St. Joseph Mercy Health System
  • Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Metro Minnesota CCOP
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Abramson Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania; Abramson Cancer Center at Presbyterian Medical Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Health System
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin-Madison
    • Wauwatosa, Wisconsin, United States, 53226
      • Aurora Cancer care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Nab-Paclitaxel and Gemcitabine; 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.; Other Names: Gemzar®; Abraxane®; Cytotoxic Antimicrotubular; Pyrimidine Antimetabolite

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Circulating Tumor Cells (CTCs)	Correlate change in CTCs to median PFS, OS, TTP, ORR and DCR.	Prior to Cycle 1, Day 1; Cycle 1 Day 8; Cycle 3, Day 1 and at Off Treatment
Stromal SPARC Expression	Correlate stromal SPARC (high versus low) expression by immunohistochemistry (IHC) with median PFS, OS, TTP, ORR and DCR.	Baseline
Fibrosis Expression	Correlate fibrosis (low, intermediate and high) by trichrome staining with median PFS, OS, TTP, ORR and DCR.	Baseline
CDA Expression	Correlate CDA (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.	Baseline
hENT Expression	Correlate hENT1 (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.	Baseline
Banking Biospecimens for Future Assessment	Optional specimen banking of patient blood specimens (including serum, plasma and buffy coat) as well as fixed left-over tissue specimens when available from all enrolled patients in this trial for possible future molecular, pharmacogenomic, and/or proteomic testing.	Prior to Cycle 1, Day 1; Cycle 1, Day 8; Cycle 3, Day 1 and at Off Treatment

Collaborators and Investigators

• Sponsor: PrECOG, LLC.
• Collaborators: Celgene Corporation
• Investigators: Study Chair: Vaibhav Sahai, MD, University of Michigan Health System in Ann Arbor, MI

Publications and helpful links

General Publications

• Sahai V, Catalano PJ, Zalupski MM, Lubner SJ, Menge MR, Nimeiri HS, Munshi HG, Benson AB 3rd, O'Dwyer PJ. Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018 Dec 1;4(12):1707-1712. doi: 10.1001/jamaoncol.2018.3277.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 9, 2014
• Primary Completion (ACTUAL): September 24, 2016
• Study Completion (ACTUAL): October 1, 2017

Study Registration Dates

• First Submitted: July 2, 2014
• First Submitted That Met QC Criteria: July 2, 2014
• First Posted (ESTIMATE): July 4, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 3, 2018
• Last Update Submitted That Met QC Criteria: September 5, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Gemcitabine; CCA; Abraxane®; Nab-Paclitaxel; Advanced Cholangiocarcinoma; Bile Duct Cancer; Metastatic Cholangiocarcinoma; Gemzar®
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Gemcitabine; Paclitaxel; Antimetabolites
• Other Study ID Numbers: PrE0204; AX-CL-OTHER-PrECOG-004080 (OTHER_GRANT: Celgene); 2015-002066-24 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data is proprietary

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No