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

NCT ID: NCT02181634

Last Updated: 2018-10-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-09
• Study Completion Date: 2017-10-01

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.

Conditions

Cholangiocarcinoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Nab-Paclitaxel and Gemcitabine

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Abraxane®; Cytotoxic Antimicrotubular; Gemzar®; Pyrimidine Antimetabolite

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene Corporation

INDUSTRY

Sponsor Role: collaborator

PrECOG, LLC.

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vaibhav Sahai, MD

Role: STUDY_CHAIR

University of Michigan Health System in Ann Arbor, MI

Locations

Colorado Cancer Research Program

Denver, Colorado, 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

Ochsner Medical Center

New Orleans, Louisiana, United States

Tufts Medical Center

Boston, Massachusetts, United States

University Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States

St. Joseph Mercy Health System

Ann Arbor, Michigan, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

University of Michigan Medical Center

Ann Arbor, Michigan, 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

Montefiore Medical Center

The Bronx, 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

University of Tennessee Medical Center

Knoxville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, 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

Medical University of Vienna

Vienna, , Austria

Countries

United States; Austria

References

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.

Reference Type: RESULT

PMID: 30178032 (View on PubMed)

Other Identifiers

AX-CL-OTHER-PrECOG-004080

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2015-002066-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PrE0204

Identifier Type: -

Identifier Source: org_study_id