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

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Brief Title

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

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months)

Secondary Outcome

 Overall Survival (OS)

Condition

Cholangiocarcinoma

Intervention

Nab-Paclitaxel and Gemcitabine

Study Arms / Comparison Groups

 Nab-Paclitaxel and Gemcitabine
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

74

Start Date

December 9, 2014

Completion Date

October 1, 2017

Primary Completion Date

September 24, 2016

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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Vaibhav Sahai, MD, , 

Location Countries

Austria

Location Countries

Austria

Administrative Informations


NCT ID

NCT02181634

Organization ID

PrE0204

Secondary IDs

AX-CL-OTHER-PrECOG-004080

Responsible Party

Sponsor

Study Sponsor

PrECOG, LLC.

Collaborators

 Celgene Corporation

Study Sponsor

Vaibhav Sahai, MD, Study Chair, University of Michigan Health System in Ann Arbor, MI


Verification Date

September 2018