Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer

September 19, 2014 updated by: Washington University School of Medicine
The overall purpose of this research is to evaluate the safety and side effects of zoledronic acid (also known as Zometa) in patients before they have surgery to remove the cancer.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Cancer of the pancreas carries an ominous prognosis. The five-year overall survival rate of this malignancy is less than 5%. Chemotherapy with gemcitabine carries a response rate of approximately 25%. Resection offers the only potential for cure; however, even with resection, the great majority of patients will die with metastatic disease. Substantial improvements are needed in the treatment of this malignancy.

Patients with this disease process have clearly developed a tolerance to their pancreatic tumor. This is evidenced by an increased number and activity immunosuppressive cells including MDSC and Treg in patients with pancreas cancer. An intervention that inhibits this population of MDSC and Treg may be highly useful in the treatment of this disease process.

A novel treatment of pancreas cancer, in this setting, would be to deplete circulating and tumor-associated immunosuppressive cells prior to resection. This would facilitate the host to mount a greater immune response against the tumor. The eventual goal would be to combine neoadjuvant zoledronic acid with gemcitabine, another agent which synergizes with zoledronic acid to target MDSC. When combined with current adjuvant chemoradiation, the use of zoledronic acid in the neoadjuvant and adjuvant setting, it is hoped that the patient could mount a greater immune response leading to increased overall survival through the prevention of local disease and distant metastasis.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • St. Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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:

  • Patient must have a newly diagnosed, histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma. The histological slides or blocks must be available for review.
  • Patient must have resectable disease and be a candidate for surgical treatment.
  • Recent CT scan demonstrating pancreatic tumor, no evidence of distant disease, and no contraindication to resection.
  • Patients must be ≥ 18 years old.
  • Performance Status: Karnofsky Performance Status (KPS) ≥ 70
  • Life Expectancy > 12 weeks.
  • No previous history of chemotherapy for pancreas cancer prior to the start of protocol treatment.
  • Patients must have recovered from uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia.
  • Patients must have adequate bone marrow function defined as an absolute neutrophil count >1,500/mm3, platelet count >100,000/mm3 and hemoglobin >10 g/dl.
  • Patients must have normal renal function defined as serum creatinine ≤ 1.3 mg/dl or creatinine clearance ≥ 90 ml/min/1.73 m2 with a serum creatinine > 1.3 mg/dl.
  • Patients must have adequate hepatic function with total bilirubin < 5.0 mg/dl and AST ≤ 3x the institutional normal value.
  • Patient must have no prior or current active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, sarcoidosis or other rheumatologic disease. Asthma and chronic obstructive pulmonary disease that does not require daily systemic corticosteroids is acceptable.
  • The patient with previous history of malignancy is eligible for this study only if the patient meets the following criteria for cancer survivor: (i) patient has undergone potentially curative therapy for all prior malignancies; (ii) the patient has been considered disease free for at least 5 years; (iii) adequately treated non-melanomatous skin cancer.
  • For all sexually active patients, the use of adequate barrier contraception (hormonal or barrier method of birth control) will be required during therapy, prior to study entry and for the duration of study participation. Non-pregnant status will be determined in all women of childbearing potential.
  • After being informed of the treatment involved, patients (or their legally authorized representative) must given written consent.

Exclusion Criteria:

  • Patient is currently receiving other investigational agents.
  • Pregnant and nursing women patients are not eligible.
  • Patients known to be HIV positive are ineligible because of the potential inability to modulate immune responses (patient self-report).
  • Patients treated with any bisphosphonate-based therapeutic for any indication, during the previous year.
  • Patients with recent (within 6 weeks) or planned dental or jaw surgery dental or jaw surgery (e.g. extraction, implants).
  • Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
  • Patients with a history of aspirin sensitive asthma.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neoadjuvant Zoledronic Acid

Zoledronic acid 4 mg IV prior to pancreatic resection (approximately 2 weeks prior to resection)

Pancreatic resection

Zoledronic acid 4 mg IV monthly for two additional doses
Drug: Zoledronic acid
Other Names:
  • Zometa

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluate the safety and feasibility perioperative neoadjuvant zoledronic acid in patients with resectable pancreas cancer.
Time Frame: 1 year postoperatively
Rate of grade 3 and 4 toxicities, especially nephrotoxicity, electrolyte imbalance and osteonecrosis of the jaw.
1 year postoperatively
Evaluate whether treatment with perioperative zoledronic acid prolongs overall survival or disease free survival.
Time Frame: 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determine the pharmacodynamics on selected immune cell subgroups in the peripheral blood and marrow by flow cytometric analysis.
Time Frame: Marrow (prior to first dose of zoledronic acid and week 10), peripheral blood (prior to first dose of zoledronic acid, week 10, and month 6)
Marrow (prior to first dose of zoledronic acid and week 10), peripheral blood (prior to first dose of zoledronic acid, week 10, and month 6)
Determine the pharmacodynamics of neoadjuvant zoledronic acid therapy on selected immune cell subgroups in the tumor microenvironment by flow cytometric analysis of pancreatic tumor samples.
Time Frame: Approximately week 2 (at time of surgery)
Approximately week 2 (at time of surgery)
Determine the pharmacodynamics of neoadjuvant zoledronic acid therapy on the neoangiogenesis.
Time Frame: Prior to zoledronic acid treatment and then completion of zoledronic acid treatment (approximately 10 weeks)
Surrogate markers of tumor-associated neoangiogenesis will be analyzed by ELISA. Serum levels of VEGF and MMP9 will be measured compared pre and post treatment.
Prior to zoledronic acid treatment and then completion of zoledronic acid treatment (approximately 10 weeks)
Determine the pharmacodynamics and surrogate markers neoangiogenesis analyzed by ELISA.
Time Frame: Prior to zoledronic acid treatment and then completion of zoledronic acid treatment (approximately 10 weeks)
Serum levels of VEGF and MMP9 will be measured compared pre and post treatment and the expression of VEGF and MMP9 in tumor samples will be analyzed.
Prior to zoledronic acid treatment and then completion of zoledronic acid treatment (approximately 10 weeks)
Measure the presence and change of micrometastatic disease present in the bone marrow at the time of surgery versus baseline using immunohistochemistry.
Time Frame: Baseline and week 2 (time of surgery)
Baseline and week 2 (time of surgery)
Evaluate the clinical response and time to disease progression.
Time Frame: 6 months postoperatively
6 months postoperatively
Correlate the presence of micrometastatic disease with time to recurrence and outcome.
Time Frame: 6 months postoperatively
6 months postoperatively
Measure the change in the amount of micrometastatic disease from baseline.
Time Frame: 6 months postoperatively
6 months postoperatively
Determine the pharmacodynamics of neoadjuvant zoledronic acid therapy on selected immune cell subgroups in the hepatic metastatic niche by flow cytometric analysis of pancreatic tumor samples
Time Frame: Approximately 2 weeks (time of surgery)
Approximately 2 weeks (time of surgery)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Investigators

  • Principal Investigator: David Linehan, M.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2009

Primary Completion (Actual)

April 1, 2013

Study Completion (Actual)

April 1, 2013

Study Registration Dates

First Submitted

May 1, 2009

First Submitted That Met QC Criteria

May 1, 2009

First Posted (Estimate)

May 4, 2009

Study Record Updates

Last Update Posted (Estimate)

September 22, 2014

Last Update Submitted That Met QC Criteria

September 19, 2014

Last Verified

September 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 09-0589 / 201109094

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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