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Neoadjuvant Zoledronic Acid in Patients With Resectable Pancreas Cancer
This study is not yet open for participant recruitment.
Verified by Washington University School of Medicine, May 2009
First Received: May 1, 2009   No Changes Posted
Sponsored by: Washington University School of Medicine
Information provided by: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00892242
  Purpose

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.


Condition Intervention Phase
Adenocarcinoma
Drug: zoledronic acid
Phase I

MedlinePlus related topics: Cancer Pancreatic Cancer Surgery
Drug Information available for: Pancrelipase Zoledronic acid Ultrase
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study
Official Title: Phase I Study of Single Dose Neoadjuvant Zoledronic Acid in Patients With Resectable Pancreas Cancer

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • To evaluate the safety and tolerability of neoadjuvant zoledronic acid in patients with resectable pancreas cancer. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine the dose limiting toxicity of neoadjuvant zoledronic acid in patients with resectable pancreas cancer. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • To measure the level of zoledronic acid at present in the pancreas at the time of surgery. [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
  • To determine the pharmacodynamics on selected immune cell subgroups in the peripheral blood and marrow by flow cytometric analysis. The effect on the immune cell subgroups will be compared pre and post treatment in the peripheral blood and bone marrow. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To 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: 1 year ] [ Designated as safety issue: Yes ]
  • To determine the pharmacodynamics and surrogate markers neoangiogenesis analyzed by ELISA. 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. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To measure micrometastatic disease in the bone marrow at enrollment and surgery. To measure the change in the amount of micrometastatic disease from baseline and correlate the presence of micrometastatic disease with time to recurrence and outcome. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To evaluate the clinical response and time to disease progression. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 48
Study Start Date: June 2009
Estimated Study Completion Date: June 2012
Estimated Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental Drug: zoledronic acid
Cohort 1: zoledronic acid 4.0 mg
2: Experimental Drug: zoledronic acid
Cohort 2: zoledronic acid 8.0 mg
3: Experimental Drug: zoledronic acid
Cohort 3: zoledronic acid 12.0 mg
4: Experimental Drug: zoledronic acid
Cohort 4: zoledronic acid 16.0 mg

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A patient will be eligible for inclusion in this study only if ALL of the following criteria apply;

  • 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 ≤ 1.5x the institutional normal value and AST ≤ 2x 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, Sjorgren'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:

A patient will be ineligible for inclusion into this study if ANY of the following criteria apply:

  • 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00892242

Contacts
Contact: David Linehan, M.D. 314-362-2938 linehand@wudosis.wustl.edu

Locations
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: David Linehan, M.D. Washington University School of Medicine
  More Information

Additional Information:
Publications:
Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W. Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 Apr 23; [Epub ahead of print]
Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, Schreiber H. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007 Jan 1;67(1):425; author reply 426. No abstract available.
Linehan DC, Tan MC, Strasberg SM, Drebin JA, Hawkins WG, Picus J, Myerson RJ, Malyapa RS, Hull M, Trinkaus K, Tan BR Jr. Adjuvant interferon-based chemoradiation followed by gemcitabine for resected pancreatic adenocarcinoma: a single-institution phase II study. Ann Surg. 2008 Aug;248(2):145-51.
Varadhachary GR, Wolff RA, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Abdalla E, Wang H, Staerkel GA, Lee JH, Ross WA, Tamm EP, Bhosale PR, Krishnan S, Das P, Ho L, Xiong H, Abbruzzese JL, Evans DB. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008 Jul 20;26(21):3487-95.
Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001 Jan 1;166(1):678-89.
Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res. 2001 Jun 15;61(12):4756-60.
Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009 Jan;58(1):49-59. Epub 2008 Apr 30.
Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res. 2007 Dec 1;67(23):11438-46.
Tassone P, Tagliaferri P, Viscomi C, Palmieri C, Caraglia M, D'Alessandro A, Galea E, Goel A, Abbruzzese A, Boland CR, Venuta S. Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro. Br J Cancer. 2003 Jun 16;88(12):1971-8.
Märten A, Lilienfeld-Toal M, Büchler MW, Schmidt J. Zoledronic acid has direct antiproliferative and antimetastatic effect on pancreatic carcinoma cells and acts as an antigen for delta2 gamma/delta T cells. J Immunother. 2007 May-Jun;30(4):370-7.
Giraudo E, Inoue M, Hanahan D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest. 2004 Sep;114(5):623-33.
Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O, Schiavon G, Angeletti S, Uzzalli F, Caraglia M, Dicuonzo G, Tonini G. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4482-6.

Responsible Party: Washington University School of Medicine ( David Linehan, M.D. )
Study ID Numbers: 08-X263
Study First Received: May 1, 2009
Last Updated: May 1, 2009
ClinicalTrials.gov Identifier: NCT00892242     History of Changes
Health Authority: United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
Neoadjuvant zoledronic acid in resectable pancreas cancer

Study placed in the following topic categories:
Digestive System Neoplasms
Zoledronic acid
Pancreatic Neoplasms
Endocrine System Diseases
Bone Density Conservation Agents
Pancrelipase
Carcinoma
Diphosphonates
Digestive System Diseases
Gastrointestinal Neoplasms
Pancreatic Diseases
Endocrinopathy
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Endocrine Gland Neoplasms

Additional relevant MeSH terms:
Zoledronic acid
Neoplasms by Histologic Type
Digestive System Neoplasms
Pancreatic Neoplasms
Physiological Effects of Drugs
Gastrointestinal Agents
Endocrine System Diseases
Bone Density Conservation Agents
Pancrelipase
Pharmacologic Actions
Carcinoma
Neoplasms
Diphosphonates
Neoplasms by Site
Digestive System Diseases
Therapeutic Uses
Pancreatic Diseases
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Endocrine Gland Neoplasms

ClinicalTrials.gov processed this record on May 07, 2009