Neoadjuvant Zoledronic Acid in Patients With Resectable Pancreas Cancer

Condition(s) targeted: Adenocarcinoma

Intervention: zoledronic acid (Drug); zoledronic acid (Drug); zoledronic acid (Drug); zoledronic acid (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: Washington University School of Medicine

Official(s) and/or principal investigator(s):
David Linehan, M.D., Principal Investigator, Affiliation: Washington University School of Medicine

Overall contact:
David Linehan, M.D., Phone: 314-362-2938, Email: linehand@wudosis.wustl.edu

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.

Official title: Phase I Study of Single Dose Neoadjuvant Zoledronic Acid in Patients With Resectable Pancreas Cancer

Study design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome: To evaluate the safety and tolerability of neoadjuvant zoledronic acid in patients with resectable pancreas cancer.

Secondary outcome:

To determine the dose limiting toxicity of neoadjuvant zoledronic acid in patients with resectable pancreas cancer.

To measure the level of zoledronic acid at present in the pancreas at the time of surgery.

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.

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.

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.

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.

To evaluate the clinical response and time to disease progression.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

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

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

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Related publications:

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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.

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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.

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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.

Starting date: June 2009
Ending date: June 2012
Last updated: May 1, 2009