Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer - Full Text View

Sponsor:	Washington University School of Medicine
Information provided by (Responsible Party):	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

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I Study of Single Dose Neoadjuvant Zoledronic Acid in Patients With Resectable Pancreas Cancer

Resource links provided by NLM:

MedlinePlus related topics: Cancer Pancreatic Cancer

Drug Information available for: Pancrelipase Zoledronic acid Ultrase

U.S. FDA Resources

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

Primary Outcome Measures:

To evaluate the safety and feasibility perioperative neoadjuvant zoledronic acid in patients with resectable pancreas cancer. To evaluate whether treatment with perioperative zoledronic acid prolongs overall survival or disease free survival. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

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: 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 ]
Determine the pharmacodynamics of neoadjuvant zoledronic acid therapy on the neoangiogenesis. 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. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
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 the presence and change of micrometastatic disease present in the bone marrow at the time of surgery versus baseline using immunohistochemistry. To 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:	December 2009
Estimated Study Completion Date:	June 2013
Estimated Primary Completion Date:	June 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1	Drug: zoledronic acid Cohort 1: zoledronic acid 4.0 mg Other Name: Zometa
Experimental: 2	Drug: zoledronic acid Cohort 2: zoledronic acid 8.0 mg Other Name: Zometa
Experimental: 3	Drug: zoledronic acid Cohort 3: zoledronic acid 12.0 mg Other Name: Zometa
Experimental: 4	Drug: zoledronic acid Cohort 4: zoledronic acid 16.0 mg Other Name: Zometa

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 < 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:

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	Recruiting
St. Louis, Missouri, United States, 63110
Sub-Investigator: Matthew Porembka, M.D.
Sub-Investigator: Benjamin Tan, M.D.
Sub-Investigator: William Hawkins, M.D.
Sub-Investigator: Kathy Weilbaecher, M.D.
Sub-Investigator: Kathryn Trinkaus, Ph.D.
Sub-Investigator: Steven Strasberg, M.D.
Sub-Investigator: Peter Goedegebuure, Ph.D.
Sub-Investigator: Elizabeth Brunt, M.D.
Sub-Investigator: Craig Lockhart, M.D.
Sub-Investigator: Andrea Wang-Gillam, M.D.
Sub-Investigator: Christine Menias, M.D.

Sponsors and Collaborators

Washington University School of Medicine

Investigators

Principal Investigator:

David Linehan, M.D.

Washington University School of Medicine

More Information

Additional Information:

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

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
ClinicalTrials.gov Identifier:	NCT00892242 History of Changes
Other Study ID Numbers:	09-0589 / 201109094
Study First Received:	May 1, 2009
Last Updated:	October 6, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:

Neoadjuvant zoledronic acid in resectable pancreas cancer

Additional relevant MeSH terms:

Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases

Pancreatic Diseases
Endocrine System Diseases
Pancrelipase
Zoledronic acid
Diphosphonates
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Bone Density Conservation Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 09, 2012