Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer

Adenocarcinoma Clinical Trial

Official title:

Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00892242
• Other study ID #: 09-0589 / 201109094
• Status: Terminated
• Phase: Phase 1
• First received: May 1, 2009
• Last updated: September 19, 2014
• Start date: December 2009
• Est. completion date: April 2013

Study information

• Verified date: September 2014
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 24
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreatic Neoplasms

Intervention

Drug:
• Zoledronic acid

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. doi: 10.1007/s00262-008-0523-4. Epub 2008 Apr 30. — View Citation

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. — View Citation

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. — View Citation

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. doi: 10.1097/SLA.0b013e318181e4e9. — View Citation

Märten A, Lilienfeld-Toal Mv, 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. — View Citation

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. — View Citation

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; National Cancer Institute of Canada Clinical Trials Group. 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 May 20;25(15):1960-6. Epub 2007 Apr 23. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. doi: 10.1200/JCO.2007.15.8642. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the safety and feasibility perioperative neoadjuvant zoledronic acid in patients with resectable pancreas cancer.	Rate of grade 3 and 4 toxicities, especially nephrotoxicity, electrolyte imbalance and osteonecrosis of the jaw.	1 year postoperatively	Yes
Primary	Evaluate whether treatment with perioperative zoledronic acid prolongs overall survival or disease free survival.		2 years	No
Secondary	Determine the pharmacodynamics on selected immune cell subgroups in the peripheral blood and marrow by flow cytometric analysis.		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)	No
Secondary	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.		Approximately week 2 (at time of surgery)	No
Secondary	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.	Prior to zoledronic acid treatment and then completion of zoledronic acid treatment (approximately 10 weeks)	No
Secondary	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.	Prior to zoledronic acid treatment and then completion of zoledronic acid treatment (approximately 10 weeks)	No
Secondary	Measure the presence and change of micrometastatic disease present in the bone marrow at the time of surgery versus baseline using immunohistochemistry.		Baseline and week 2 (time of surgery)	No
Secondary	Evaluate the clinical response and time to disease progression.		6 months postoperatively	No
Secondary	Correlate the presence of micrometastatic disease with time to recurrence and outcome.		6 months postoperatively	No
Secondary	Measure the change in the amount of micrometastatic disease from baseline.		6 months postoperatively	No
Secondary	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		Approximately 2 weeks (time of surgery)	No

External Links

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