Perioperative Treatment With Zoledronic Acid in Patients With Resectable Pancreas Cancer

NCT00892242 | Terminated Phase 1 DMC

• 1 other identifier: 09-0589 / 201109094
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Adenocarcinoma

Keywords

Neoadjuvant zoledronic acid in resectable pancreas cancer

Outcome Measures

Primary Outcomes (2)

• 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

• Evaluate whether treatment with perioperative zoledronic acid prolongs overall survival or disease free survival.

  2 years

Secondary Outcomes (9)

• 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)

• 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)

• Determine the pharmacodynamics of neoadjuvant zoledronic acid therapy on the neoangiogenesis.

  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.

  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.

  Baseline and week 2 (time of surgery)

Study Arms (1)

Neoadjuvant Zoledronic Acid

EXPERIMENTAL

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

Interventions

Zoledronic acid DRUG

Also known as: Zometa

Neoadjuvant Zoledronic Acid

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (12)

• 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. doi: 10.1200/JCO.2006.07.9525. Epub 2007 Apr 23.

  PMID: 17452677 BACKGROUND

• 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. doi: 10.1158/0008-5472.CAN-06-3037. No abstract available.

  PMID: 17210725 BACKGROUND

• 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.

  PMID: 18650621 BACKGROUND

• 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.

  PMID: 18640929 BACKGROUND

• 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. doi: 10.4049/jimmunol.166.1.678.

  PMID: 11123353 BACKGROUND

• 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.

  PMID: 11406548 BACKGROUND

• 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.

  PMID: 18446337 BACKGROUND

• 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. doi: 10.1158/0008-5472.CAN-07-1882.

  PMID: 18056472 BACKGROUND

• 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. doi: 10.1038/sj.bjc.6600986.

  PMID: 12799645 BACKGROUND

• Marten A, Lilienfeld-Toal Mv, Buchler 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. doi: 10.1097/CJI.0b013e31802bff16.

  PMID: 17457212 BACKGROUND

• 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. doi: 10.1172/JCI22087.

  PMID: 15343380 BACKGROUND

• 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. doi: 10.1158/1078-0432.CCR-07-0551.

  PMID: 17671133 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Adenocarcinoma

Interventions

Zoledronic Acid

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• David Linehan, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2009
• First Posted: May 4, 2009
• Study Start: December 1, 2009
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: September 22, 2014

Record last verified: 2014-09

Locations

US (1)