Genetics in Predicting Risk of Bisphosphonate-Related Osteonecrosis of the Jaw in Patients With Cancer Receiving Zoledronic Acid

POPULATION PHARMACOMETRICS FOR ASSESSING RISK OF BISPHOSPHONATE-RELATED OSTEONECROSIS OF THE JAW (BRONJ)

This randomized clinical trial studies genetics in predicting risk of bisphosphonate-related osteonecrosis of the jaw in patients with cancer receiving zoledronic acid. Zoledronic acid is an anti-resorptive drug used as part of cancer treatment. A serious side effect of these drugs is death of the jawbone, commonly called bisphosphonate-related osteonecrosis of the jaw (BRONJ). Genetic research may help doctors understand risk factors for BRONJ or who is more likely to get BRONJ and why.

Study Overview

• Status: Withdrawn
• Conditions: Malignant Neoplasm; Musculoskeletal Complications
• Intervention / Treatment: Other: pharmacological study; Drug: zoledronic acid

Detailed Description

PRIMARY OBJECTIVES:

I. To develop a pharmacometric model to predict jawbone zoledronic acid (Zol) concentrations in oncologic patients by conducting a prospective cohort study of Zol pharmacometrics in BRONJ patients, measuring drug in plasma, urine, and jawbone tissue obtained during surgical treatment for BRONJ.

SECONDARY OBJECTIVES:

I. To clinically assess and validate our predictive pharmacometric model, and develop a risk model for BRONJ in oncologic patients receiving intravenous Zol.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive zoledronic acid intravenously (IV) over 15 minutes on day 1.

ARM II: Patients receive zoledronic acid IV over 30 minutes on day 1.

After completion of study treatment, patients are followed up for 1 month.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • San Diego, California, United States, 92121
      • J.Craig Venter Institute-San Diego

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• PATIENTS WITH BRONJ:
• All cancer patients > 18 years of any ethnicity who have been treated with intravenous zoledronate (zoledronic acid) for >=1 year duration
• Clinical diagnosis of BRONJ subsequent to oral surgery as established by standard clinical protocol per American Association of Oral and Maxillofacial Surgeons (AAOMS) diagnostic criteria
• Willingness to have photographs taken to document lesions
• Consent for sample collection for urine, hematology, histopathology and microbial profiling
• Cognitively able and willing to provide consent
• Have a World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance score =< 2 and life expectancy > 6 months
• PATIENTS WITHOUT BRONJ:
• Cancer patients without BRONJ who have been treated with intravenous zoledronate for >= 1 year duration
• No signs or symptoms of BRONJ
• Willingness to provide consent for sample collection for blood, urine and saliva

Exclusion Criteria:

• WHO/ECOG performance score > 2 and life expectancy of < 6 months
• Coagulopathy
• Active systemic infection or autoimmune disease
• Currently pregnant or within 3 months post-partum, or unwilling to undergo pregnancy testing or report possible pregnancy promptly
• Severe cardiovascular, pulmonary or other systemic conditions that prevent participation in the study
• Salivary gland hypofunction regardless of underlying pathology
• Neutropenia (serum absolute neutrophil count [ANC] < 1,000/uL)
• Cognitive, language or hearing problems
• Renal disease, and we will use a calculated serum creatinine clearance over 30 ml/min at the screening appointment as an exclusion criteria
• Participation in another research project that might interfere with completion of this study
• Patients undergoing active antibiotic therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (zoledronic acid over 15 minutes); Patients receive zoledronic acid IV over 15 minutes on day 1.	Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: zoledronic acid; Given IV; Other Names: Zometa; CGP 42446; CGP42446A; NDC-zoledronate; zoledronate
Experimental: Arm II (zoledronic acid over 30 minutes); Patients receive zoledronic acid IV over 30 minutes on day 1.	Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: zoledronic acid; Given IV; Other Names: Zometa; CGP 42446; CGP42446A; NDC-zoledronate; zoledronate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentrations of Zol collected at visits 2, 3, 4, and 5	Data will be iteratively fit to the model using non-parametric modeling, simulation, and clinical dosing software. The parameters will be estimated, as well as their relationships to each other. Each measured patient concentration is Fisher weighted.	Up to 1 month
Urine concentrations of Zol collected at visits 2, 3, 4, and 5	Data will be iteratively fit to the model using non-parametric modeling, simulation, and clinical dosing software. The parameters will be estimated, as well as their relationships to each other. Each measured patient concentration is Fisher weighted.	Up to 1 month
Jawbone tissue concentrations of Zol collected during surgical treatment for BRONJ	Data will be iteratively fit to the model using non-parametric modeling, simulation, and clinical dosing software. The parameters will be estimated, as well as their relationships to each other. Each measured patient concentration is Fisher weighted.	Up to 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify potential risk factors for BRONJ	The magnitude of associations between the study variables and BRONJ status will be estimated. For categorical variables, the univariate association with each variable and with BRONJ will be determined using Wald's test of association. For continuous variables, the association with each variable and BRONJ will be determined using Wald's test. Logistic regression will be used to evaluate the risk of BRONJ for development of the final risk model.	Up to1 month

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Parish Sedghizadeh, University of Southern California

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2016
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: February 7, 2014
• First Submitted That Met QC Criteria: February 19, 2014
• First Posted (Estimate): February 24, 2014

Study Record Updates

• Last Update Posted (Actual): April 11, 2017
• Last Update Submitted That Met QC Criteria: April 9, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Musculoskeletal Diseases; Stomatognathic Diseases; Bone Diseases; Jaw Diseases; Neoplasms; Osteonecrosis; Bisphosphonate-Associated Osteonecrosis of the Jaw; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: 0S-13-3 (Other Identifier: USC Norris Comprehensive Cancer Center); P30CA014089 (U.S. NIH Grant/Contract); NCI-2014-00207 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No