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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Malignant Neoplasm, Musculoskeletal Complications

Intervention / Treatment
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* Drug: zoledronic acid
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (zoledronic acid over 15 minutes)<br>Patients receive zoledronic acid IV over 15 minutes on day 1. | Drug: zoledronic acid<br>* Given IV<br>* Other names: Zometa;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Arm II (zoledronic acid over 30 minutes)<br>Patients receive zoledronic acid IV over 30 minutes on day 1. | Drug: zoledronic acid<br>* Given IV<br>* Other names: Zometa;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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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 |