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.

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.

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