OT1-01-01: Prospective Clinical Trial Evaluating Efficacy of Zoledronic Acid (ZA) Prophylaxis for Prevention of Aromatase Inhibitor Associated Musculoskeletal Symptoms: ZAP-AIMSS Trial.
Authors: Bardia A , Blackford A , Jeter S , Tarpinian K , Fetting JF , Miller R , Slater S , Henry NL , Giles J , Stearns V 
Published: June 2012

Brief background: Aromatase inhibitor associated musculoskeletal symptoms (AIMSS) occur in approximately 50% of patients receiving AIs (Henry 08). However, interventions to prevent or treat AIMSS have not been established. In a retrospective study (Muslimani 09), patients receiving bisphosphonates along with AIs were less likely to report AIMSS compared to those not taking bisphosphonates (35% vs. 60%). However, the efficacy of bisphosphonates in reducing incidence of AIMSS has not been studied prospectively, so it cannot be recommended for routine clinical practice.

Trial design: We are conducting a single arm, phase II clinical trial of 4 mg intravenous zoledronic acid (ZA) given at baseline and at 6 months, in combination with letrozole 2.5 mg daily for one year. Development of AIMSS will be assessed using the standardized Health Assessment Questionnaire (HAQ-DI) and pain Visual Analog Scale (VAS) at baseline,1, 3, 6, and 12 months. Secondary endpoints include mammographic breast density (when intact contralateral breast), bone mineral density, bone turnover metabolites, circulating inflammatory markers, and patient reported quality of life measures. Prevalence of AIMSS will be compared to historical controls from a recently completed multi-institutional study designated Exemestane and Letrozole Pharmacogenetics (ELPh trial, ClinicalTrials.gov #NCT00228956). The current study has the same eligibility criteria, method and intervals of outcome assessment, and AI medication, as the ELPh trial, ensuring that the two cohorts are comparable.

Eligibility criteria: Postmenopausal women who have completed local therapy and chemotherapy for hormone receptor positive DCIS or stage I-III breast cancer and who are scheduled to receive adjuvant AI. Prior tamoxifen therapy is permitted.

Specific aims:

1. Percentage of women experiencing AIMSS at 1, 3, 6, and 12 months after initiation of ZA and letrozole, as compared to historical controls.

2. Change in bone mineral density and breast density between baseline and 12 months for those receiving ZA and letrozole, as compared to historical controls.

3. Change in bone turnover markers and inflammatory markers between baseline and 1, 3, 6 and 12 months for those receiving ZA and letrozole, as compared to historical controls.

Statistical methods: Allowing for a 20% dropout rate, a total sample size of 59 patients yields 80% power to detect reduction in AIMSS incidence from 50% to 30% with a two sided type I error rate of 5%. The rates of AIMSS and other endpoints at each time point and across all time points between controls and patients will be compared with a logistic regression model that adjusts for potential confounding variables and include random effects as appropriate to account for correlation between outcomes in the same patient.

Present accrual and target accrual: The Johns Hopkins Institutional Review Board approved the study and it opened to accrual in January 2011. Since that time, 12 participants have signed consent and started therapy, and 2 have completed the 3 month evaluation.

Funding: Trial supported by BCRF. ZA and letrozole kindly supplied by Novartis.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-01.