| General information |
| Database: | DB00472 |
| Objective: | This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid. |
| Authors: | Broom RJ, et al |
| Title: | Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: a randomized firstlinephase II trial. |
| Journal: | Clin Genitourin Cancer |
| Year: | 2015 |
| PMID: | 25163397 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | everolimus
|
| Target: | Serine/threonineprotein kinase mTOR
|
| Cancer Type: | renal cell carcinoma |
| Cancer Subtype: | renal cell carcinoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | Everolimus + zoledronic acid |
| Study Type: | an openlabel, multicenter, parallelgroup, randomizedphase II trial |
| Key Patients Feature: | Histologically or cytologically confirmed RCC (clear cell variants papillary, chromophobe, and collecting duct carcinomas were also eligible)Evidence of 1 bone metastasis on imaging (computed tomography, magneticresonance imaging, plain radiography, or nuclear bone scintiscan)No prior therapy for mRCC (prior radiotherapy allowed, but must have beencompleted >4 weeks prior; prior bisphosphonates allowed, but not within 4weeks of randomization)Age >18 yearsLife expectancy >3 moECOG PS 2 (Karnofsky PS 60%)Normal organ and marrow function, as defined below:Hemoglobin >90 g/LLeukocytes > 3.0 103 cells/mLAbsolute neutrophil count > 1.5 103 cells/mLPlatelets >100, 000 cells/mLTotal bilirubin within institutional reference limitsAST/ALT < 2.5 institutional reference upper limitCalcium, 2.03.0 mmol/LCreatinine clearance >35 mL/min (as calculated by the CockcroftGaultformula)Women of childbearing potential and men must have agreed to use adequatecontraception before study entry and for the duration of participationFasting serum cholesterol 7.75 mmol/L and fasting triglycerides 2.5 reference upper limit (if one or both of these thresholds were exceeded, thepatient could be included only after initiation of statin therapy and when theabove values were achieved)Ability to understand and willingness to sign a written informed consentdocument |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4weekly) |
| Treatment Info: | patients with RCC and more than and equal to 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4weekly). Bonespecific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). |
| Primary End Point: | urine Ntelopeptide (uNTX) level |
| Secondary End Point: | plasma Ctelopeptide (CTX), quality of life (Functional Assessment of Cancer TherapyBone Pain [FACTBP], Brief Pain Inventory [BPI]), progression free survival (PFS), SREs, and safety. |
| Patients Number: | 30 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | Median time to first SRE was 9.6 months (95% CI, 4.315.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.68.2) on everolimus (P = .03). |
| Median PFS A vs. C: | 7.5 months (95% CI, 3.411.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.26.3) on everolimus (P =0 .009). |
| Median OS A vs. C: | 13.6 months (95% CI, 9.622.2) for everolimus plus zoledronic acid compared with 10.7 months (95% CI, 3.514.7) for everolimus (P .088). |
| Adverse Event(agent arm): | Overall, everolimus was relatively well tolerated; the AEs seen were consistent with the known side effect profile of the drug. The only noticeable difference in AEs between treatment arms was for the category pain, where there were 5 grade 3 AEs and 1 grade 4 AE in the everolimus group compared with 2 grade 3 AEs in the everolimus plus zoledronic acid group. Furthermore, when the site of pain was considered, there were 5 patients on everolimus with grade 3 bone pain and no grade 3 bone pain events on everolimus plus zoledronic acid. The proportions with any (nontreatmentrelated or treatmentrelated) grade 3 or higher AE was identical(12 of 15; 80%) on both treatment arms. The 95% CI for the difference was 28.6% to 28.6% (P = 1.0). There were no cases of ONJ. |
| Conclusions: | In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control. |