Background: Sunitinib is a standard first-line treatment for patients (pts) with metastatic renal cell carcinoma (RCC). CXCR4 and its only known ligand, SDF-1, are both overexpressed in tumor and vascular cells of clear cell RCC. LY2510924 is a selective peptide antagonist of CXCR4. We compared the results of open-label treatment with LY2510924 + sunitinib vs sunitinib alone. Methods: Previously untreated metastatic clear cell RCC pts were randomized (2:1) to receive standard-dose sunitinib (50 mg qd for 4 weeks [wk], then 2 wk off) + LY2510924 (20 mg sc, qd) (Arm A) or sunitinib alone (Arm B). Pts were evaluated (per RECIST v.1.1) every 8 wk. The primary analysis was done when all pts completed 72 wk of treatment, discontinued, progressed, or died and compared progression-free survival (PFS) between arms using a Bayesian time to event analysis incorporating prior information about sunitinib along with the trial data. PFS was also analyzed using the hazard ratio (HR) with only trial data. The Bayesian design was simulated to size the trial. The objective response rates (ORR) in each arm were compared using the chi-squared test. Results: 72 and 36 pts were treated in Arms A and B, respectively. Key pt characteristics (ECOG PS, Motzer risk score, prior nephrectomy) were similar in Arms A and B. Median number of cycles administered in each arm was 5. Median PFS was 8.1 and 12.3 months in Arms A and B, respectively (HR [95% CI]: 1.19 [0.73, 1.94]). The ORR (95% CI) was 30.6% (19.9%, 41.2%) in Arm A and 38.9% (23.0%, 54.8%) in Arm B. The most frequent ( > 5% Arm A) grade 3/4 AEs (Arm A, Arm B) were hypertension (13.9%, 19.4%), fatigue (9.7%, 13.9%), diarrhea (6.9%, 16.7%), thrombocytopenia (8.3%, 5.6%), and anemia (8.3%, 2.8%). Of interest, there were more bleeding-related events (mostly grade 1 or 2) in Arm A than B (39%, 14%). More pts in Arm A discontinued treatment due to AE (18.1%, 8.3%). Two deaths in Arm A were due to adverse events (pulmonary edema/respiratory arrest/cardiac arrest and intracranial tumour hemorrhage). Conclusions: Adding the CXCR4 inhibitor LY2510924 to sunitinib as first-line treatment for metastatic RCC was tolerated but did not improve efficacy. Clinical trial information: NCT01391130