Background: OPTIC RCC (NCT05361720) uses RNA sequencing (seq) of tumor tissue to assign therapy in front-line metastatic clear cell renal cell carcinoma (mccRCC) patients. The operational characteristics of tumor tissue procurement, sequencing, cluster assignment and start of therapy are presented. Methods: Patients diagnosed with mccRCC without prior systemic therapy are eligible for enrollment. RNAseq of primary and/or metastatic tumor tissue is performed by Tempus (Chicago, IL) and data analyzed via an automated cloud-based informatics tool. Results: Twenty-three patients have been screened. Twelve patients (52%) had both primary and metastatic tumors submitted for RNAseq, 4 (17%) had primary only, and 7 (30%) had only metastatic tumor available. Three patients (13%) failed screening because no tumors passed RNAseq quality control (QC). When possible, patients were assigned to clusters based on data from metastatic tumor (15/20, 75%). However, 5/20 (25%) of patients were assigned to clusters based on primary tumor sequencing data because the metastatic tumor was not available or failed QC. Eight patients (40%) were assigned to cluster 1/2, 7 (35%) were assigned to cluster 4/5, and 5 (25%) were assigned to cluster 3/6/7. Primary tumors were more likely to be assigned to cluster 1/2 (12/14, 86%) than metastatic tumors (5/10, 50%) (p<0.01, Fisher’s exact test). Of the 9 pts with both primary and metastatic RNAseq, 5 patients had discordant tumor clusters (primary cluster 1/2 and metastatic cluster 4/5 or 3/6/7); 4 patients with concordant tumor clusters (both cluster 1/2). The mean time from consent to cluster assignment was 32 days (SD +/- 18), though this improved over time. Ten patients have started therapy. Conclusions: Patients with mccRCC can be enrolled on clinical trials that utilize tissue-based RNA sequencing biomarkers. Accrual and analysis correlating cluster assignment with treatment response are ongoing. This trial is funded by the DOD Kidney Cancer Research Program (W81XWH-22-1-1033). Clinical trial information: NCT05361720.