Background: Patients (pts) with rare cancers are under-represented in precision medicine trials despite making up ~22% of cancer incidence. We created the TCF-001 TRACK (Target RAre Cancer Knowledge, NCT04504604) study to provide a home-based, patient-centered trial utilizing comprehensive genomic profiling (CGP) at enrollment and progression with review by a molecular tumor board (MTB). Methods: Pts with rare cancers (incidence<6/100,000) were enrolled and consented remotely (WCG IRB 1287011). Liquid (blood via mobile phlebotomy) and tissue biopsy samples were sent for CGP at Foundation Medicine. A fully remote MTB was convened following availability of each test. MTB notes and therapy recommendations were returned to patients and local physicians. Results: TRACK activated on 1 Oct 2020. The MTB included medical/surgical oncologists, genomics experts, molecular pathologists, a basic scientist, a pharmacist, a genetic counselor, regulatory staff, a scribe, an oncology fellow (“mentern”), and a medication acquisition specialist. MTB members were from 8 states. 132 eligible pts with evaluable results were enrolled from 41 states. Tissue and liquid biopsy results were available in 89 pts; tissue only in 5; liquid only in 38. 128 pts had an MTB before the 30 June2023 cut-off date (mean age 54.1 y; female 61.7%). There were >40 rare/ultra-rare cancers, including cholangiocarcinoma (62) and soft tissue tumors (24). No pts had identical molecular alterations. The median number of pathogenic alterations per tissue sample was 3 (range: 0-14) and blood was 2 (range: 0-40). 3 patients had no pathogenic alterations on tissue or liquid CGP. The most commonly altered genes found by tissue biopsy CGP on study (n=68) were TP53(33.8%), CDKN2A (25.0%), KRAS (23.5%), CDKN2B (17.6%), IDH1 (17.6%), and MTAP (14.7%); by liquid biopsy (n=126), they were TP53 (31.7%), KRAS (11.9%), and IDH1 (8.7%), as well as genes often associated with clonal hematopoiesis: DNMT3A (22.2%), ATM (12.7%), and CHEK2 (8.7%). The sensitivity of liquid biopsy for pathogenic alterations found in tissue was 89.3% for pts with ctDNA tumor fraction (TF) ≥1% and 28.1% for TF <1%. 1 pt had microsatellite instability. Median tumor mutational burden (TMB) by tissue was 2.5 mutations/megabase and by blood was 1.3. 3 pts had TMB≥10. Liquid biopsy results were available more quickly than tissue (median processing time, 9.1 vs 13.3 days); time from submission to processing was shorter for blood than tissue (2.4 vs 4.9 weeks). TRACK staff encountered 0.94 queries/sample. MTB recommendations based on CGP were generated for 87.5% of the 128 pts presented. Conclusions: A fully remote, advocacy driven, national precision genomics trial is feasible for managing rare cancers. CGP with expert MTB review can identify potentially targetable alterations and inform therapeutic options. Clinical trial information: NCT04504604.