Cirmtuzumab is a drug that was developed through support by the California Institute of Regenerative Medicine to specifically bind and inhibit ROR1 on cancer cells. ROR1 is an attractive target for a new therapy to treat patients with cancer because it is expressed on cancer cells, but not on normal post-partum tissues. Previous studies have determined that cirmtuzumab binds specifically to ROR1 and blocks Wnt signaling, which is important in cancer and cancer stem cells. We report the results of a Phase 1 clinical trial to evaluate the safety and activity of this Cirmtuzumab in 26 patients with chronic lymphocytic leukemia (CLL), a disease with high expression of ROR1. Cirmtuzumab was well-tolerated, without any severe toxicities. Patients did not experience weight loss, pancreatitis, hyperglycemia, or other drug-dependent toxicities, consistent with the notion that cirmtuzumab does not bind to normal tissues. We confirmed that ROR1 was blocked in the leukemic cells, based on decreased levels of some intermediary molecules, HS1 and Rac1. Strikingly, we found that the overall genetic signature of the leukemic cells was significantly modified by cirmtuzumab. Prior to treatment, the leukemia cells turned on genes in a manner resembling stem-cells; this was reversed by cirmtuzumab and the leukemic cells became more similar to normal blood cells. The majority of treated patients had stable disease with remissions that were durable without subsequent therapy for a median of 8.6 months. In summary, the results support further development of cirmtuzumab as a specific and safe inhibitor of ROR1/Wnt signaling, and the safety profile of cirmtuzumab makes it an ideal agent to combine with other therapies. A phase 1b/2 combination clinical trial has been initiated based on these findings in patients with CL, lymphoma, breast cancer, and other intractable cancer-stem-cell-driven cancers in which ROR1 is implicated.