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Background: Yttrium‐90 FF‐21101 (90Y–FF‐21101) is a radiopharmaceutical that targets P‐cadherin as a therapy against solid tumors. A previously reported, first‐in‐human study determined that a dose of 25 mCi/m2 was safe, and a patient with clear cell carcinoma of the ovary achieved a complete response. In this article, the authors report the results of 90Y–FF‐21101 treatment in an ovarian carcinoma expansion cohort and in patients with selected solid tumors who had known high P‐cadherin expression. Methods: The trial was conducted as an open‐label study in patients with advanced/metastatic disease. Radiologic response and safety were evaluated in patients who received 25 mCi/m2 intravenously once every three cycles of 28 days until they developed progressive disease. Evaluation of the ovarian cohort was conducted in a Simon two‐stage manner to determine further enrollment. Results: Fifty‐seven patients (20 with ovarian carcinoma) were enrolled and treated. Patients who had ovarian and solid tumors had received a median of five and three prior therapies, respectively. No complete or partial responses were observed, so the trial was ended. The median progression‐free survival was 118 days for the ovarian cohort and 55 days for the solid‐tumor cohort. The most common treatment‐related adverse events were thrombocytopenia (40%) and neutropenia (54%). One patient each developed fatal veno‐occlusive disease and intracranial hemorrhage. Patients with higher P‐cadherin levels remained on the study longer. Conclusions: 90Y–FF‐21101 did not meet the predefined efficacy criteria, and adverse events were consistent with 90Y agents. These data may assist in the development of other P‐cadherin–directed therapies (ClinicalTrials.gov identifier NCT02454010). A clinical trial of yttrium‐90–FF‐21101 directed against P‐cadherin did not meet predefined efficacy criteria. Because imaging studies indicated FF‐21101 uptake by tumors, other warheads combined with P‐cadherin–directed vehicles like FF‐21101 may have greater success. [ABSTRACT FROM AUTHOR]