Abstract Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody–drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody–drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target. Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks. Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies. Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459