Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies

• Published in: Clinical cancer research Vol. 27; no. 16; pp. 4521 - 4530
• Main Authors: Johnson, Melissa, El-Khoueiry, Anthony, Hafez, Navid, Lakhani, Nehal, Mamdani, Hirva, Rodon, Jordi, Sanborn, Rachel E, Garcia-Corbacho, Javier, Boni, Valentina, Stroh, Mark, Hannah, Alison L, Wang, Song, Castro, Henry, Spira, Alexander
• Format: Journal Article
• Language: English
• Published: United States 15.08.2021
• Subjects: Adult; Aged; Female; Humans; Immunoconjugates - therapeutic use; Male; Middle Aged; Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - pathology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-21-0194

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. 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. 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. The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. .