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

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.

• Authors: Melissa Johnson, Anthony El-Khoueiry, Navid Hafez, Nehal Lakhani, Hirva Mamdani, Jordi Rodon, Rachel E Sanborn, Javier Garcia-Corbacho, Valentina Boni, Mark Stroh, Alison L Hannah, Song Wang, Henry Castro, Alexander Spira
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 16 Pg. 4521-4530 (08 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34083236 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Immunoconjugates
• CX-2029

Topics

• Adult
• Aged
• Female
• Humans
• Male
• Middle Aged
• Immunoconjugates (therapeutic use)
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)