TY - JOUR
T1 - Phase I, first-in-human study of the Probody therapeutic CX-2029 in adults with advanced solid tumor malignancies
AU - Johnson, Melissa
AU - El-Khoueiry, Anthony
AU - Hafez, Navid
AU - Lakhani, Nehal
AU - Mamdani, Hirva
AU - Rodon, Jordi
AU - Sanborn, Rachel E.
AU - Garcia-Corbacho, Javier
AU - Boni, Valentina
AU - Stroh, Mark
AU - Hannah, Alison L.
AU - Wang, Song
AU - Castro, Henry
AU - Spira, Alexander
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/8/15
Y1 - 2021/8/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-0194
DO - 10.1158/1078-0432.CCR-21-0194
M3 - Article
C2 - 34083236
AN - SCOPUS:85113782282
SN - 1078-0432
VL - 27
SP - 4521
EP - 4530
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -