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Published on: August 15, 2019
Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies
Melissa Johnson1, Anthony El-Khoueiry2, Navid Hafez3
1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee. Melissa.Johnson@sarahcannon.com.
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.
Insights
CX-2029, a novel Probody-drug conjugate targeting CD71, showed clinical activity in advanced solid tumors. The recommended Phase II dose is 3 mg/kg, with partial responses observed in squamous histologies.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- CD71 (transferrin receptor 1) is highly expressed on many tumors but challenging to target with antibody-drug conjugates (ADCs) due to normal cell expression.
- The Probody therapeutic platform masks anti-CD71 antibodies, enabling targeted unmasking by tumor proteases to reduce off-tumor toxicity.
- This approach aims to create a therapeutic window for CD71, a previously undruggable target in cancer therapy.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029 in a first-in-human study.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of CX-2029.
- To establish the recommended Phase II dose for CX-2029 in patients with advanced solid tumors.
Main Methods:
- A phase I, dose-escalation, multicenter trial involving 45 patients with advanced solid tumors.
- CX-2029 was administered intravenously every 3 weeks.
- Safety endpoints included MTD and DLTs; efficacy was assessed by objective response.
Main Results:
- No DLTs were observed up to 4 mg/kg; DLTs occurred at 5 mg/kg (febrile neutropenia, pancytopenia) and 4 mg/kg expansion (infusion-related reaction, neutropenia/anemia).
- The maximum tolerated dose was exceeded at 4 and 5 mg/kg.
- The recommended Phase II dose is 3 mg/kg. Common toxicities included dose-dependent anemia and neutropenia. Three confirmed partial responses were seen in patients with squamous histologies.
Conclusions:
- The Probody platform allows targeting of CD71 at tolerable doses, demonstrating clinical activity.
- CX-2029 represents a promising therapeutic strategy for previously undruggable ADC targets.
- This study supports the potential of CX-2029 in treating advanced solid tumors, particularly those with squamous histology.
