CX-2029, a PROBODY drug conjugate targeting CD71 (transferrin receptor): Results from a first-in-human study (PROCLAIM-CX-2029) in patients (Pts) with advanced cancer.

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Background: CX-2029 is a PROBODY drug conjugate (PDC) of MMAE, a potent microtubule inhibitor, directed against CD71 (transferrin receptor 1). In addition to being an abundant tumor antigen, CD71 is highly expressed on normal cells, precluding targeting by a traditional antibody drug conjugate (ADC). PDCs are masked ADCs, unmasked predominantly by tumor-associated proteases, thereby restricting target engagement to tumors. Both a CD71 PDC and ADC displayed broad activity in multiple xenograft tumor models; in toxicology studies, the PDC was tolerable at doses consistent with efficacy in non-clinical tumor models while the ADC was not. Methods: In a phase 1/2 first-in-human study of PDC CX-2029 in advanced solid tumors (NCT03543813), pts with ECOG 0–1 and ≥1 prior systemic therapy were enrolled into escalating dose cohorts of the PDC CX-2029 given IV every 21 days. Endpoints included evaluation of MTD, safety, antitumor activity, and potential biomarkers; plasma and tissue samples were collected for PK/PD analyses. Preliminary results are reported. Results: As of 30 November 2019, 34 pts were enrolled (median age 59 y; 59% male; 71% ECOG 1; median [range] of 3 [1–16] prior therapies). Pts received a median of 3 (1–12) CX-2029 doses. Starting dose for escalation was 0.1 mg/kg. Following a single CX-2029 dose, median molar ratio of masked CX-2029 to total CX-2029 for AUCtau was 0.938 (0.864–0.942); the ratio of free MMAE to total CX-2029 was Conclusions: The observed safety profile for CX-2029 effectively reduces on-target toxicity for this previously undruggable target, supporting the PROBODY platform. Evidence of anti-tumor activity was observed. Dose escalation continues. Clinical trial information: NCT03543813.