Preliminary Single-Dose Clinical Pharmacokinetics Of An Anti-Pd-L1 Probody Therapeutic (Pb-Tx) In Cancer Patients.

e14558 Background: CX-072 is a protease-activatable antibody prodrug directed against programmed cell death ligand 1 (PD-L1). Probody therapeutics (Pb-Txs) are designed to be preferentially activated by tumor-associated proteases but not in healthy tissue. Once activated, the Pb-Tx can bind with high affinity to target antigen on tumor cells. Pb-Txs are thus designed to widen the therapeutic index by minimizing target interaction in healthy tissue while retaining antitumor activity. Methods: The phase 1-2 PROCLAIM-CX-072 (Probody Clinical Assessment In Man; NCT03013491) trial is a first-in-human study of CX-072 to characterize the safety, tolerability, pharmacokinetics (PK), and antitumor activity of CX-072 administered intravenously as a single agent or in combination with ipilimumab or vemurafenib in adult patients (pts) with cancer. Here the PK results of the dose-escalation segment of the trial in pts receiving a single dose of CX-072 monotherapy are reported. PK samples were collected intensively following the first dose of CX-072, with sparse collection thereafter. Analytes quantified in plasma samples are Intact Pb-Tx, representing the prodrug form of CX-072, and Total Pb-Tx, representing the sum of intact and activated species. Results: Preliminary single-dose PK data are available for pts enrolled in the dose-escalation segment of PROCLAIM-CX-072 receiving one dose of 0.03-30 mg/kg CX-072 as a single agent. Single-dose PK data suggest CX-072 circulates predominantly as the intact, prodrug species; there does not appear to be monotonic trending of the estimates of clearance and the volume of distribution across the 0.1-30 mg/kg dose levels. A mechanistic PK model suggests target-mediated drug disposition (TMDD) may not be an important contributor to the clearance of intact, protected CX-072 across the dose range evaluated. Single-agent CX-072 plasma PK and tumor biopsy data continue to be collected, and updated data will be presented. Conclusions: Preliminary single-agent, single-dose CX-072 PK data suggest that CX-072 behaves as designed: it circulates predominantly as the intact prodrug species, and TMDD does not strongly influence its PK. Clinical trial information: NCT03013491.