Model‐Informed Drug Development of the Masked Anti‑PD‑L1 Antibody CX‐072

Abstract

CX‑072 is an anti‑PD‑L1 (programmed death ligand 1) Probody therapeutic (Pb‐Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Here, we report the model‐informed drug development of CX‐072. A quantitative systems pharmacology (QSP) model that captured known mechanisms of Pb‐Tx activation, biodistribution, elimination, and target engagement was used to inform clinical translation. The QSP model predicted that a trough level of masked CX‐072 (intact CX‐072) of 13–99 nM would correspond to a targeted, 95% receptor occupancy in the tumor. The QSP model predictions appeared consistent with preliminary human single‑dose pharmacokinetic (PK) data following CX‐072 0.03–30.0 mg/kg as monotherapy: CX‑072 circulated predominantly as intact CX‐072 with minimal evidence of target‐mediated drug disposition. A preliminary population PK (POPPK) analysis based upon 130 subjects receiving 0.03–30.0 mg/kg as monotherapy included a provision for a putative time‐dependent and dose‐dependent antidrug antibody (ADA) effect on clearance (CL) with a mixture model. Preliminary POPPK estimates for intact CX‐072 time‐invariant CL and volume of distribution were 0.306 L/day and 4.84 L, respectively. Exposure–response analyses did not identify statistically significant relationships with best change from baseline sum of measurements and either adverse events of grade ≥ 3 or of special interest. Simulations suggested that > 95% of patients receiving CX‐072 10 mg/kg every two weeks would exceed the targeted trough level regardless of ADA, and that dose adjustment by body weight was not necessary, supporting a fixed 800 mg dose for evaluation in phase II.

CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study

“…As shown in figure 3, the observed preliminary ipilimumab plasma concentrations after administration of 10 mg/kg pacmilimab followed by 3, 6, or 10 mg/kg ipilimumab administered were generally contained within the respective 90% prediction intervals of simulated ipilimumab concentrations based on the population PK model of Feng et al, suggesting pacmilimab is not a perpetrator of a PK drug-drug interaction with ipilimumab. 24 As reported previously, 22 patients maintained circulating plasma levels of pacmilimab following 10 mg/ kg pacmilimab in combination with 3 mg/kg ipilimumab that were targeted for efficacy based on quantitative systems pharmacology modeling.…”

“…Based in part on evidence of preliminary antitumor efficacy with similar tolerability across dose levels in those cohorts, and PK and pharmacodynamic considerations described previously, 22 10 mg/kg of pacmilimab was chosen for further investigation as monotherapy and thus was the dose level of focus in combination therapy. In the combination therapy study, the MTD/recommended phase 2 dose of pacmilimab 10 mg/kg+ipilimumab 3 mg/ kg was established.…”

“…Pacmilimab concentrations were assayed as reported elsewhere. 22 Ipilimumab concentrations were assayed via a validated assay (online supplemental methods).…”

“…Based in part on evidence of preliminary antitumor efficacy with similar tolerability across dose levels in those cohorts, and PK and pharmacodynamic considerations (figure 3), 22 the recommended phase 2 dose was established as pacmilimab 10 mg/kg+ipilimumab 3 mg/kg. Abdominal pain 1 (17) 0 0 1 (13) 0 2 ( 7) 2 ( 7)…”

CX-072 (pacmilimab), a Probody®PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study

“…In the absence of an MTD, the 10 mg/kg dose level was selected as the recommended phase 2 dose based on overall tolerability in addition to pharmacokinetic and pharmacodynamic considerations. 21 The AE profile in the dose-escalation phase is summarized in table 2 and detailed in online supplemental tables 2 and 3. Grade 3-4 treatment-related AEs were observed in eight patients (15%), with no AE occurring in more than one patient.…”