Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of cergutuzumab amunaleukin: a phase I study in patients with advanced and/or metastatic solid tumors

BACKGROUND: Cergutuzumab amunaleukin (CA) is a novel immunocytokine comprising an interleukin-2 variant moiety with abolished CD25 (interleukin-2 receptor α) binding, fused to a bivalent anti-carcinoembryonic antigen (CEA) monoclonal antibody. This first-in-human phase I study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CA.

MATERIAL AND METHODS: Patients had CEA-positive advanced and/or metastatic solid tumors that had progressed on standard-of-care treatment. The study consisted of two parts: patients received single-dose CA 0.1-6 mg (n = 5) in part I and multiple ascending doses of 10-40 mg every 2 weeks (q2w; n = 31) or 6-30 mg weekly (qw; n = 24) in part II. Patients with advanced renal cell carcinoma or melanoma (CEA-negative) were permitted in part II.

RESULTS: Sixty patients were enrolled. Most common primary tumor sites in part I, part II q2w, and part II qw were the colon (40%, 44%, and 57%, respectively) and rectum (40%, 19%, and 14%, respectively). Four dose-limiting toxicities (DLTs) established an MTD of 30 mg q2w [grade (Gr)4 hypophosphatemia and thrombocytopenia at 40 mg; Gr2 capillary leak syndrome and Gr3 fatigue at 30 mg]. Dose escalation was halted in the qw regimen due to DLTs at 25 mg (Gr3 hypotension and thrombocytopenia). The most frequently reported adverse events were pyrexia (68%) and infusion-related reaction (52%). The pharmacokinetics of CA were consistent with target-mediated drug disposition, but approximate dose-proportional exposure was observed at 6-40 mg doses. In the blood, CA preferentially and significantly expanded CD8+ T cells and natural killer cells, but not regulatory T cells (T reg). There were no objective responses; 6/53 (11%) evaluable patients had stable disease (median duration 4.5 months).

CONCLUSIONS: Consistent with its mechanism of action, CA had a manageable safety profile and expanded immune effector cells but not T reg. Further development in combination with additional immunomodulatory agents is warranted.