Phase I study of an anti-CD30 Fc engineered humanized monoclonal antibody in Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) patients: Safety, pharmacokinetics (PK), immunogenicity, and efficacy

Abstract

8531 Background: XmAb2513 is a novel 2nd-generation humanized monoclonal antibody (mAb) directed against CD30 (a cell surface antigen expressed on Reed-Sternberg cells of HL and ALCL), with an Fc region engineered to have increased binding affinity to Fcγ receptors (FcγRs) leading to improved FcγR-dependent effector cell functions. In vitro, XmAb2513 was more potent and more efficacious than 1st-generation anti-CD30 mAbs (e.g., SGN-30 & MDX-060). In cynomolgus monkeys (cynos), XmAb2513 exposure was dose-proportional with half-lives ranging from 12 - 17d in repeat dose studies, which suggested biweekly (QOW) dosing in man. A Phase 1 study has been initiated to examine the safety and efficacy of XmAb2513 in patients (pts) with relapsed HL and ALCL. Methods: Phase 1 open-label study with QOW dosing of XmAb2513; dose-escalation study design with doses of 0.3, 1, 3, 6, 9, and 12 mg/kg via IV-infusion to establish the maximum tolerated dose (MTD). Pts receive up to 4 cycles (8 infusions) with sample collections at regular intervals for safety, PK, soluble CD30 (sCD30) and detection of immunogenicity [i.e., human Abs to humanized Abs (HAHA)]. Tumor response is assessed every 2 cycles. Results: 13 HL pts have been enrolled in the 1st 4 dose levels (0.3 to 6 mg/kg). XmAb2513 has been well tolerated. The MTD has not been achieved. 1 pt with an extensive treatment history and chronic immunosuppression died due to fungal pneumonia after a single 3 mg/kg dose. The event was considered unrelated to XmAb2513. PK parameters were computed for the 1st dose alone and for the entire course of XmAb2513 treatment. PK parameters appeared non-linear across the dose range from 0.3 - 3 mg/kg. Half-life appeared to increase after multiple infusions and ranged from 5.3 - 30.2 days in the 1 and 3 mg/kg cohorts. Immunogenicity (HAHA) results have been negative. Tumor reduction has been observed in 1 pt in the 1 mg/kg cohort and 2 in the 3 mg/kg cohort. Conclusions: The MTD of XmAb2513 has not yet been reached due to its tolerability and lack of immunogenicity. PK results are on track with simulations based on PK results from cynos. XmAb2513 has demonstrated encouraging biologic activity in patients with refractory HL. [Table: see text]