Author(s): D. M. Benson, S. Padmanabhan, C. C. Hofmeister, C. E. Bakan, R. Abonour, A. Suvannasankha, Y. A. Efebera, P. J. Squiban, M. A. Caligiuri, S. Farag

ABSTRACT:

Background: A natural killer (NK) cell immune response against MM has been well documented; however, this process is impaired by upregulation of MHC class I antigens on MM cells which serve as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIR). In allogeneic transplantation, KIR/MHC mismatch has improved outcomes in MM by disrupting this relationship. Preclinical data (Blood. 2009;114:2667) demonstrate that IPH2101 (formerly 1-7F9), a human IgG4 monoclonal antibody recognizing common inhibitory KIR, mimics this effect in the autologous setting by enhancing the NK cell vs MM effect. We present results of a phase I study of IPH2101 in patients with MM.

Methods: A 7-cohort, open-label, single-agent, dose-escalation, safety and tolerability study was conducted in patients with heavily pre-treated MM. IPH2101 was dose-escalated from 0.0003 to 3 mg/kg IV q28 D for up to 4 cycles in a standard 3+3 trial design. Re-dosing was based on safety data from the prior cycle and data on KIR occupancy, pharmacokinetics (PK), pharmacodynamics (PD), and comprehensive biological effects of IPH2101 were collected. A 7 patient (pt) extension phase of the trial is nearing completion currently at the 3 mg/kg dose level in pts with one prior therapy.

Results: Data from 24 treated pts are available at present. 13 pts have received at least 2 doses of IPH2101. No DLT has been observed. One pt at dose level 1 was replaced and dose level 4 was expanded to 6 pts due to SAE (acute renal failure deemed possibly related to IPH2101). To date, IPH2101 has been well tolerated with AEs related to IPH2101 observed in 4 pts (17%). Full KIR occupancy through the majority of the dosing interval was observed at the 1 mg/kg dose with a clear relationship between Cmax and KIR occupancy. PK and PD data closely approximate predicted values and preliminary analyses suggest 3 pts have had disease stabilization with IPH2101.

Conclusions: IPH2101 enhances the NK cell vs. MM effect by blocking inhibitory KIR and appears to be safe and well tolerated. Clinical results will be presented, including data from the final, dose extension phase of the study. This immunotherapeutic approach holds promise for the treatment of MM, and further study is warranted.