IPH2101, a Novel Anti-Inhibitory KIR Monoclonal Antibody for Multiple Myeloma: Interm Phase 1 Trial Results and Correlative Biologic and Safety Data
Authors: Benson Don M , Bakan Courtney E , Padmanaban Swaminathan , Abonour Rafat , Suvannasankha Attaya , Jagannath Sundar , Chari Ajai , Clever David , Kalu Chidimma , Collins Shauna , Alghothani Yousef , Hofmeister Craig C. , Efebera Yvonne , Blanchet Stephane , Caligiuri Michael A. , Farag Sherif 
Published: October 2019

Abstract
Abstract 1966

Introduction:
A potent natural killer (NK) cell versus multiple myeloma (MM) effect has been reported in clinical observations and characterized mechanistically in translational studies. However, the NK cell versus MM effect is lost as the disease methodically progresses due, in part, to upregulation of MHC Class 1 antigens on MM tumor cells which serve as ligands to inhibitory KIR on NK cells. Our group has shown that IPH-2101, a novel IgG4 monoclonal blocking antibody against commonly expressed inhibitory KIR (KIR2DL-1, -2 and -3), may augment NK cell function against MM tumor cells. A single-agent phase 1 open-label, dose escalation study of IPH-2101 is nearing completion to determine the safety, tolerability and biologic effects of inhibitory KIR blockade as a novel form of therapy for MM.

Methods:
A single-agent, open-label, Phase 1 dose escalation study is being performed with 7 cohorts in standard 3+3 design. The protocol was amended to include 7 additional patients with less heavily pretreated disease in the final cohort. Doses from 0.0003 mg/kg to 3mg/kg are being evaluated. Patients enrolled on the 7 cohorts had heavily pre-treated, relapsed/refractory MM with at least one prior therapy, whereas 7 additional patients accrued to the final cohort are limited to one prior therapy only. IPH-2101 is administered intravenously once every 28 days, with 4 cycles of therapy possible as determined by safety, tolerability and disease characteristics. Extensive pharmacodynamic (PD), pharmacokinetic (PK), KIR occupancy, and correlative biologic data are being collected.

Results:
Currently, 32 patients have been enrolled, and 5 patients remain on study in the final cohort. IPH-2101 has been well tolerated without determination of a dose limiting toxicity (DLT). 1 patient at dose level 1 was replaced and 3 additional patients were enrolled at dose level 4 due to an SAE (acute renal failure) deemed possibly related to drug. PK and PD data closely approximate those predicted by preclinical modeling. Full KIR occupancy across the dosing interval appears to be achieved in most cases with the 1mg/kg dose. No evidence of autoimmunity and no deleterious effect on NK cell maturation has been observed to date. Ongoing correlative studies will characterize NK cell phenotype, cytotoxicity, and effects of IPH-2101 on immunomodulation. To date, no objective responses have been observed; however, preliminary analyses suggest that several patients may have achieved disease stabilization.

Conclusions:
IPH-2101 improves autologous NK cell-mediated cytotoxicity against MM tumor cells and appears to be well tolerated and safe with achievement of biologic endpoints independent of DLT or maximally tolerated dose. Preliminary data suggest that several patients may have disease stabilization on therapy. Updated correlative, biologic data will be presented at the meeting.

Disclosures:
No relevant conflicts of interest to declare.