A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma; however, multiple myeloma cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against multiple myeloma; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class antiinhibitory KIR antibody, has acceptable safety and tolerability in multiple myeloma as a single agent. The present work sought to characterize lenalidomide and IPH2101 as a novel, steroid-sparing, dual immune therapy for multiple myeloma.

Experimental design: A phase I trial enrolled 15 patients in three cohorts. Lenalidomide was administered per os at 10 mg on cohort 1 and 25 mg on cohorts 2 and 3 days 1 to 21 on a 28-day cycle with IPH2101 given intravenously on day 1 of each cycle at 0.2 mg/kg in cohort 1, 1 mg/kg in cohort 2, and 2 mg/kg in cohort 3. No corticosteroids were utilized. The primary endpoint was safety, and secondary endpoints included clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD).

Results: The biologic endpoint of full KIR occupancy was achieved across the IPH2101 dosing interval. PD and PK of IPH2101 with lenalidomide were similar to data from a prior single-agent IPH2101 trial. Five serious adverse events (SAE) were reported. Five objective responses occurred. No autoimmunity was seen.

Conclusions: These findings suggest that lenalidomide in combination with antiinhibitory KIR therapy warrants further investigation in multiple myeloma as a steroid-sparing, dual immune therapy. This trial was registered at www.clinicaltrials.gov (reference: NCT01217203).

Conflict of interest statement

Disclosure of Conflicts of Interest: No other authors have conflicts to disclose.

©2015 American Association for Cancer Research.

Figures

Figure 1

Changes in pro-inflammatory cytokines observed in cycles 1 and 2. The 2 patients who experienced a potential DLT of clinically evident, infusion-related, cytokine release syndrome are marked (“*”).

Figure 2

(A.) Pharmacokinetic data demonstrate the IPH2101 serum concentration over time is associated with dose. (B.) Pharmacodynamic data suggest that KIR occupancy is a function of IPH2101 dose and time. Most patients treated at 1 mg/kg dosage achieved full KIR occupancy over the dosing interval of 28 days. (C.) IPH2101 dose correlates with KIR occupancy. (D.) Co-administration of lenalidomide with IPH2101 does not appear to affect serum concentration of IPH2101 as compared to data from a prior single-agent IPH2101 study.

Figure 2

(A.) Pharmacokinetic data demonstrate the IPH2101 serum concentration over time is associated with dose. (B.) Pharmacodynamic data suggest that KIR occupancy is a function of IPH2101 dose and time. Most patients treated at 1 mg/kg dosage achieved full KIR occupancy over the dosing interval of 28 days. (C.) IPH2101 dose correlates with KIR occupancy. (D.) Co-administration of lenalidomide with IPH2101 does not appear to affect serum concentration of IPH2101 as compared to data from a prior single-agent IPH2101 study.

Figure 3

(A.) Serial changes in individual subject MM biomarkers per cohort. (B.) Progression free survival curve for enrolled subjects in the present trial.

Figure 3

(A.) Serial changes in individual subject MM biomarkers per cohort. (B.) Progression free survival curve for enrolled subjects in the present trial.