title: A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Don.benson@osumc.edu.
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.affiliation: University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Cohen
authors.affiliation: Mount Sinai School of Medicine, New York, New York.
authors.forename: Sundar
authors.initials: S
authors.lastname: Jagannath
authors.affiliation: Dana Farber Cancer Institute, Boston, Massachusetts. Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: St. Francis Hospital, Greenville, South Carolina.
authors.forename: Gary
authors.initials: G
authors.lastname: Spitzer
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Efebera
authors.affiliation: Innate Pharma, Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Andre
authors.affiliation: Innate Pharma, Marseille, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Zerbib
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007107:Immune System; D007074:Immunoglobulin G / Q000737:chemistry; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000166:cytology; D000077269:Lenalidomide; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009364:Neoplasm Recurrence, Local; D054340:Receptors, KIR / Q000737:chemistry; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D008024:Ligands; D054340:Receptors, KIR; D013792:Thalidomide; C558235:IPH-2101; D000077269:Lenalidomide