A Phase I Study of the Anti-Natural Killer Inhibitory Receptor (KIR) Monoclonal Antibody (1-7F9, IPH2101) in Elderly Patients with Acute Myeloid Leukemia (AML): Clinical and Immunological Effects of a Single Dose Followed by Repeated Dosing.
Authors: Vey Norbert , Bourhis Jean-Henri , Dombret Herve , Bordessoule Dominique , Prébet Thomas , Charbonnier Aude , de Botton Stephane , Boissel Nicolas , d'Arnoux Christine , Romagne Francois , Andre Pascale , Tiollier Jerome , Squiban Patrick , Blaise Didier , Olive Daniel 
Published: October 2019

Abstract 632

Background: Non cytotoxic treatments such as immunotherapy represent promising approaches for the post-remission therapy of elderly patients with AML for which relapse free survival is short. The therapeutic potential of natural Killer (NK) cells has been revealed by the KIR mismatch allogeneic transplant model where the anti-leukemic effect of the graft is due to unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts (Miller et al. 2005; Ruggeri et al. 2002). To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs), the 1-7F9/IPH2101, was generated (Romagne et al., Blood 2009). We present the results of the First in Human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60-80 years with non promyelocytic AML in first CR following induction and 1-6 cycles of consolidation chemotherapy, normal renal and hepatic functions, KIR-expression on NK-cells and who signed informed consent were eligible for Protocol IPH2101-101. Dose escalation (IPH2101: 0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg as iv infusion) was studied using a 3+3 scheme. Patients still in CR who had tolerated the single dose administration were eligible for an extension trial (Protocol IPH2101-102) investigating repeated doses of IPH2101 (1/ month x 6 months) using the dose the patient was allocated to in protocol IPH2101-101. Pharmacokinetic (PK) and circulating cytokines (IL-1b, IL-6, IFN-g, MIP-1β and TNF-a) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: 23 patients, median age 71 years (range 61-79) in first CR of AML for a median of 20 weeks have been included in IPH2101-101. 3 patients (13%) had achieved CR after 2 induction courses, 5 patients (22%) had unfavorable cytogenetics, and 5 patients (22%) had high WBC at diagnosis. Planned dose escalation has been completed and no Dose Limiting Toxicity (DLT) has been recorded. 2 patients (in DL 4 and 5) have been replaced (one relapsed before 4 weeks of follow-up; the other had no detectable antibody after injection). Related Adverse Events seen in 14/23 patients (61%) were mild (grade ≤2) and transient. For doses above 0.075 mg/kg, ½ life ranged between 11-28 days. For doses above 0.3mg/kg, full saturation (>90% KIR occupancy) has been observed for 28 days to up to 6 weeks (at the 3 mg/kg DL). IPH2101 had no effect on the number and distribution of the peripheral lymphocyte subsets or the expression of NK receptors (KIRs, CD94/NKG2A, CD85j, NKp46, NKp30 or NKG2D). NK cell function tested by ex vivo cytotoxicity assay was not impaired after treatment. From dose 1 mg/kg (5/6 patients), IL-1b and IL-6 increased 6h post-dosing (2 to 8 fold increase and 2 to 15 fold increase compare to pre-dose, respectively) and decreased to pre-dose concentrations within 24h. Furthermore increase in TNF-a during the first hour was often correlated with CD69 up-regulation on NK cells. 8 patients received repeated doses of IPH2101 (0.0003 mg/kg: 2 patients, 0.003 mg/kg: 2 patients, 0.015 mg/kg: 1 patient, 1 mg/kg: 3 patients, 3 mg/kg pending) as part of the extension trial. No grade 3-4 related toxicities were observed. 2 patients completed the 6 courses, 5 patients were withdrawn for relapse and 1 patient is still ongoing at 1mg/kg. In accordance with the pre-clinical PK/PD model there is a clear relationship between exposure (Cmax) and KIR occupancy. Moreover the inter-patient variability is low (PK data) to moderate (KIR occupancy data). Median follow-up is 47 weeks. Among the 21 evaluable patients 11 patients are alive, 15 relapsed with 10 death, 6 are still in remission (1 patient in DL1, 2 patients in DL6 and 3 patients in DL7). Conclusions: Anti KIR treatment is safe and well tolerated and MTD has not been reached for doses producing full KIR saturation for 4 weeks, confirming the specificity of the immunological effects. Retreatment for prolonged period of time is feasible and safe. Signs of NK cell activation can be observed for doses above 0.3 mg/kg. IPH2101 deserves further investigation in patients with AML.

Disclosures:

Vey: INNATE PHARMA: Consultancy. d'Arnoux:INNATE PHARMA: Employment. Romagne:INNATE PHARMA: Employment. Andre:INNATE PHARMA: Employment. Tiollier:INNATE PHARMA: Employment. Squiban:INNATE PHARMA: Employment. Blaise:INNATE PHARMA: Consultancy. Olive:INNATE PHARMA: Research Funding.