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|Ref Type||Journal Article|
|Authors||Bagot M, Porcu P, Marie-Cardine A, Battistella M, William BM, Vermeer M, Whittaker S, Rotolo F, Ram-Wolff C, Khodadoust MS, Bensussan A, Paturel C, Bonnafous C, Sicard H, Azim HA, Kim YH|
|Title||IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial.|
|Journal||The Lancet. Oncology|
|Abstract Text||IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma.We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045.Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1]).IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.Innate Pharma.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Lacutamab||IPH-4102|IPH 4102|IPH4102||Lacutamab (IPH4102) is a monoclonal antibody that targets KIR3DL2, which potentially results in increased anti-tumor immune response against KIR3DL2-expressing tumor cells, and reduced tumor growth (PMID: 25361998, PMID: 31253572).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Sezary's disease||not applicable||Lacutamab||Phase I||Actionable||In a Phase I trial, Lacutamab (IPH4102) demonstrated safety, and treatment resulted in an overall response rate of 43% (15/35; 2 complete responses, 13 partial responses), a median progression-free survival (PFS) of 11.7 months, and a median duration of response (DOR) of 13.8 months in patients with Sezary syndrome, with a median PFS of 16.8 months, and a median DOR of 13.8 months in Sezary syndrome patients with prior Poteligeo (mogamulizumab-kpkc) treatment (PMID: 31253572; NCT02593045).||31253572|
|Unknown unknown||cutaneous T cell lymphoma||not applicable||Lacutamab||Phase I||Actionable||In a Phase I trial, Lacutamab (IPH4102) demonstrated safety, and cutaneous T-cell lymphoma patients treated with IPH4102 demonstrated an overall response rate of 36% (16/44), a median progression-free survival of 8.2 months, and a median duration of response of 13.8 months (PMID: 31253572; NCT02593045).||31253572|
|Unknown unknown||mycosis fungoides||not applicable||Lacutamab||Phase I||Actionable||In a Phase I trial, Lacutamab (IPH4102) demonstrated safety, and treatment resulted in a median progression-free survival of 3.9 months, and a response in 1 and stable disease in 7 of 8 patients with mycosis fungoides (PMID: 31253572; NCT02593045).||31253572|