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
| العنوان: | 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 |
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| المؤلفون: | Maarten H. Vermeer, Martine Bagot, Federico Rotolo, Cécile Bonnafous, Hélène Sicard, Anne Marie-Cardine, Hatem A. Azim, Caroline Ram-Wolff, Sean Whittaker, Maxime Battistella, Michael S. Khodadoust, Carine Paturel, Armand Bensussan, Pierluigi Porcu, Basem M. William, Youn H. Kim |
| المساهمون: | Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche & Développement, Innate Pharma |
| المصدر: | Lancet Oncology Lancet Oncology, Elsevier, 2019, 20 (8), pp.1160-1170. ⟨10.1016/S1470-2045(19)30320-1⟩ |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Skin Neoplasms, Maximum Tolerated Dose, [SDV]Life Sciences [q-bio], Population, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Humans, education, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, Mycosis fungoides, Dose-Response Relationship, Drug, business.industry, Cutaneous T-cell lymphoma, Not Otherwise Specified, Receptors, KIR3DL2, Middle Aged, medicine.disease, Lymphoma, T-Cell, Cutaneous, 3. Good health, Lymphoma, Clinical trial, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business |
| الوصف: | Summary Background 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, Sezary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma. Methods 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 . Findings Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sezary 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 Sezary syndrome (43% [28·0–59·1]). Interpretation IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sezary 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 Sezary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2. Funding Innate Pharma |
| تدمد: | 1470-2045 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::28ce3c922b3a855c25f033db0b020d6bTest https://doi.org/10.1016/s1470-2045Test(19)30320-1 |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....28ce3c922b3a855c25f033db0b020d6b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14702045 |
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