About this program
Lacutamab (IPH4102) is a first-in-class anti-KIR3DL2 humanized cytotoxicity-inducing antibody, designed for treatment of cutaneous T-cell lymphoma (CTCL), an orphan disease. This group of rare cutaneous lymphomas of T lymphocytes has a poor prognosis with few therapeutic options at advanced stages.
KIR3DL2 is an inhibitory receptor of the KIR family, expressed by approximately 65% of patients across all CTCL subtypes and expressed by up to 85% of them with certain aggressive CTCL subtypes, in particular, Sézary syndrome. It has a restricted expression on normal tissues.
Lacutamab was granted orphan drug status in the European Union and in the United States for the treatment of CTCL. In January 2019, the US Food and Drug Administration (FDA) granted Innate Pharma Fast Track designation for lacutamab for the treatment of adult patients with relapsed or refractory Sézary syndrome who have received at least two prior systemic therapies.
TELLOMAK, a global, multi-cohort, Phase II study evaluating the potential of lacutamab in different subtypes of T-cell lymphomas, has been initiated in the first half of 2019 (see clinical development).
Mechanism of action of lacutamab
The Phase II study TELLOMAK evaluating the potential of lacutamab in different subtypes of T-cell lymphomas (TCL) has been initiated in the first half of 2019.
TELLOMAK is a global, open-label, multi-cohort Phase II clinical trial conducted in the United States and Europe. In this trial, lacutamab is being evaluated alone and in combination with chemotherapy in patients with advanced TCL.
TELLOMAK is expected to recruit up to 250 patients, with lacutamab evaluated:
- As a single agent in approximately 60 patients with Sézary syndrome who have received at least two prior treatments, including mogamulizumab,
- As a single agent in approximately 90 patients with Mycosis fungoides (MF) who have received at least two prior treatments, and
- In combination with standard chemotherapy (gemcitabine and oxaliplatin) in approximately 100 patients with peripheral T-cell lymphoma (PTCL) who have received at least one prior treatment.
In patients with MF and PTCL, the study is designed to evaluate the benefit of lacutamab according to KIR3DL2 expression. The study will comprise two cohorts for each of the 2 indications, testing Lacutamab in KIR3DL2 expressing and non-expressing patients. These cohorts will follow a Simon 2-stage design that will terminate if treatment is considered futile. The Sézary syndrome arm of the study could enable the registration of lacutamab in this indication.
The primary endpoint of the trial is objective response rate. Key secondary measures include incidence of treatment emergent adverse events, quality of life, overall response rate, progression-free survival and overall survival.
A Phase I trial has been conducted as an open label and multicenter study, performed in Europe (France, Netherlands, United Kingdom) and in the US. Participating institutions include several hospitals with internationally recognized expertise: the Saint-Louis Hospital (Paris, France), the MD Anderson Cancer Center (Houston, Texas), the Stanford University Medical Center (Stanford, CA), the Ohio State University (Columbus, OH), the Leiden University Medical Center (Leiden, Netherlands), and the Guy’s and St Thomas’ Hospital (London, United Kingdom).
- The dose-escalation part has accrued 25 KIR3DL2-positive CTCL patients in 10 dose levels. The objective was to characterize lacutamab (IPH4102) safety profile, identify the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D); the dose escalation followed an accelerated 3+3 design. Results of the dose-escalation were presented at the EORTC CLTF meeting in October 2017.
- The cohort expansion enrolled 15 patients with Sézary Syndrome and 4 tMF receiving Lacutamab (IPH4102) at the RP2D until progression.
The primary objective of this trial was to evaluate the safety and tolerability of repeated administrations of single agent lacutamab in this patient population. The secondary objectives include assessment of the drug’s antitumor activity. Clinical endpoints include global objective response rate, response duration and progression-free survival. Exploratory analyses are aimed at identifying biomarkers of clinical activity.
In a presentation at EORTC CLTF meeting in September 2018 and updated results presented at the 2018 ASH Annual Meeting, lacutamab showed encouraging clinical activity, demonstrated by high response rate and long progression-free survival.
Willemze et al, 2019. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas Blood Pr Martine Bagot et al, 2019. 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 The Lancet Oncology Van Der Weyden et al, 2018. IPH4102, a monoclonal antibody directed against the immune receptor molecule KIR3DL2, for the treatment of cutaneous T-cell lymphoma Expert Opin Investig Drugs. Wilcox et al, 2017. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management Am J Hematol. Battistella et al, 2017. KIR3DL2 expression in cutaneous T-cell lymphomas: expanding the spectrum for KIR3DL2 targeting Blood Hurabielle et al, 2017. Usefulness of KIR3DL2 to Diagnose, Follow-Up, and Manage the Treatment of Patients with Sézary Syndrome Clin Cancer Res. Trautinger et al, 2017. European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2017 Eur J Cancer. Battistella M et al, 2016. KIR3DL2 (CD158k) is a potential therapeutic target in primary cutaneous anaplastic large cell lymphoma Br J Dermatol Whittaker et al, 2016. How I treat mycosis fungoides and Sézary syndrome Blood Wilcox et al, 2016. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management Am J Hematol. Zinzani et al, 2016. Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Cutaneous T-cell lymphomas Crit Rev Oncol Hematol. Sicard et al, 2014. IPH4102, a Humanized KIR3DL2 Antibody with Potent Activity against CutaneousT-cell Lymphoma Cancer Research Kempf et al, 2011. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma Blood Bouaziz et al, 2010. Absolute CD3+ CD158k+ lymphocyte count is reliable and more sensitive than cytomorphology to evaluate blood tumour burden in Sezary syndrome Br J Dermatol Willemze et al, 2010. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. Agar et al, 2010. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal J Clin Oncol. Kim et al, 2003. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression Arch Dermatol. Bagot et al, 2001. CD4(+) cutaneous T-cell lymphoma cells express the p140-killer cell immunoglobulin-like receptor Blood Willemze et al, 1997. EORTC classiﬁcation for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer (EORTC) Blood