Elsevier

The Lancet Oncology

Volume 20, Issue 8, August 2019, Pages 1160-1170
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(19)30320-1Get rights and content

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, Sézary 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 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]).

Interpretation

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.

Funding

Innate Pharma

Introduction

Cutaneous T-cell lymphomas are a heterogeneous group of rare, extranodal, non-Hodgkin lymphomas, with approximately 3000 new cases diagnosed in the USA every year.1 The most common subtype of cutaneous T-cell lymphoma is mycosis fungoides, which accounts for 50–60% of all cases.2 Sézary syndrome is a rare, leukaemic subtype that is characterised by erythroderma, lymphadenopathy, and high burden of neoplastic T cells (Sézary cells) in the blood.3 Patients with Sézary syndrome typically have severe pruritus, frequent infections, and body disfigurement resulting in poor quality of life.4 Prognosis is dismal, with median survival ranging from 2·5 to 4 years.5, 6

On the basis of the results of two randomised trials, brentuximab vedotin and mogamulizumab were approved for the treatment of subsets of patients with cutaneous T-cell lymphoma who received at least one prior systemic therapy.7, 8 Only the trial with mogamulizumab included patients with Sézary syndrome. In more refractory patients (ie, those who have received at least two prior systemic therapies), vorinostat is the only approved agent in the USA with modest clinical activity in patients with Sézary syndrome.8 Notably, no agents are approved in Europe for such patients.

Research in context

Evidence before this study

We searched the scientific literature to identify reports of patients with cutaneous T-cell lymphoma, Sézary syndrome, and KIR3DL2. We searched Medline for studies published in English from Jan 1, 1990, to Dec 31, 2018. Search items included “cutaneous T-cell lymphoma”, “KIR3DL2”, and “Sézary syndrome”. Cutaneous T-cell lymphoma is an uncommon and incurable form of non-Hodgkin lymphoma. Sézary syndrome accounts for around 5–10% of cutaneous T-cell lymphomas and is the leukaemic and most aggressive form, with median survival rarely exceeding 4 years. Affected patients typically have severe pruritus, frequent infections, and body disfigurement resulting in poor quality of life. In 2018, two novel drugs, brentuximab vedotin and mogamulizumab, were approved for the treatment of subsets of patients with cutaneous T-cell lymphoma who received at least one previous systemic therapy. However, patients with Sézary syndrome were included only in the trial of mogamulizumab. In more refractory patients (ie, those who have received at least two prior systemic therapies), no drugs are proven to be effective in patients with Sézary syndrome. Vorinostat is the only approved agent in the USA, which in a phase 3 trial showed an overall response of 2% in patients with Sézary syndrome. KIR3DL2 (CD158k) is a member of the highly polymorphic family of killer-cell immunoglobulin-like receptors and is widely expressed in cutaneous T-cell lymphoma, and in more than 85% of patients with Sézary syndrome, and was proposed as the most sensitive diagnostic and prognostic marker for these patients.

Added value of this study

To our knowledge, this study is the first reported trial of the anti-KIR3DL2 antibody IPH4102. We report activity of this novel, targeted drug in a rare form of cutaneous T-cell lymphoma, Sézary syndrome, with a high unmet medical need. Unlike previous studies of drugs in patients with refractory cutaneous T-cell lymphoma who received at least two previous systemic therapies, this study used the international consensus response criteria. This study shows high activity of IPH4102 in patients with Sézary syndrome who received at least two previous systemic therapies. The treatment was well tolerated with no identified dose-limiting toxicity. These results represent a potential new treatment for patients with refractory Sézary syndrome.

Implications of all the available evidence

On the basis of our results, IPH4102 received fast-track designation from the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory Sézary syndrome who have received at least two prior systemic therapies. 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.

KIR3DL2 (CD158k) is a member of the highly polymorphic family of killer-cell immunoglobulin-like receptors and is widely expressed in cutaneous T-cell lymphoma; it is expressed in more than 85% of patients with Sézary syndrome.9 KIR3DL2 was proposed as the most sensitive diagnostic and prognostic marker for Sézary syndrome,10 suggesting that it could serve as an ideal therapeutic target for these patients.

IPH4102 is a humanised, first-in-class, monoclonal antibody that is designed to deplete KIR3DL2-expressing cells via antibody-dependent cell cytotoxicity and phagocytosis.11 The drug has shown anti-tumour activity in mouse xenograft models and ex-vivo autologous assays using patient-derived natural killer cells and Sézary cells.11 We report the results of the first-in-human, phase 1 study assessing IPH4102 in patients with relapsed or refractory cutaneous T-cell lymphoma.

Section snippets

Study design and participants

We did an international, first-in-human, open-label, phase 1 study in five academic hospitals in the USA, France, the UK, and the Netherlands (appendix p 2). The study was composed of dose-escalation and cohort-expansion portions and was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was approved by the institutional review board at each participating site and is included in the appendix. All patients provided

Results

Between Nov 4, 2015, and Nov 20, 2017, 54 patients with relapsed or refractory cutaneous T-cell lymphoma were screened; 34 for the dose-escalation part and 20 for the cohort-expansion part (figure 1). 44 patients were enrolled and received at least one dose of IPH4102; 25 in the dose-escalation part and 19 in the cohort-expansion part (figure 1). Recruitment in the cohort-expansion part was restricted because of a shortage in drug supply.

Patient characteristics are summarised in table 1. The

Discussion

This study investigated the safety and activity of IPH4102 in patients with relapsed or refractory cutaneous T-cell lymphoma. IPH4102 showed a favourable safety profile and was associated with high frequency of durable global response and an improvement of quality of life, particularly in the subset of patients who had Sézary syndrome, which represented most patients included in this trial.

No dose-limiting toxicities or IPH4102 immune-related adverse events were observed and only four patients

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