TELLOMAK: T-CELL LYMPHOMA ANTI-KIR3DL2 THERAPY: AN OPEN LABEL, MULTI-COHORT, MULTI-CENTER, INTERNATIONAL PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF IPH4102 ALONE OR IN COMBINATION WITH CHEMOTHERAPY IN PATIENTS WITH ADVANCED T-CELL LYMPHOMA

Background: KIR3DL2 is a killer immunoglobulin-like receptor that is expressed by tumor cells across different subtypes of T-cell lymphomas (> 85% of Sézary Syndrome (SS), ~50% of mycosis fungoides (MF), and ~50% in peripheral T-cell lymphomas (PTCL)). IPH4102 is a humanized first-in-class anti-KIR3DL2 monoclonal antibody designed to deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity (ADCC) and phagocytosis. A first-in-human study including 44 patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) showed that the drug is safe and has very robust clinical activity. The majority of the patients enrolled had relapsed/refractory SS (n=35). In this population, IPH4102 produced an overall response rate (ORR) of 42.9%, and median progression free survival (PFS) of ~1 year leading to FDA fast track designation in January 2019. IPH4102 has not been previously investigated in PTCL. Preclinical studies have shown that gemcitabine and oxaliplatin can upregulate KIR3DL2 expression on T-cell lymphoma cell lines. Furthermore, IPH4102 anti-tumor activity was enhanced in-vitro by each of these chemotherapy agents, and even more by the combination. Methods: This is an open-label, multi-cohort, multi-center, international phase II trial. Patients will be allocated to one of five cohorts: Cohort 1: SS, Cohorts 2&3: MF stratified according to KIR3DL2 expression, Cohorts 4&5: PTCL stratified according to KIR3DL2 expression. In the SS and MF cohorts, patients should have received ≥2 prior systemic therapies and have no evidence of large cell transformation as detected centrally. In the SS cohort, prior treatment with mogamulizumab is required. In the PTCL cohorts, only patients with PTCL-NOS, AITL and ALCL who have received ≥ 1 line of prior systemic therapy are eligible. All patients will undergo KIR3DL2 testing at baseline in a central laboratory. In the SS and MF cohorts, IPH4102 will be administered as single agent at a flat dose of 750mg weekly x 4 weeks, every 2 weeks x 20 weeks (10 doses), then every 4 weeks. In the PTCL cohorts, IPH4102 will be administered using the same schedule in combination with gemcitabine and oxaliplatin (GEMOX), which will be administered every 2 weeks for a maximum of 8 cycles. In all cohorts, IPH4102 treatment will continue until progression or unacceptable toxicity. The primary endpoint is overall response, evaluated using the International Consensus Criteria for MF/SS and the Lugano Criteria for PTCL. Secondary endpoints include safety, other efficacy endpoints, and biomarker analyses. Each cohort has a separate design and dedicated statistical analysis plan. A biomarker-stratified design is applied in cohorts 2-5 using a Simon 2-stage design to inform on the activity of assigned treatment according to KIR3DL2 expression. In total, approximately 140-260 patients will be recruited across 30-40 sites in the US and Europe. Keywords: mycosis fungoides (MF); peripheral T-cell lymphomas (PTCL); Sezary syndrome. Disclosures: Porcu, P: Consultant Advisory Role: Innate Pharma; Research Funding: Kyowa Kirin, Viracta. Kim, Y: Honoraria: kyowa Kirin, Eisai, Millennium/Takeda, Seattly Genetics, miRagen, Innate Pharma; Research Funding: Kyowa Kirin, Merck, Soligenix, Forty-Seven, Neumedicines, Portola Pharma, and Horizon. Zinzani, P: Honoraria: SERVIER, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, MSD, Celltrion, Celgene, Roche; Other Remuneration: Speaker bureau: Verastem, SERVIER, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, MSD, Celltrion, Celgene, Roche. Sicard, H: Employment Leadership Position: Innate Pharma; Stock Ownership: Innate Pharma. Azim Jr, H: Employment Leadership Position: Innate Pharma; Stock Ownership: Innate Pharma. Bagot, M: Consultant Advisory Role: Innate Pharma; Other Remuneration: Travel fees: Innate Pharma, Kyowa Kirin. Speaker Bureau: Acetlion. Patency: IPH4102.