A Phase I Study of Anti-ICOS Antibody MEDI-570 for Relapsed/Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Angioimmunoblastic T-Cell Lymphoma (AITL) (NCI-9930)

Background:T-follicular helper (T_FH) cells are a novel CD4+ T-cell subset that participates in germinal center maintenance/proliferation. Proliferation of T_FH is a postulated mechanism of pathogenesis for T-cell lymphomas (AITL, PTCL and others). The inducible T-cell costimulator (ICOS) is highly expressed in T_FHand hence in AITL, PTCL FH type, and some cutaneous T cell lymphomas (CTCL) and follicular lymphomas (FL). MEDI-570 is a human afucosylatedIgG1 kappa monoclonal antagonistic antibody directed against ICOS, which binds to and eliminates ICOS expressing cells in preclinical in vivo models. We investigate the safety, pharmacokinetics (PK) and clinical activity of ICOS blockade by MEDI-570 in T-cell lymphomas.

Methods: NCI-9930 is a Phase I study of MEDI-570 in R/R malignant lymphomas. It is a 3+3 study design that evaluated 5 dose levels . MEDI-570 was administered intravenously (IV) every 3 weeks for 12 cycles. Eligibility criteria included: age >18 years, ECOG <2, diagnosis of R/R PTCL, AITL, CTCL, mycosis fungoides, or FL, that have received and are refractory to at least 1 line of therapy (at least 2 lines of therapy and post autologous cell transplantation for FL), adequate organ functions and CD4+ T-cells >200 cells/uL (>100 for AITL). Primary endpoints are safety of MEDI-570, dose limiting toxicities (DLT)s and its recommended phase 2 dose (RP2D). Secondary endpoints include: pharmacokinetics (PK), overall response rate (ORR) based on Lugano classification and progression-free survival (PFS). Exploratory endpoints include various correlative studies. This study is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN) and Early Drug Development Opportunity Program (EDDOP) (NCT02520791).

Results: As of June 2020, the dose escalation phase has been completed. Patients were enrolled and evaluable for safety and efficacy. Median age is 63 (range: 29-80), female/male ratio=5/13, histologic types consisted in AITL (n= 12, 71%), PTCL NOS (n=3, 18%) and CTCL (n=2, 12%). The median number of prior therapies were 7.5 (1 - 16), stage III/IV in 83%, prior autologous HCT in 18%. There were 4 partial remissions (PR) and 7 with stable disease (SD), all patients with AITL. Two patients (1 PR and 1 SD) remain on treatment. One patient completed treatment and remains in a stable PR for over a year without further treatment. One patient in PR underwent allogeneic hematopoietic transplantation (HCT) and remains in remission. The most common grade 3/4 AEs were decreased CD4+ T-cells as expected anemia (12%), hypophosphatemia (12%), thrombocytopenia (6%), infusion related reactions (6%). No DLTs were reported, and the maximum tolerated dose was not established. Initial PK analyses demonstrated that MEDI-570 systemic exposure increased in a dose-dependent manner, and a RP2D was determined. Peripheral blood flow cytometry analysis of T-cell subsets showed that MEDI-570 caused a rapid and sustained decrease in CD4+ T-cells. It also resulted in reductions in circulating of certain ICOS+ T-cells, especially on days 7-21 post treatment.

Conclusion: MEDI-570 was safe, well tolerated and showed promising clinical activity in poor-risk refractory and heavily pretreated AITL. A RP2D was established. MEDI-570 results in sustained reduction of the targeted ICOS+T lymphocytes. The study continues enrolling in the expansion phase.