Interleukin-15 (IL-5) in Combination with Avelumab in Relapsed/Refractory Mature T-Cell Malignancies
Authors: Miljkovic Milos D. , Conlon Kevin C , Dubois Sigrid , Hsu Jennifer , Schlom Jeffrey , Gulley James , Waldmann Thomas A. 
Published: November 2019

Background: Programmed death-ligand 1 (PD-L1) is expressed in many T-cell malignancies, including 75-100% of advanced cutaneous T-cell lymphomas, 75% of ALK-negaive anaplastic large cell lymphoma (ALCL), and 28% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). In 27% of patients with adult T-cell leukemia/lymphoma (ATLL) expression of PD-L1 is upregulated through 3'-UTR disruption; however, immune checkpoint inhibition has been associated with hyperprogression in three patients with indolent ATLL. In T-cell malignancies, PD-L1 expression was associated with worse outcomes.
Avelumab is a fully human IgG1 anti-PD-L1 antibody which inhibits PD-1/PD-L1 interactions; unlike other approved immune checkpoint inhibitors, it also induces lysis of tumor cells in vitro via antibody-dependent cell-mediated cytotoxicity (ADCC). As ADCC is mediated by natural killer (NK) cells, agents which increase NK cell number and activity may act sinergistically with avelumab. Administration of recombinant human (rh)IL-15 by continuous intravenous infusion (CIV) into adult cancer patients has produced a 15-75-fold expansion in the number of circulating NK cells at well-tolerated doses. Preclinical syngeneic and xenograft murine lymphoid malignancy models have shown increased efficacy with combined administration of IL-15 and anti-tumor antibodies compared to either alone. We therefore hypothesized that rhIL-15 may increase the efficacy of avelumab in PD-L1 expressing T-cell malignancies, and are testing the combination in a phase I trial.
Primary objective: determine the safety, toxicity profile and the maximum tolerated dose of CIV IL- 15 administration in combination with with a fixed dose of avelumab.
Secondary objectives: 1) determine the efficacy of combined CIV rhIL-15 and avelumab treatment to patients with T-cell lymphomas other than ATL (overal response, duration of response, progression-free survival, event-free survival, and overall survival), 2) correlate response with level of PD-L1 expression in tumor cells (&lt;50% and ≥50%) 3) better understand the in vivo biological effects of avelumab and rhIL-15 treatment by analyzing changes in peripheral blood lymphocyte subsets, quantify ADCC performed ex vivo on PBMCs obtained from the patients, and examine treatment-related changes in tumor deposits by immunohistochemical and molecular analysis of core biopsies obtained before and during treatment.
Exploratory objectives: 1) assess the role of circulating tumor DNA (ctDNA) in T-cell malignancies, 2) assess the role of exosomes in T-cell malignancies, 3) identify other potential biomarkers of response, such as cytokine levels and T-cell clonality.
Eligibility criteria: 1) age ≥18 years, 2) histologically proven PTCL-NOS, ALK-negative ALCL, or mycosis fungoides/Sézary syndrome that is refractory to at least one line of systemic treatment, 3) ECOG ≤1, 4) WBC count ≥ 3 ⨉ 109/L, with absolute neutrophil count ≥ 1.0 ⨉ 109/L, lymphocyte count ≥ 0.5 x 109/L, platelet count ≥ 100 ⨉ 109/L, and hemoglobin ≥ 9 gm/dL (may have been transfused), 5) no prior treatment with drugs targeting PD-1/PD-L1, or receipt of any organ transplantation including allogeneic stem cell transplantation.
Study design: Open-label, single-center, non-randomized Phase 1 study with a 3+3 phase dose escalation design enrolling up to 30 patients. IL-15 will be administered by continuous intravenous infusion with a dose of 1 mcg/kg/day (DL1), 2 mcg/kg/day (DL2), 3 mcg/kg/day (DL3), or 4 mcg/kg/day (DL4) on days 1-5 of each cycle. Avelumab 10 mg/kg IV over 1 hour)will be administered on days 8 and 22 of the cycle. Treatment will continue for a maximum of 6 cycles, or until toxicity or progressive disease.
Correlative studies: tumor (skin or lymph node) biopsy at baseline and before the second dose of avelumab (C1D22); lymphocyte subset testing, ADCC capacity of ex vivo NK cells, ctDNA, exosomes, cell and plasma banking (days 1 and 8 of each cycle).
One patients has been treated so far at DL1. Enrollment is ongoing.
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Disclosures
Waldmann: Bioniz: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Avelumab off-label use for treatment of T-cell malignancies.