rhIL-15 / National Cancer Institute - LARVOL DELTA

Phase 2 trial (NCI-COTC030) of adjuvant inhaled recombinant human IL-15 combined with amputation and adjuvant chemotherapy in dogs with appendicular osteosarcoma. (PubMed, Front Immunol) - "Correlative assays suggest significant immunological effects of amputation and chemotherapy on immune responses. These data have important implications on novel immunotherapy strategies involving multimodality approaches including surgery and chemotherapy."

IO biomarker • Journal • P2 data • Melanoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IL15 • IL6

Correlative Analysis of a Phase I Study of Autologous Activated NK Cells ± rhIL-15 in Children and Young Adults with Refractory Solid Tumors (SITC 2025) - "Autologous NK cells were expanded ex vivo using artificial antigen-presenting cells (aAPC) expressing human 4-1BBL and human IL-15Rα and administered after lymphodepleting cyclophosphamide without (Cohort A) and with (Cohort B) continuous rhIL-15 infusion. This clinical trial and its intriguing correlative analyses provide a platform to build iterative approaches to enable future cell therapy trials to induce a more complete immune response. Continued research is necessary to determine the best method to maintain sustained activation of NK cells in an immune surveillance role.Ethics Approval This study was approved by the Institutional Review Board of the National Cancer Institute (NCI) at the NIH, approval number 13-C-0152, and was conducted in accordance with good clinical practices and the Declaration of Helsinki."

Clinical • IO biomarker • P1 data • Oncology • Solid Tumor • IL15

Phase I Trial of rhIL-15 Plus Dinutuximab Plus Irinotecan/Temozolomide for Children and Young Adults With Relapsed/Refractory Neuroblastoma (clinicaltrials.gov) - P1 | N=34 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting

Enrollment open • Neuroblastoma • Oncology • Solid Tumor

A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies. (PubMed, Blood Neoplasia) - P1 | "Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at www.ClinicalTrials.gov as #NCT04185220."

Clinical • Journal • P1 data • Acute Kidney Injury • Adult T-Cell Leukemia-Lymphoma • Cutaneous T-cell Lymphoma • Dermatology • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Lymphoma • Mycosis Fungoides • Myositis • Nephrology • Non-Hodgkin’s Lymphoma • Oncology • Renal Disease • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • IL15

Phase 1 study of recombinant interleukin 15 in combination with nivolumab and ipilimumab in subjects with refractory cancers. (ASCO 2025) - P1 | "These data suggest the addition of rhIL-15 to the combination of ipilimumab and nivolumab is safe, elicited a pharmacodynamic response from the immune system in blood but not tumor, and did not improve overall response rate."

Clinical • Combination therapy • IO biomarker • P1 data • Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • CD8 • IL15 • PD-1 • PD-L1

Phase I Trial of rhIL-15 Plus Dinutuximab Plus Irinotecan/Temozolomide for Children and Young Adults With Relapsed/Refractory Neuroblastoma (clinicaltrials.gov) - P1 | N=34 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1 trial • Neuroblastoma • Oncology • Solid Tumor

Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers (clinicaltrials.gov) - P1 | N=31 | Completed | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Completed | N=50 ➔ 31 | Trial completion date: Dec 2025 ➔ May 2025 | Trial primary completion date: Dec 2025 ➔ Nov 2024

Checkpoint inhibition • Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Oncology • Prostate Cancer • Solid Tumor • PD-L1

Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Oncology • Prostate Cancer • Solid Tumor • PD-L1

Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Checkpoint inhibition • Combination therapy • Trial completion date • Trial primary completion date • Oncology • Prostate Cancer • Solid Tumor • PD-L1

[VIRTUAL] First-in-human phase I study of NKTR-255 in patients with relapsed/refractory hematologic malignancies (SITC 2020) - P1 | "Background NKTR-255, an investigational IL-15Rα-dependent polymer-conjugated recombinant human IL-15 (rhIL-15) agonist, maintains the full spectrum of IL-15 biology and provides sustained pharmacodynamic (PD) responses without the need for daily dosing...In preclinical studies, NKTR-255 enhanced antibody-dependent cellular cytotoxicity(ADCC) of each of daratumumab, rituximab, trastuzumab and cetuximab, resulting in synergistic anticancer activity...This 63 y/o male had high-risk recurrent stage III MM with complex cytogenetics (relapsing after VRd, DRd, and carfilzomib plus dexamethasone)...NKTR-255 was well tolerated, with minimal treatment-related toxicities. Our preclinical and preliminary clinical data provide evidence of synergistic effects enhancing ADCC and support continued dose escalation of NKTR-255."

Clinical • P1 data • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • CD8 • IL2 • IL6 • NCAM1

Phase I Study of Recombinant Human IL-15 (rhIL-15) and Mogamulizumab for People With Refractory or Relapsed Adult T-Cell Leukemia and Mycosis Fungoides/Sezary Syndrome (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Sep 2023 ➔ May 2022

Trial completion • Trial completion date • Adult T-Cell Leukemia-Lymphoma • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Leukemia • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • Solid Tumor • T Cell Non-Hodgkin Lymphoma • IL15 • TNFRSF8

Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Dec 2022 ➔ Dec 2023

Checkpoint inhibition • Combination therapy • Trial completion date • Trial primary completion date • Oncology • Prostate Cancer • Solid Tumor • PD-L1

Phase I trial of recombinant human interleukin 15 (rhIL-15) in combination with nivolumab and ipilimumab in refractory cancers (AACR 2019) - P1; "Two had prior immunotherapy (pembrolizumab & brachyury vaccine). The doublet arms met safety endpoints, and the trial is currently enrolling pts for the triplet combination. In addition to the biomarker studies in blood, tumor biopsies will be collected at the MTD to assess the tumor immune microenvironment, including the proximity of T-cells to tumor cells, and the expression of intrinsic apoptosis biomarkers. Funded in part by NCI Contract HHSN261200800001E."

Combination therapy • IO biomarker • Late-breaking abstract • P1 data • PD(L)-1 Biomarker • Oncology • Thyroid Gland Carcinoma

Phase Ib/II study of ALT-803 in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer. (ASCO-GI 2017) - P1/2; "However, the use of rhIL-15 in the clinic however has been limited by its short half-life (30 minutes) and cytokine related adverse effects, such as fever and hypotension. Prior nab-paclitaxel is not allowed Current enrollment: Enrollment to the first dose level is ongoing. Complete accrual of phase Ib is expected within nine months."

Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

Phase I trial of recombinant human Interleukin 15 (rhIL-15) administered as continuous intravenous infusion (CIV) for 10 days (240 hours) in patients with refractory metastatic cancers. (AACR 2017) - "Immunohistochemical analyses of pre and on treatment tumor biopsies obtained from several other patients are currently being performed to better characterize the immunologic effects of this regimen. The results of this trial indicate CIVrhIL-15 treatment generates considerable in vivo immune activation and has important synergistic potential for combination therapy with other Immunotherapeutics."

Combination therapy • P1 data • Biosimilar • Gastrointestinal Cancer • Gene Therapies • Immunology • Oncology • Pain • Pancreatic Cancer • Reperfusion Injury • Sarcoma

Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Mar 2025 ➔ May 2022

Combination therapy • Trial completion • Trial completion date • Cutaneous T-cell Lymphoma • Dermatology • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • IL15 • IL5 • TNFRSF8

Avelumab (Bavencio) With IL-15 in Subjects With Clear-Cell Renal Carcinoma (clinicaltrials.gov) - P2 | N=2 | Terminated | Sponsor: National Cancer Institute (NCI) | Completed ➔ Terminated; This study was terminated early due to manufacturer withdrawal of support (study medication) due to lack of enrollment.

Trial termination • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CTLA4

Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies. (PubMed, Blood Adv) - P1 | "To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase I single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52+ mature T-cell malignances (NCT02689453). Immediately following 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, while the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK cell activation, as well as increased ex vivo ADCC activity of NK cells, while inhibitory receptors PD1 and Tim3 were decreased."

IO biomarker • Journal • Hematological Disorders • Neutropenia • Oncology • CD52 • CD8 • HAVCR2 • IL15 • NKG2D

Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: National Cancer Institute (NCI) | Completed ➔ Terminated; The study was closed after > 1 year of inactivity.

Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • IL15

Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Mar 2022 ➔ Mar 2021

Combination therapy • Trial primary completion date • Cutaneous T-cell Lymphoma • Dermatology • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • TNFRSF8

Interleukin-15 (IL-5) in Combination With Avelumab (Bavencio) in Relapsed/Refractory Mature T-cell Malignancies (clinicaltrials.gov) - P1; N=8; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Jun 2026 ➔ Mar 2025

Combination therapy • Trial completion date • Cutaneous T-cell Lymphoma • Dermatology • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma • TNFRSF8

Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia (clinicaltrials.gov) - P1; N=1; Completed; Sponsor: National Cancer Institute (NCI); Active, not recruiting ➔ Completed; Trial completion date: Dec 2023 ➔ Dec 2021; Trial primary completion date: Jun 2023 ➔ Dec 2021

Trial completion • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Human IL-15 (rhIL-15) and Obinutuzumab for Relapsed and Refractory Chronic Lymphocyte Leukemia (clinicaltrials.gov) - P1; N=1; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Suspended ➔ Active, not recruiting

Enrollment closed • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology

Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers (clinicaltrials.gov) - P1; N=50; Recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Sep 2022 ➔ Dec 2022; Trial primary completion date: Sep 2022 ➔ Dec 2022

Checkpoint inhibition • Clinical • Combination therapy • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • MRI • PD-L1

Phase I study of recombinant interleukin-15 in combination with checkpoint inhibitors nivolumab and ipilimumab in subjects with refractory cancers. (ASCO 2018) - P1; "Recombinant human IL-15 (rhIL-15), a nonglycosylated single-chain peptide, increased circulating CD8+T-cells, NK cells and inflammatory cytokines in clinical trials (Conlon et al, 2015. Currently, cohort A has enrolled 1 of 3 planned pts. Assessment of intrinsic apoptosis biomarkers, PD-L1 levels, T-cell phenotypic markers, markers of T-cell activation/inhibition (Zap70 pY493/pY580 SHP2), cell enumeration, proximity of tumor cells to T cells at the maximally tolerated dose using a validated/quantitative immunofluorescence assay, is planned."

Checkpoint inhibition • Clinical • Combination therapy • IO biomarker • P1 data • PD(L)-1 Biomarker • Solid Tumor