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A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma

ABSTRACT: The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

DISEASE(S): Dlbcl, Diffused Large B Cell Lymphoma,Malignant Solid Tumor,Urothelial Cancer,Triple Negative Breast Neoplasms,Melanoma,Advanced Solid Tumor (nsclc, Rcc, Pancreatic Cancer, Urothelial Cancer, Head And Neck Squamous Cell Carcinoma, Microsatellite Stable Colorectal Cancer, Triple Negative Breast Cancer, Cutaneous Melanoma) And Diffuse Large B-cell Lymphoma (dlbcl),Tnbc, Triple Negative Breast Cancer,Nsclc, Non Small Cell Lung Cancer,Pancreatic Cancer,Diffuse Large B-cell Lymphoma,Rcc, Renal Cell Cancer,Lymphoma,Mcrpc, Metastatic Castration Resistant Prostate Cancer,Mss, Microsatellite Stable Colon Cancer,Advanced Solid Tumors And Non-hodgkin Lymphoma,Nsclc,Carcinoma, Renal Cell,Lymphoma, Non-hodgkin,Head And Neck Cancer,Solid Tumors

PROVIDER: 2248580 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas. It is characterized by the presence of rare Hodgkin and Reed/Sternberg (HRS) cells embedded in an extensive inflammatory infiltrate. Constitutive activation of nuclear factor-kappaB (NF-kappaB) in HRS cells which transcriptionally regulates expression of multiple anti-apoptotic factors and pro-inflammatory cytokines plays a central role in the pathogenesis of cHL (1, 2). In non-stimulated condition, NF-kappaB proteins are rendered inactive by binding to their inhibitors (IkappaB s), which sequester them in the cytoplasm. Stimulation of multiple receptors activates the IkappaB kinase (IKK) complex that phosphorylates IkappaB at two specific serine residues, followed by its ubiquitination and proteasomal degradation, thereby releasing NF-kappaB proteins and allowing their nuclear translocation (3). Recently, two studies provided further insights into the molecular mechanisms of IKK activation upon TNF stimulation (4, 5). Activation of the IKK complex and subsequent NF-kappaB activation requires Lys63 polyubiquitination of RIP1, a kinase which is recruited to the receptor upon TNF stimulation. IKK-ï§ï (NEMO), the regulatory subunit of the IKK complex, specifically recognizes these Lys63-linked polyubiquitins attached to RIP1 and thereby activates IKK and NF-kappaB (4, 5). A20 is an ubiquitin-modifying enzyme that inhibits NF-kappaB activation in succession of tumor necrosis factor (TNF) receptor and Toll-like receptor induced signals (6-8). This enzyme removes Lys63 linked ubiquitin chains from RIP1 and adds Lys48 polyubiquitins to RIP1, thereby targeting this factor for proteasomal degradation, thus explaining the molecular mechanism of NF-kappaB inhibition by A20 (6). A20 likely inhibits NF-kappaB acitivity also by additional means, including interaction with TRAF1 and TRAF2 (9). SNP 6.0 array (Affymetrix) analyses were performed according to the manufacturer's directions on DNA extracted from three Hodgkin cell lines (L1236, HDLM-2, U-HO1), HapMap samples included in the Genotyping Console Software 3.0 were used as references.

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A Phase 2 Study of NIR178 in Combination With PDR001 in Patients With Solid Tumors and Non-Hodgkin Lymphoma

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