avadomide (CC-122) / BMS - LARVOL DELTA

Subtype-Specific Mechanisms of Treatment Resistance and Relapse in Diffuse Large B Cell Lymphoma (DLBCL) (ASH 2024) - "Methods : Tumor biopsies (N=228) collected at the time of relapse were obtained from n=85 participants in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource (MER), n=73 in the Mayo Clinic Biobank, and n=38 from CC-122-DLBCL-001 or n=32 CC-122-ST-001 trials...For example, rrDLBCL patients may be strong candidates for MYC pathway targeting agents (BETi), or a Lenalidomide-based regimen (R2 or Tafa-Len), as Lenalidomide has been shown to reprogram the LME via PD-L1 expression in addition to downregulation of MYC and MYC target genes. Or, due to enrichment of variants affecting anti-apoptotic proteins including BCL6 or BCL2 in DZsig and GCB rrDLBCL, a venetoclax-based therapeutic may be considered. Further targeted strategies should be considered as development of a more personalized approach remains an unmet need."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • B2M • BCL2 • BCL6 • CD79B • CD8 • CD83 • EP300 • LRP1B • MYBPC2 • MYC • PD-L1 • PRKCB • TCF4 • TP53

Cell-Intrinsic and Immune-Mediated Effects in Lymphoma Patients Treated with Golcadomide and Associations with Treatment Outcome (ASH 2024) - "Introduction : Compounds inducing cereblon-mediated degradation of Ikaros and Aiolos (I/A), like lenalidomide (LEN) and avadomide, have demonstrated antitumor activity in non-Hodgkin lymphoma (NHL), with significant but limited cell-autonomous activity in diffuse large B-cell lymphoma (DLBCL) cell lines...In the CC-99282-NHL-001 study, GOLCA ± rituximab showed a manageable, predictable safety profile characterized by an on-target toxicity of neutropenia and promising efficacy in relapsed/refractory NHL in heavily pretreated pts (Chavez JC et al Blood 2023)...BL immune profiles and their modulation on treatment link to treatment effect and imply an immune contribution to GOLCA efficacy. These data support broader activity of GOLCA than IMiDs in NHL, with high potential for combination with anti-lymphoma agents acting on tumor B cells and/or TME."

Clinical • IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CD4 • CD8 • CRBN • IFNA1 • IKZF1 • PD-1 • TNFA

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease. (PubMed, PLoS One) - "These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens...Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics for sickle cell disease and other β-hemoglobinopathies."

Journal • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34 • HBG1 • IKZF1 • ZBTB7A

A Study of CC-122 to Assess the Safety and Tolerability in Japanese Patients With Advanced Solid Tumors and Non-Hodgkin's Lymphoma (NHL) (clinicaltrials.gov) - P1 | N=15 | Terminated | Sponsor: Celgene | Completed ➔ Terminated; Replaced it with another clinical trial.

Trial termination • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Advancing Multiple Myeloma Treatment: A Systematic Review and Meta-Analysis of Cereblon E3 Ligase Modulatory Drugs (CELMoDs) Impact on Patient Outcomes (SOHO 2024) - "CELMoDs used were mezigdomide (176/350), iberdomide (172/350), and avadomide (2/350)... This study indicates favorable outcomes with CELMoDs in the treatment of MM; however, treatment-related adverse effects remain a major limitation. Further clinical trials are essential to determine the effectiveness and safety of this promising class of drugs for managing MM."

Retrospective data • Review • Hematological Malignancies • Multiple Myeloma • Oncology • CRBN

The ability of immunomodulatory imide drugs (IMiDs) to inhibit the polarization of T helper cells towards Th2 phenotype depends on cereblon (IMMUNOLOGY 2024) - "Thalidomide, Lenalidomide, Pomalidomide, as well as the second generation Iberdomide and Avadomide are current IMiDs used in the clinic...While it had not substantial effect on Th cell polarization, pre-treatment of Th cells with 14a rescued the degradation of neosubstrates and cytokine response stimulated by Iberdomide, with the exception of IL-9 levels, indicating a CRBN-independent effect. Pertaining to the significance of these IMiD drugs that are currently used for cancer and proposed for treating autoimmune diseases, this study shows that these small molecules can program T helper cells independent of influence from other immune cells."

Immunomodulating • Immunology • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • IKZF3 • IL17RB • IL9

The Atlas of Blood Cancer Genomes: A resource for therapeutic and biomarker development (AACR 2024) - "Thus, we can interrogate immune and other signatures across the spectrum of cancers to uncover potential biomarkers of response.The ABCG project will enable the comprehensive study of genomic and clinicopathological features of all blood cancers. We anticipate that our data, approaches and results will provide a lasting resource for molecular classification and therapeutic development in all leukemias and lymphomas."

Biomarker • IO biomarker • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ABL1 • BCR • BRAF • CD22 • CRBN • IDH2

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1 | N=174 | Terminated | Sponsor: Celgene | Active, not recruiting ➔ Terminated; Replaced with another clinical trial.

Trial termination • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

A Rollover Study of CC-122 (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

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

Molecular Classification of Relapsed DLBCL Reveals Novel Biologic Subgroups (ASH 2023) - P1 | "Methods Data used in this study included RNA (n=143) and whole exome (n=126) sequencing data from available FFPE tumor samples at the time of a relapse (any line of treatment, r1-r10 relapse timepoints included in analysis, one per patient), consented to the Molecular Epidemiology Resource (n=61), banked in the Mayo Lymphoma Biobank (n=50), or consented to the CC-122-ST-001 clinical trial (n=32, NCT01421524). In summary, we show for the first time that rrDLBCL patients can be classified into four gene expression clusters that are associated with distinct pathway, TME, and genetic programs. These clusters should now be tested to learn if they can help select patients for newer therapies for rrDLBCL such as CAR-T and bispecific antibodies."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • BCL7A • CD4 • CD8

Study of CC-122 to Evaluate the Safety, Tolerability, and Effectiveness for Patients With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple Myeloma (clinicaltrials.gov) - P1 | N=271 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed | Phase classification: P1a/1b ➔ P1

Phase classification • Trial completion • Brain Cancer • CNS Lymphoma • CNS Tumor • Diffuse Large B Cell Lymphoma • Glioblastoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1 | N=174 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1b ➔ P1 | Trial completion date: Oct 2023 ➔ Jan 2024 | Trial primary completion date: Oct 2023 ➔ Jan 2024

Phase classification • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

Effect of Mild or Moderate Hepatic Impairment on the Pharmacokinetics of Ozanimod (ACG 2023) - P1 | "A prior phase 1 study of single-dose OZA 0.23 mg showed a 31%–33% reduction of CC112273, the major active metabolite (MET) of OZA, in participants (ptps) with mild or moderate (MOD) hepatic impairment (HI) vs healthy ptps. All dosed ptps (N=26) completed the study: 8 in each HI group and 10 with normal HF (6 matched to both mild and MOD HI ptps). Of the 16 HI ptps, 13 had documented hepatic cirrhosis. There were no clinically meaningful differences in total and unbound PK parameters for OZA and its major METs between healthy and HI ptps on D1, D5, or D8 ( Table )."

PK/PD data • CNS Disorders • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Liver Cirrhosis • Multiple Sclerosis • Ulcerative Colitis

A Phase 1b Open-label Study to Evaluate the Safety and Efficacy of CC-122 With Obinutuzumab (GA101) in Relapsed/Refractory DLBCL and iNHL. (clinicaltrials.gov) - P1b | N=75 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CD20 • MYC

Effect of Mild or Moderate Hepatic Impairment on the Pharmacokinetics of Ozanimod (MSMilan 2023) - "A prior phase 1 study of single-dose OZA 0.23 mg showed a 31%–33% reduction of CC112273, the major OZA active metabolite (MET), in participants (PTs) with mild or moderate (MOD) hepatic impairment (HI) vs healthy PTs. There was no clinically meaningful difference in exposure of OZA or its METs between HI and healthy PTs over the dose titration period. The systemic exposure (AUC0-last,u) of the major METs was doubled in HI PTs after accounting for protein binding. Multiple oral doses of OZA were safe and generally well tolerated."

PK/PD data • CNS Disorders • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Liver Cirrhosis • Multiple Sclerosis • Ulcerative Colitis

EFFECT OF MILD OR MODERATE HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF OZANIMOD (UEGW 2023) - P1 | "A previous phase 1 study of single dose OZA 0.23 mg showed a 31%–33% reduction of CC112273, the predominant active metabolite (MET) of OZA, in mild or moderate hepatic impaired participants (ppts) vs healthy ppts. Due to the lack of OZA PK differences between hepatic-impaired and healthy ppts during dose titration and the 2-fold increase of AUC0-last of both METs in hepatic-impaired ppts, a dose adjustment of OZA 0.92 mg once every other day is recommended in patients with mild or moderate hepatic impairment after completing the standard 1-week dose titration."

PK/PD data • CNS Disorders • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Liver Cirrhosis • Multiple Sclerosis • Ulcerative Colitis

A Study of CC-122 to Assess the Safety and Tolerability in Japanese Patients With Advanced Solid Tumors and Non-Hodgkin's Lymphoma (NHL) (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed

Metastases • Trial completion • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

A Phase 1b Open-label Study to Evaluate the Safety and Efficacy of CC-122 With Obinutuzumab (GA101) in Relapsed/Refractory DLBCL and iNHL. (clinicaltrials.gov) - P1b | N=75 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Feb 2023 ➔ Aug 2023 | Trial primary completion date: Feb 2023 ➔ Aug 2023

Combination therapy • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BCL2 • CD20 • MYC

Novel agents in relapsed/refractory diffuse large B-cell lymphoma (ICML 2023) - "In recent years, numerous agents have been approved specifically for patients with DLBCL (RED) including tafasitamab, loncastuximab tesirine, polatuzumab vedotin, selinexor, rituximab, and pembrolizumab (for patients with Primary Mediastinal B-cell lymphoma)...Significant grade 3-4 toxicities were neutropenia and thrombocytopenia with 48.6% of patients requiring dose modifications, and 22.9% discontinuing treatment for toxicity.12 Ongoing and planned trials with loncastuximab include a phase III trial with rituximab, gemcitabine, and oxaliplatin (R-GemOx) (Tables 1 and 3)...Encouraging clinical activity, without unanticipated toxicities was observed when polatuzumab was combined with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) with an ORR of 89% (CR 61%).24 Combination of polatuzumab with lenalidomide and rituximab (R2) in 49 patients demonstrated an ORR of 35% (CR 29%), with median DOR, PFS, and OS of 8.1, 6.3, and 10.9 months, respectively...One notable..."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CARD11 • CD79B • CDKN1A • CRBN • CTLA4 • EZH2 • IKZF1 • IRAK4 • LYN • MALT1 • MCT1 • MYC • MYD88 • NF-κβ • PD-L1 • ROR1 • SIRPA • SYK • XPO1

Anti-tumor effect of avadomide in gemcitabine-resistant pancreatic ductal adenocarcinoma. (PubMed, Cancer Chemother Pharmacol) - "Our findings suggest that avadomide could be a novel therapeutic option to overcome gemcitabine resistance in patients with PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA5

Study of CC-122 to Evaluate the Safety, Tolerability, and Effectiveness for Patients With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple Myeloma (clinicaltrials.gov) - P1a/1b | N=271 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Apr 2023 ➔ Jul 2023 | Trial primary completion date: Apr 2023 ➔ Jul 2023

Metastases • Trial completion date • Trial primary completion date • Brain Cancer • CNS Lymphoma • CNS Tumor • Diffuse Large B Cell Lymphoma • Glioblastoma • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1b | N=174 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Apr 2023 ➔ Jul 2023 | Trial primary completion date: Apr 2023 ➔ Jul 2023

Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CD20

A Rollover Study of CC-122 (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Treatment of triple-class refractory disease: beyond immunotherapy (EMN 2023) - "Selinexor in combination with dexamethasone has emerged as an important therapeutic approach for heavily pretreated TCR patients with safe and manageable toxicity. Melflufen in combination with dexamethasone was granted accelerated approval by FDA in February 2021 for RRMM in patients who have previously failed at least four lines of therapy...This group includes iberdomide (CC-220), which binds to cereblon with an affinity that is twenty times higher than that of either lenalidomide or pomalidomide, leading to more efficient degradation of Ikaros and Aiolos...Avadomide (CC122) is another glutarimide-based cereblon modulator that has broader activity than lenalidomide, possibly due to deeper and faster kinetics of Aiolos degradation. Mezigdomide (CC-92480), another promising drug, showed significant antimyeloma activity in cell lines, including those resistant to pomalidomide and lenalidomide. In addition, venetoclax has demonstrated significant activity in t(11;14) MM..."

Hematological Malignancies • Immune Modulation • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • XPO1

PLATFORM: A Safety and Efficacy Trial of JCAR017 Combinations in Subjects With Relapsed/Refractory B-cell Malignancies (clinicaltrials.gov) - P1/2 | N=62 | Completed | Sponsor: Celgene | Active, not recruiting ➔ Completed

Trial completion • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6