eftozanermin alfa (ABBV-621) / AbbVie, Apogenix - LARVOL DELTA

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Jan 2025 ➔ Jul 2025 | Trial primary completion date: Jan 2025 ➔ Jul 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Jul 2024 ➔ Jan 2025 | Trial primary completion date: Jul 2024 ➔ Jan 2025

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: AbbVie | Phase classification: P1b ➔ P1 | Trial completion date: Oct 2024 ➔ Jul 2024 | Trial primary completion date: Oct 2024 ➔ Jul 2024

Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study. (PubMed, Cancer Chemother Pharmacol) - P1 | "The study results, including a pharmacokinetic profile consistent with weekly dosing and low incidence of immunogenicity, support further investigation of eftozanermin alfa."

Journal • P1 data • PK/PD data • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

[VIRTUAL] The Combinatorial Activity of Eftozanermin (ABBV-621), a Novel and Potent TRAIL Receptor Agonist Fusion Protein, in Pre-Clinical Models of Hematologic Malignancies (ASH 2020) - P1 | "In DLBCL cell line-derived xenograft (CDX) preclinical models, we observed combination activity of ABBV-621 with pevonedistat (PEV) a selective NEDD8 inhibitor. Additionally, synergistic activity was observed with ABBV-621 with either bendamustine (BED) or rituximab (RTX) alone, or BED/RTX together...A clinical trial assessing the activity of ABBV-621 in combination with bortezomib and dexamethasone in R/R MM patients is planned...The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication."

Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Oncology • TNFA

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b | N=40 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Aug 2023 ➔ Oct 2024 | Trial primary completion date: Aug 2023 ➔ Oct 2024

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] The combinatorial activity of Eftozanermin ABBV621, a novel and potent TRAIL receptor agonist fusion protein, in pre-clinical models of hematologic malignancies (AACR 2021) - P1 | "In DLBCL cell line-derived xenograft (CDX) preclinical models, we observed combination activity of ABBV-621 with pevonedistat (PEV) a selective NEDD8 inhibitor. Additionally, synergistic activity was observed with ABBV-621 with either bendamustine (BED) or rituximab (RTX) alone, or BED/RTX together...The pre-clinical data presented here support expanding the indications and settings where ABBV-621 may have utility. A clinical trial assessing the activity of ABBV-621 in combination with bortezomib and dexamethasone in R/R MM patients is planned."

Preclinical • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • TNFA • TNFRSF10A • TNFRSF10B

Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621. (ASCO 2019) - P1; "ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209."

P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

Activity of eftozanermin alfa plus venetoclax in preclinical models and patients with acute myeloid leukemia. (PubMed, Blood) - P1 | "These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. Registered at www.clinicaltrials.gov as NCT03082209."

IO biomarker • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • FLT3 • TNFRSF10B • TP53

Therapeutic targeting of TRAIL death receptors. (PubMed, Biochem Soc Trans) - "In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field."

Journal • Oncology

[VIRTUAL] First-In-Human Study of a Trail Receptor Agonist Fusion Protein, Eftozanermin Alfa, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Diffuse Large B-Cell Lymphoma (SOHO 2020) - "Aims: Evaluate pharmacokinetic (PK) profile of Eftozanermin alfa (ABBV-621; eftoza) as monotherapy (eftoza-mono) or eftoza and venetoclax (eftoza-VEN); assess safety and tolerability, preliminary antitumor activity, and exploratory biomarkers. Eftoza-mono and eftoza-VEN were tolerated in patients with RR AML and DLBCL. Antitumor activity was observed in patients with AML treated with eftoza-VEN at 3.75- or 7.5-mg/kg doses. Abstract was previously published at EHA25."

Clinical • P1 data • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • IDH1

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b | N=40 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b | N=40 | Recruiting | Sponsor: AbbVie | Trial primary completion date: Jan 2023 ➔ Aug 2023

Combination therapy • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Study to Determine Recommended Phase 2 Dose of Intravenous (IV) Eftozanermin Alfa in Combination With IV or Subcutaneous (SC) Bortezomib and Oral Dexamethasone Tablet and to Assess Change in Disease Symptoms in Adult Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b | N=40 | Recruiting | Sponsor: AbbVie | Trial completion date: Jan 2023 ➔ Aug 2023

Combination therapy • Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Eftozanermin alfa (ABBV-621) monotherapy in patients with previously treated solid tumors: findings of a phase 1, first-in-human study. (PubMed, Invest New Drugs) - P1 | "The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017))."

Journal • Monotherapy • P1 data • Colorectal Cancer • Fatigue • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Respiratory Diseases • Solid Tumor

A Study of the Safety and Tolerability of ABBV-621 in Participants With Previously-Treated Solid Tumors and Hematologic Malignancies (clinicaltrials.gov) - P1 | N=153 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • KRAS

A Study of the Safety and Tolerability of ABBV-621 in Participants With Previously-Treated Solid Tumors and Hematologic Malignancies (clinicaltrials.gov) - P1; N=153; Active, not recruiting; Sponsor: AbbVie; Recruiting ➔ Active, not recruiting; Trial completion date: Aug 2022 ➔ Feb 2022; Trial primary completion date: Aug 2022 ➔ Feb 2022

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • KRAS

[VIRTUAL] Pharmacodynamic effects in blood and tumor tissue of eftozanermin alfa, a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist. (ASCO 2020) - P1 | "Background: Eftozanermin alfa (eftoza; formerly known as ABBV-621), a 2nd-generation tumor necrosis factor-related apoptosis-inducing ligand receptor agonist, is being evaluated in previously treated solid and hematologic malignancies (NCT03082209)... Pharmacodynamic effect of eftoza was successfully demonstrated in blood and tumor tissue, including induction of apoptosis and modulation of PI3K and MEK signaling pathways. Research Funding: AbbVie, Inc."

PK/PD data • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Pancreatic Cancer • Solid Tumor • KRAS • PARP • PARP1 • TNFA

[VIRTUAL] A Phase 1b, Open-Label Study of Eftozanermin Alfa in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (ASH 2020) - P1 | "Biomarker analyses may include evaluation of death receptor 4/5 expression, chromosomal abnormalities, and minimal residual disease status. Approximately 20 sites in 6 countries are planned to be involved in the study, which is anticipated to start in September 2020."

Clinical • Combination therapy • IO biomarker • P1 data • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Pain • Solid Tumor • CD38

First-in-Human Study of Abbv-621, a TRAIL Receptor Agonist Fusion Protein, in Patients (Pts) with Relapsed/Refractory (RR) Acute Myeloid Leukemia (AML) and Diffuse Large B-Cell Lymphoma (DLBCL) (ASH 2019) - P1; "Venetoclax (VEN), a highly selective small-molecule BCL2 inhibitor, has shown antitumor activity in combination therapy in AML and DLBCL. ABBV-621 was tolerated and showed antitumor activity in combination with VEN in pts with RR AML."

Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • TP53

[VIRTUAL] FIRST-IN-HUMAN STUDY OF A TRAIL RECEPTOR AGONIST FUSION PROTEIN, EFTOZANERMIN ALFA, IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA (EHA 2020) - P1 | "Background Eftozanermin alfa (ABBV-621; eftoza) is a next-generation tumor necrosis factor-related apoptosis‑inducing ligand (TRAIL) receptor agonist that targets death receptor 4 and 5 and induces apoptotic cell death. Venetoclax (VEN) is a potent, highly selective BCL-2 inhibitor approved for treatment of adults with chronic lymphocytic leukemia and newly diagnosed acute myeloid leukemia (AML)...Antitumor activity was observed in pts with AML treated with eftoza-VEN at 3.75- or 7.5-mg/kg doses. Updated data will be presented at the meeting."

Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • IDH1 • TNFA

First-in-human study of ABBV-621 in patients (pts) with previously treated sold tumours: Dose-optimization cohorts (ESMO 2019) - P1; "Administration of ABBV-621 in pts with R/R CRC and pancreatic cancer shows an acceptable safety profile at all DL and evidence of antitumor activity. Clinical trial identification: NCT03082209. Legal entity responsible for the study: AbbVie Inc."

Clinical • P1 data

Phase 1, first-in-human study of TRAIL receptor agonist fusion protein ABBV-621. (ASCO 2019) - P1; "ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209."

P1 data

Hexavalent TRAIL fusion protein eftozanermin alfa optimally clusters apoptosis-inducing TRAIL receptors to induce on-target antitumor activity in solid tumors. (PubMed, Cancer Res) - P1 | "To build upon the OR of ABBV-621 monotherapy in CRC (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a pre-clinical rationale for the ongoing Phase-1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in cancer patients."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • BCL2L1 • CASP8 • KRAS

[VIRTUAL] Ex Vivo Drug Sensitivity and Functional Genomics Platform Identifies Novel Combinations Targeting Intrinsic and Extrinsic Apoptotic Signaling Pathways in Multiple Myeloma (ASH 2020) - "Venetoclax (Ven) is a selective, small-molecule inhibitor of BCL-2 that exhibits clinical activity in MM cells, particularly in patients harboring the t(11;14) translocation. Navitoclax (Nav) is a small-molecule that targets multiple antiapoptotic BCL-2 family proteins, including BCL-XL, BCL-2, and BCL-W to initiate the intrinsic apoptotic pathway. Eftozanermin alfa (Eftoza) is a novel, second generation TRAIL receptor agonist that induces cell death via death receptor pathways and is under investigation in multiple solid and heme malignancies. In addition, the pan-BET inhibitor mivebresib (Miv) and the BDII selective BET inhibitor ABBV-744 have shown synergistic activity with Ven in cell line models of multiple heme malignancies. Results reported here describe ex vivo drug sensitivities and functional genomic analyses of Ven, Nav, Eftoza, Miv, and ABBV-744 alone or in combination with standard-of-care agents, including bortezomib, carfilzomib, panobinostat, daratumumab,..."

IO biomarker • Preclinical • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • BCL2 • BCL2L1 • BCL2L2 • MCL1