mirzotamab clezutoclax (ABBV-155) / AbbVie - LARVOL DELTA

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=169 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Dec 2024 ➔ Jun 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=169 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Mar 2024 ➔ Dec 2024

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=169 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Nov 2023 ➔ Mar 2024 | Trial primary completion date: Nov 2023 ➔ Mar 2024

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=169 | Active, not recruiting | Sponsor: AbbVie | Trial completion date: Apr 2023 ➔ Nov 2023 | Trial primary completion date: Apr 2023 ➔ Nov 2023

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=168 | Active, not recruiting | Sponsor: AbbVie | Recruiting ➔ Active, not recruiting

Enrollment closed • First-in-human • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=176 | Recruiting | Sponsor: AbbVie | Trial completion date: Sep 2022 ➔ Apr 2023 | Trial primary completion date: Sep 2022 ➔ Apr 2023

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=176 | Recruiting | Sponsor: AbbVie | Trial primary completion date: Dec 2021 ➔ Sep 2022

First-in-human • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=176 | Recruiting | Sponsor: AbbVie | Trial completion date: Dec 2021 ➔ Sep 2022

First-in-human • Trial completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=125 | Not yet recruiting | Sponsor: AbbVie

First-in-human • New P1 trial • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=125 | Recruiting | Sponsor: AbbVie | Not yet recruiting ➔ Recruiting

Enrollment open • First-in-human • Breast Cancer • HER2 Breast Cancer • Non Small Cell Lung Cancer • Small Cell Lung Cancer • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=125 | Suspended | Sponsor: AbbVie | Recruiting ➔ Suspended

First-in-human • Trial suspension • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=125 | Recruiting | Sponsor: AbbVie | Suspended ➔ Recruiting | Trial completion date: Sep 2020 ➔ Apr 2021 | Trial primary completion date: Sep 2020 ➔ Apr 2021

Enrollment open • First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=152 | Recruiting | Sponsor: AbbVie | Trial completion date: Apr 2021 ➔ Dec 2021 | Trial primary completion date: Apr 2021 ➔ Dec 2021

First-in-human • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • ALK • BRAF • EGFR • HER-2 • ROS1

A Study With ABBV-155 Alone and in Combination With Taxane Therapy in Adults With Relapsed and/or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=168 | Completed | Sponsor: AbbVie | Active, not recruiting ➔ Completed | Trial completion date: Jun 2025 ➔ Sep 2025 | Trial primary completion date: Jun 2025 ➔ Sep 2025

First-in-human • Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

Anti-Leukemia Combinatorial Efficacy of ABBV155, a B7H3-BCL-XL Inhibitor Antibody-Drug Conjugate, in Combination with Venetoclax through BCL-XL/BIM and BCL-2/BIM Complex Dissociations (ASH 2024) - "The combination targeted engagement of BCL-XL with B7H3-ADC and of BCL-2 with VEN significantly inhibits leukemia burden and prolongs survival in AML PDX models through synergistic release of BH3-only proteins. These findings suggest a promising therapeutic strategy for AML, particularly in cases resistant to venetoclax-based treatments."

Clinical • Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CD276 • DNMT3A • FLT3 • IDH1 • MCL1 • NPM1 • PTPRC

Evaluation of the efficacy of novel ADCs as potential therapy options for colorectal cancer using a patient derived organoid model (DGHO 2025) - "This study investigates novel ADCs targeting B7-H3 (mirzotamab clezutoclax, ABBV-155) and EGFR (ABBV-637) linked to a Bcl-xL inhibitor as payload as therapeutic strategies for colorectal cancer using a PDO system. Four selected PDOs from CRC patients were maintained in long-term culture...Additionally, an internalization assay utilizing a pH-sensitive fluorescent dye (pHAb) was performed to assess drug uptake and intracellular localization of the ADCs. Untargeted inhibition of Bcl-xL with small molecule inhibitor A-1331852 caused significant cell viability loss (max reduction: 97% at 10 µM) and organoid structural disintegration, with efficacy correlating with baseline protein expression (r = 0.92)...Combinatorial targeting (ABBV-155 + Mcl-1 inhibitor ABBV-467) synergistically enhanced cell death (viability reduction: 62.6% vs. 0% monotherapy). These data provide critical insights into the use of novel ADCs as therapeutic options for CRC patients and suggest that..."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • BCL2L1 • EGFR

Study of ABBV-637 or ABBV-155 With ERAS-801 for People With Glioblastoma (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center

New P1 trial • Brain Cancer • CNS Tumor • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma. (PubMed, Nat Commun) - "Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • TP53

Targeting BCL-XL with Mirzotamab Cletuzoclax (ABBV-155) and standard of care therapies overcomes apoptotic resistance in glioblastoma (SNO 2024) - "Conventional GBM therapies (e.g., temozolomide (TMZ), irradiation (IR)) transiently halt tumor growth of glioblastoma (GBM) but fail to induce apoptosis, inevitably leading to disease progression and poor patient survival. Moreover, these combinations decrease tumor burden and extend survival in patient derived orthotopic xenografts. Taken together, these results demonstrate that the combination of DNA damaging therapy and ABBV-155 can have a synergistic anti-tumor impact in p53 WT GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • BCL2L1 • CD276

BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors. (PubMed, Sci Adv) - "While an unprecedented BCL-XL-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-XL-targeting agent to enter human clinical trials."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • BCL2L1 • EGFR

Targeted delivery of BCL-Xl selective inhibitors alleviates on-target toxicity of systemically dosed inhibitors in preclinical models (ACS-Sp 2024) - "To overcome this liability, antibody-drug conjugates were developed using novel BCL-X L inhibitors, unique linker technologies and targeting antibodies. Although a novel BCL-X L -mediated toxicity was uncovered in monkey kidneys upon repeat dosing of ADC, this toxicity was mitigated by modification of a drug-linker that has been incorporated into mirzotamab clezutoclax, the first BCL-X L selective agent to enter human clinical trials."

Preclinical • Cardiovascular • Oncology • BCL2L1

Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose expansion results. (ASCO 2023) - P1 | " In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post–CDK4/6 inhibitor breast cancer (BrCa) with Mirzo-C + paclitaxel. Mirzo-C demonstrated a tolerable safety profile as monotherapy and with taxanes. No thrombocytopenia or neutropenia was observed with monotherapy. No single-agent activity of Mirzo-C was observed in SCLC."

Combination therapy • Monotherapy • Breast Cancer • Fatigue • Febrile Neutropenia • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Neutropenia • Non Small Cell Lung Cancer • Oncology • Pain • Small Cell Lung Cancer • Solid Tumor • Thrombocytopenia • BCL2L1 • CD276 • HER-2

Phase 1 Study of ABBV-155 ± Paclitaxel in Relapsed/Refractory Solid Tumors: Results in Japanese Patients (JSMO 2023) - No abstract available

Clinical • P1 data • Oncology • Solid Tumor

[VIRTUAL] New Targetable Pathways in Chronic Lymphocytic Leukemia (CLL) (SOHO 2021) - P1/2 | "AZD5991 is a highly selective BH3-mimetic that demonstrates high in vitro potency in MCL1-dependent cell lines with an IC50 <1 nM.7 We have demonstrated that direct MCL1 inhibition with AZD5991 disrupts survival of neoplastic B-cells in lymph-node mimicking conditions, induces mitochondrial dysfunction and cooperates with BCL2/X inhibitors in vitro and in vivo.8 A phase 1 clinical trial of AZD5991 alone or in combination with venetoclax in hematologic malignancies is ongoing (NCT03218683)...AMG-176 demonstrated synergy with venetoclax in AML models; however, it also caused cytopenias.9 AMG-176 was shown to induce apoptosis of CLL cells independent of prognostic markers and overcame the protective effect of stromal microenvironment.10 However, suppressive effects on hematopoiesis will likely become the dose- limiting factor in clinical trials of MCL1-targeting agents. The effect of MCL1 inhibition on cord blood-derived CD34+ cells was studied using a..."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • CD19 • CD34 • CDK7 • ROR1 • SYK

ED016. Novel Antibody Drug Conjugates (AACR 2022) - "The second talk will discuss BCL-XL inhibitors as warheads for ADCs, including the development of ABBV-155, a BCL-XL inhibitor linked to an anti-B7H3 targeting antibody. The final speaker will address the challenges and opportunities with selecting patients for ADC therapeutics, including how such approaches may differ when ADCs with non-chemotherapy payloads are administered."

Oncology • Solid Tumor • BCL2L1 • CD276