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

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

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

Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor 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

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

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

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

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

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

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

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

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

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ALK • BRAF • EGFR • HER-2 • ROS1

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

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

Combination therapy • Enrollment closed • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • HER-2

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

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

Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • HER-2

[VIRTUAL] Looking at BCL-XL Inhibitor Antibody Drug Conjugates: A Novel Approach to Increase the Therapeutic Index of ADCs (ADC-USA 2021) - "Reviewing the narrow therapeutic index of cytotoxic-based ADCs placing limits on their clinical utility Describing the preclinical development and characterization of BCL-XL inhibitor ADCs and how they expand TI Evaluating preclinical characterization and status of the lead program mirzotamab clezutoclax (ABBV-155)"

BCL2L1

[VIRTUAL] A First-in-human Study of Mirzotamab Clezutoclax as Monotherapy & in Combination with Taxane Therapy in Relapsed/Refractory Solid Tumors (ADC-USA 2021) - "Mirzotamab clezutoclax is a first-in-class antibody-drug conjugate targeting the intrinsic apoptosis pathway Reviewing how Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile; monotherapy MTD not reached Presenting on the anti-tumor activity seen with objective responses (by RECIST 1.1) in combination with taxane"

Combination therapy • Monotherapy • P1 data • Oncology • Solid Tumor

[VIRTUAL] A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results. (ASCO 2021) - P1 | "Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors . Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing."

Combination therapy • Monotherapy • P1 data • Anemia • Breast Cancer • Cardiovascular • Fatigue • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Musculoskeletal Pain • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Small Cell Lung Cancer • Solid Tumor • BCL2L1 • CD276

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

Clinical • Combination therapy • Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • HER-2

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

Clinical • Combination therapy • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • CD276 • HER-2

AbbVie to Showcase Breadth of Oncology Portfolio and Pipeline at the 2021 ASCO and EHA Annual Congresses (PRNewswire) - “AbbVie…will present results from 43 abstracts across 12 types of cancer during the upcoming virtual American Society of Clinical Oncology (ASCO) Annual Meeting (June 4-8) and the virtual European Hematology Association (EHA) congress (June 9-17)….Presentations include nine oral presentations (two at ASCO and seven at EHA) and 32 poster presentations (13 at ASCO and 19 at EHA).”

Clinical data • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor

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

Clinical • Combination therapy • Trial suspension • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • CD276 • HER-2

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

Clinical • Combination therapy • Enrollment open • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Small Cell Lung Cancer • CD276 • HER-2

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

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • CD276 • HER-2