tolinapant (ASTX660) / Otsuka - LARVOL DELTA

Translational investigation of tolinapant (ASTX660) in Acute Myeloid Leukemia using integrated clinical, bioinformatic, and pharmacological approaches (ASH 2025) - P1 | "Inacute myeloid leukemia (AML), a study evaluating tolinapant as a single agent and in combination withcedazuridine (ASTX727) in patients with relapsed/refractory AML was prematurely terminated(NCT04155580)...Although tolinapant displayed limited single-agent activity, its combination with venetoclax yieldedsynergistic or additive cytotoxic effects in resistant models. These findings support further investigationof tolinapant-based combination therapies, particularly in biomarker-defined AML subsets. Supported byFAPESP, CAPES, and CNPq."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • T Cell Non-Hodgkin Lymphoma • ANXA5 • BIRC2 • BIRC3 • XIAP

Integrated multiomics identifies inhibitors of apoptosis (IAPs) and death-inducing signaling complex (DISC) components as novel vulnerabilities to overcome immune evasion in TP53-inactivated Acute Myeloid Leukemia (ASH 2025) - "Notably, AML patients with TP53 mutations have limited benefit from standard inductionchemotherapy or from recently approved venetoclax-based combination regimens...We found that IAPinhibitors birinapant and tolinapant, as well as IAP PROTAC-degrader CST-626, potently sensitized TP53-inactivated AML to CAR-T/TCR-T and NK-92-mediated cytotoxicity...Pharmacological inhibition of thecaspase 8-cFLIP heterodimer with emricasan alone, or combined with IAP antagonists, effectivelyovercomes this checkpoint and sensitizes AML cells to immune cytotoxicity. These findings establish astrong preclinical rationale for combining cell death–promoting agents with T or NK cell–basedimmunotherapies to overcome immune resistance in TP53-mutated high-risk AML subset."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • BIRC2 • BIRC3 • CASP8 • FADD • TP53 • XIAP

ASTX660-01 Phase 2: A Case Study of Tolinapant-Induced Pseudoprogression in CTCL (ASH 2023) - P1/2 | "Our data offer a cellular and molecular insight into a case of clinical pseudoprogression observed during tolinapant treatment. Understanding pseudoprogression is important for clinical investigators and patients to ensure treatment with tolinapant, or other IAP antagonists, are not discontinued prematurely."

Case study • Clinical • P2 data • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Skin Cancer • T Cell Non-Hodgkin Lymphoma • CD4 • CD7 • CD8 • CXCL1 • CXCL10 • CXCR3 • DPP4 • GZMA • GZMH • PRF1 • XIAP

Epigenetic Priming By Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-Cell Lymphoma (ASH 2023) - P1/2 | "We demonstrate that tolinapant acts as an immune modulator via promoting ICD, and this can be enhanced by epigenetic reprogramming with decitabine. These findings provide a rationale to support the on-going combination study of tolinapant with ASTX727 (oral decitabine and cedazuridine) that recently started in PTCL (ASCERTAIN-P, NCT05403450). It has also identified putative biomarkers of immunomodulatory activity that could be utilized in clinic."

Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CASP8 • CXCL10 • HMGB1

Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: National Cancer Institute (NCI) | N=42 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: National Cancer Institute (NCI) | N=127 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Carcinosarcoma • Epithelial Ovarian Cancer • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor

Early-phase trial of IAP antagonist tolinapant and definitive radiation in cisplatin-ineligible patients with advanced head and neck cancer. (PubMed, Clin Cancer Res) - "Tolinapant + RT is well tolerated and induced proliferation of activated T cells in a subset of patients. Larger prospective studies are needed to better assess efficacy."

Journal • Dermatitis • Dermatology • Fatigue • Gastrointestinal Disorder • Head and Neck Cancer • Immunology • Oncology • Pain • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Xerostomia • CD8

Early-phase trial of IAP antagonist tolinapant and definitive radiation in cisplatin-ineligible patients with previously untreated, locally advanced head and neck cancer (AACR 2025) - P1 | "Tolinapant + RT is safe and feasible in cisplatin-ineligible HNSCC patients. In the absence of platinum chemotherapy, the combination of IAP-antagonizing drugs with RT may induce proliferation and circulation of activated T cells. The study was supported by a grant from Astex Pharmaceuticals/Taiho Oncology to NCS and NFS."

Clinical • Metastases • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8

Tolinapant and Radiation for Cisplatin-Ineligible, Previously Untreated, Locally Advanced Head and Neck Cancer (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Emory University | Recruiting ➔ Active, not recruiting

Enrollment closed • Head and Neck Cancer • Hypopharyngeal Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

ASTX660-03: A Study of Tolinapant in Combination With Oral Decitabine/Cedazuridine and Oral Decitabine/Cedazuridine Alone in Participants With Relapsed/Refractory Peripheral T-cell Lymphoma (R/R PTCL) (clinicaltrials.gov) - P1/2 | N=33 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | N=132 ➔ 33 | Trial primary completion date: Dec 2025 ➔ Dec 2024

Enrollment change • Trial primary completion date • Follicular Lymphoma • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RIPK1

The IAP antagonist tolinapant enhances the anti-tumor activity of cell therapies. (PubMed, Eur J Pharmacol) - "Our study suggests that the combination of tolinapant improves the efficacy of cell-based cancer therapies by inducing both cancer cell death and CAR-T cell proliferation. This combination therapy may overcome the current limitations of cell-based therapies and enhance their anti-cancer effect."

Journal • Oncology • TNFA

Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Suspended | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Suspended

Trial suspension • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RIPK1

A Phase I/II Study of ASTX660 in Patients With Relapsed or Refractory T-cell Lymphoma (clinicaltrials.gov) - P1/2 | N=61 | Terminated | Sponsor: Otsuka Pharmaceutical Co., Ltd. | Trial completion date: Sep 2024 ➔ Nov 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Sep 2024 ➔ Nov 2024; The study was terminated early due to Sponsor decision, the decision to terminate was not based on any safety concerns.

Trial completion date • Trial primary completion date • Trial termination • Adult T-Cell Leukemia-Lymphoma • Cutaneous T-cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

ASTX660-01: Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas (clinicaltrials.gov) - P1/2 | N=230 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Trial completion date: Oct 2024 ➔ Dec 2025

Metastases • Trial completion date • Follicular Lymphoma • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Oncology • Peripheral T-cell Lymphoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=127 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Nov 2024 ➔ May 2025

Trial initiation date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor

Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=42 | Recruiting | Sponsor: National Cancer Institute (NCI) | Not yet recruiting ➔ Recruiting | Initiation date: Nov 2024 ➔ Aug 2025

Combination therapy • Enrollment open • Metastases • Trial initiation date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RIPK1

The preclinical pharmacokinetics of Tolinapant-A dual cIAP1/XIAP antagonist with in vivo efficacy. (PubMed, Pharmacol Res Perspect) - "Pharmacodynamic modulation and efficacy were demonstrated in A375 mouse xenograft models at dose ranges between 5 and 20 mg/kg. On-target engagement, as measured by reduction of cIAP 1 protein levels, was confirmed in NHP surrogate tissues and applied to target activity assessments in tolinapant phase1/2 clinical trials."

Journal • PK/PD data • Preclinical • XIAP

Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P1 | N=33 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

Combination therapy • Metastases • New P1 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • RIPK1

Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=127 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Jun 2024 ➔ Nov 2024

Trial initiation date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor

Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres. (PubMed, BMC Cancer) - "If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome."

Clinical protocol • Combination therapy • Journal • P1 data • P1 data • Cervical Cancer • Oncology • Solid Tumor

ASTX660-01 PHASE 2: A CASE STUDY OF TOLINAPANT-INDUCED PSEUDOPROGRESSION IN CTCL (EHA 2024) - No abstract available

Case study • Clinical • P2 data • Cutaneous T-cell Lymphoma

Epigenetic priming by hypomethylation enhances the immunogenic potential of tolinapant in T-cell lymphoma. (PubMed, Cancer Res Commun) - "We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in interferon signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation."

Journal • Hematological Malignancies • Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=127 | Not yet recruiting | Sponsor: National Cancer Institute (NCI)

New P1/2 trial • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Sarcoma • Solid Tumor

Proof-of-concept and preliminary efficacy of triple IAP blockade to maximize immunogenic cell death and induce efficient adaptive immune response: First report on the ASTEROID phase 1 trial (AACR 2024) - "ASTX660-pembrolizumab is is well-tolerated with durable antitumor responses in pts with immunologically cold tumors, providing the first clinical proof-of-concept of immunogenic cell death induction leading to effective adaptive immune response when combined with ICI. Recommended Phase 2 dose optimization and expansion cohorts in immunologically cold cancers are ongoing."

Clinical • Immunogenic cell death • P1 data • Biliary Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor • B3GAT1 • CD8 • ER • HER-2 • XIAP