tolinapant (ASTX660) / Otsuka, Taiho - LARVOL DELTA

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

CRAIN: A Phase Ib Tite-CRM Dose Escalation Study of Tolinapant with Chemoradiotherapy for Locally Advanced Cervical Cancer Including Clinical and Translational Endpoints (ASTRO 2026) - "Reduced in vivo clonogenic survival following Tolinapant, cisplatin and radiation versus radiation alone is seen with no impact on acute gastro-intestinal (GI) toxicity in the crypt assay. Tolinapant remains a potential candidate in combination with CRT for cervical cancer and based on CRAIN the recommended dose for phase 2 studies is 90mg daily. Translational sample analysis is feasible, but with small numbers, conclusions are limited. Urine was a better source of cfDNA than plasma and may have a role in screening and follow up."

Clinical • IO biomarker • Late-breaking abstract • Metastases • P1 data • Cervical Cancer • Oncology • Solid Tumor • BCL2 • SLC2A1 • SOX2 • XIAP

Targeting of BIRC3 Sensitises Multiple Myeloma Cells to Proteasome Inhibitors (IMS 2026) - "Subsequent analysis using BV-6 in combination with PIs (carfilzomib/bortezomib) across five cell lines revealed at least an additive relationship between these drugs (Bliss Synergy score ≥ 5.08)...Importantly, similar synergistic effects were observed using a clinically relevant SM, tolinapant (Bliss Synergy score ≥ 12.44), further confirming BIRC3 as a PI-sensitiser gene... The results of this study reveal that BIRC3 is a PI-sensitiser gene which, when targeted therapeutically, increases PI sensitivity even in PI-resistant cells. Future work will aim to further delineate the role of TNFα signalling in SM/PI-induced cell death. Ultimately, the discovery of this synergistic drug combination could have important implications in developing new strategies to overcome treatment resistance in MM."

Hematological Malignancies • Multiple Myeloma • BIRC3 • CASP8 • CASP9 • TNFA

Tolinapant Enhances Cytotoxic Effects of Docetaxel in Human Prostate Cancer Cells (MA-AUA 2026) - No abstract available

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

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 | Trial completion date: Jul 2026 ➔ Jul 2027

Trial completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Inhibitors of IAP/XIAP enhance activity of sacituzumab govitecan. (PubMed, J Natl Cancer Inst) - "In PDXs, birinapant enhanced the antitumor activity of several chemotherapeutics, especially irinotecan, a metabolic precursor of payload SN-38. We subsequently demonstrated that combinations of SG with birinapant or tolinapant had greater antitumor activity and significantly prolonged event-free survival compared with SG alone. In vitro, IAP antagonists significantly synergized with SG on inhibition of cell viability and colony formation, and on apoptosis induction. These findings suggest that SG combination with IAP inhibitors may represent an effective therapeutic strategy for breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • XIAP

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 | N=33 | Terminated | Sponsor: Taiho Oncology, Inc. | Trial completion date: Mar 2026 ➔ Jul 2026 | Active, not recruiting ➔ Terminated; ASTX660-03 was closed according to protocol as no safe and tolerable dosing for the combination of tolinapant and decitabine/cedazuridine was identified based on protocol defined criteria.

Trial completion date • Trial termination • 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

ASTEROID: A Trial of ASTX660 in Combination With Pembrolizumab (clinicaltrials.gov) - P1 | N=61 | Active, not recruiting | Sponsor: Institute of Cancer Research, United Kingdom | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2026 ➔ Dec 2026 | Trial primary completion date: Mar 2026 ➔ Dec 2026

Enrollment closed • Trial completion date • Trial primary completion date • Brain Cancer • Breast Cancer • Cervical Cancer • Glioblastoma • Head and Neck Cancer • HER2 Breast Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • EGFR • ER • HER-2 • TERT

Addition of Tolinapant to standard radical chemoradiotherapy for locally advanced cervical cancer: CRAIN, a phase 1b TiTECRM dose escalation study (ESTRO 2026) - "Purpose/Objective: The standard of care for locally advanced cervical cancer in the UK is concurrent chemoradiotherapy with weekly cisplatin (1). The 90mg dose was best tolerated for patients and selected by the SRC as the recommended phase II dose. A phase II study exploring the efficacy is warranted References: 1) Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized S419 Clinical - Gynaecological ESTRO 2026 trials."

Metastases • P1 data • Cervical Cancer • CNS Disorders • Epilepsy • Neutropenia • Oncology • Solid Tumor • Squamous Cell Carcinoma • Thrombocytopenia • Thrombosis • TNFA • XIAP

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 Adenocarcinoma • Cervical Cancer • Cholangiocarcinoma • Estrogen Receptor Positive Breast Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • B3GAT1 • CD8 • ER • HER-2 • XIAP

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

ASTX660-01: Phase 1-2 Study of ASTX660 in Subjects With Advanced Solid Tumors and Lymphomas (clinicaltrials.gov) - P1/2 | N=253 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Trial completion date: Dec 2025 ➔ Dec 2027

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

A Phase I/II Study of ASTX660 in Patients With Relapsed or Refractory T-cell Lymphoma (clinicaltrials.gov) - P1/2 | N=8 | Terminated | Sponsor: Otsuka Pharmaceutical Co., Ltd. | N=61 ➔ 8

Enrollment change • 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

ASTX660-03: 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 | N=33 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Phase classification: P1/2 ➔ P1 | Trial completion date: Dec 2026 ➔ Mar 2026

Phase classification • Trial 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

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 | Trial completion date: Oct 2025 ➔ Jul 2026

Trial completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Translational investigation of tolinapant (ASTX660) in acute myeloid leukemia by integrating clinical, bioinformatic and pharmacological approaches. (PubMed, Blood Res) - No abstract available

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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

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