TAS0612 / Otsuka - LARVOL DELTA

Roles of Ribosomal S6 Kinases in Acute Leukemia and Normal Hematopoiesis (ASH 2023) - "Isoform expression influences early-fate decisions to differentiate into erythroid and myeloid lineages. RSK inhibitors PMD-026 and TAS0612 are effective at targeting AML and ALL cells with limited cytotoxicity to healthy cells, making them promising candidates for translation into clinical trials for AML and ALL."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • CD14 • CD34 • ITGAM • RPS6KA3 • TFRC

The Anti-Myeloma Efficacy of TAS0612, a Triple Inhibitor of RSK, AKT, and S6K, and Itssynergistic Combination with Venetoclax in Multiple Myeloma Irrespective of Cytogeneticabnormalities (ASH 2024) - "These suggest that TAS0612, as the single agent, is an attractive candidate drug for MM regardless of cytogenetic and genetic abnormalities. Moreover, combining TAS0612 with VEN represents a potent new therapeutic strategy for MM, irrespective of the presence of t(11; 14), facilitating its future clinical development."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • BCL2 • FBXO32 • HBP1 • MIR375 • PDPK1 • RPS6KA3 • YPEL3

The Universal Antitumor Activity of TAS0612, a Triple Inhibitor for RSK, AKT, and S6K, in B-Cell Lymphomas Regardless of Disease Subtype (ASH 2023) - "Moreover, gene set enrichment analysis identified that TAS0612 significantly downregulated the gene sets driven by the upregulation of MYC and mTORC1, reactive oxygen species, and the unfolded protein response. Thus, this study revealed that the concomitant blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel universally active therapeutic target for the various disease subtypes of BCLs, and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development."

B Cell Lymphoma • Burkitt Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Splenic Marginal Zone Lymphoma • MYC • PDPK1 • PLK1 • RPS6KA3 • TP53INP1

TAS0612, a Triple Inhibitor for RSK, AKT, and S6K, Is a Promising Anti-Myeloma Agent Regardless of Types of Cytogenetic/Genetic Abnormality (ASH 2023) - "Our findings strongly support the potential of TAS0612 as an effective anti-myeloma agent. Further preclinical investigations are necessary to substantiate these results and facilitate its future clinical development."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • HBP1 • PDPK1 • RPS6KA3 • SDC1 • YPEL3

Targeting ribosomal S6 kinase for the treatment of pediatric acute leukemia (AACR 2025) - "Both compounds have minimal toxicity to healthy hematopoietic cells. Therefore, PMD-026 and TAS0612 are strong candidates for translation into future clinical trials for AML and ALL."

Clinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia • IL6

A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1 | N=47 | Terminated | Sponsor: Taiho Oncology, Inc. | N=100 ➔ 47 | Trial completion date: Jul 2027 ➔ Nov 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Apr 2025 ➔ Nov 2024; Taiho Oncology as the sponsor of study TAS0612-101, has made a strategic decision to terminate the TAS0612-101 study, taking into consideration the safety profile of TAS0612 and the absence of encouraging anti-tumor activity.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • NF1 • PTEN

A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Taiho Oncology, Inc. | Recruiting ➔ Active, not recruiting | Trial primary completion date: Aug 2024 ➔ Apr 2025

Enrollment closed • Metastases • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • NF1 • PTEN

Robust anti-myeloma effect of TAS0612, an RSK/AKT/S6K inhibitor, with venetoclax regardless of cytogenetic abnormalities. (PubMed, Leukemia) - "Moreover, the combination of TAS0612 with venetoclax (VEN) showed the synergy in inducing apoptosis in HMCLs irrespective of the t(11;14) translocation status. TAS0612 alone and combined with VEN are new potent candidate therapeutic strategies for MM, regardless of cytogenetic/genetic profiles, facilitating its future clinical development."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • PDPK1 • RPS6KA3

A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Taiho Oncology, Inc. | N=242 ➔ 100 | Trial completion date: Jun 2024 ➔ Jul 2027 | Trial primary completion date: Oct 2023 ➔ Jul 2024

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • NF1 • PTEN

TAS0612, a novel RSK, AKT, and S6K inhibitor, exhibits antitumor effects in preclinical tumor models. (PubMed, Mol Cancer Ther) - "Additionally, TAS0612 demonstrated the persistence of blockade of downstream growth and anti-apoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent re-expression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for cancer patients to improve clinical responses and overcome resistance mechanisms."

Journal • Preclinical • Oncology • BRAF • EGFR • ERBB3 • HER-2 • KRAS • PTEN

Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas. (PubMed, Cancer Sci) - "At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development."

Journal • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC • PDPK1 • PLK1 • RPS6KA3 • TP53INP1

A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1; N=242; Recruiting; Sponsor: Taiho Oncology, Inc.; Trial completion date: Dec 2023 ➔ Jun 2024; Trial primary completion date: Jun 2023 ➔ Oct 2023

Clinical • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • NF1 • PTEN

A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1; N=200; Recruiting; Sponsor: Taiho Oncology, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • NF1 • PTEN

A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer (clinicaltrials.gov) - P1; N=200; Not yet recruiting; Sponsor: Taiho Oncology, Inc.

Clinical • New P1 trial • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • NF1 • PTEN

Phase update (clinicaltrials.gov) - Preclinical➔P1, Oncology

Phase shift • Oncology

Targeting phosphorylation of Y-box binding protein YBX1 by TAS0612 and everolimus in overcoming antiestrogen resistance. (PubMed, Mol Cancer Ther) - "Here we found that increased expression of pYBX1 was accompanied by acquired resistance to antiestrogens, fulvestrant and tamoxifen. TAS0612 also demonstrated antitumor effect against triple-negative breast cancer in vivo. Taken together our findings suggest that pYBX1 represents a potential therapeutic target for treatment of antiestrogen resistant and progressive breast cancer."

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