itacnosertib (TP-0184) / Sumitomo Pharma - LARVOL DELTA

TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax. (PubMed, Leukemia) - "Treatment with TP-0184 or in combination with BCL2 inhibitor, venetoclax dramatically inhibited leukemia growth in FLT3-mutated AML cell lines and patient-derived xenograft models in a dose-dependent manner. These findings suggest that ACVR1 is a novel biomarker and plays a role in AML resistance to FLT3 inhibitors and that FLT3/ACVR1 dual inhibitor TP-0184 is a novel potential therapeutic tool for AML with FLT3 mutations."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ACVR1 • FLT3 • TGFB1

A Study of TP-0184 to Treat Anemia in Adults With IPSS-R Low or Intermediate Risk MDS (clinicaltrials.gov) - P1/2 | N=2 | Terminated | Sponsor: Sumitomo Pharma Oncology, Inc. | Completed ➔ Terminated; Due to limitations imposed by the COVID pandemic and the competitive landscape for myelodysplastic syndrome, this study was unable to enroll a sufficient patient population.

Trial termination • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Phase 1/2 Study of Oral TP-0184 for the Treatment of Anemia in Adults with Low- or Intermediate-Risk Myelodysplastic Syndromes (ASH 2021) - P1/2 | "In phase 2, the efficacy of TP-0184 at the RP2D will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy."

Clinical • P1/2 data • Anemia • Atrial Fibrillation • Bone Marrow Transplantation • Cardiovascular • Congestive Heart Failure • Gastroenterology • Gastrointestinal Disorder • Heart Failure • Hematological Disorders • Hematological Malignancies • Immunology • Inflammation • Multiple Myeloma • Myelodysplastic Syndrome • Myocardial Infarction • Oncology • Thrombosis • Transplantation • Venous Thromboembolism • ACVR1 • TGFB1

Activin-like Kinase 2 (ALK2/ACVR1) Is a Resistance Factor and Therapeutic Vulnerability to FLT3 Inhibition in Acute Myeloid Leukemia (ASH 2022) - "We also measured ACVR1 expression using qRT-PCR in FLT3-mutant AML cell lines (molm-13, molm-14, and MV4-11) treated with different doses of FLT3i (gilteritinib or midostaurin), as well as in peripheral blood mononuclear cells isolated from patients with FLT3-mutant AML treated with FLT3i...Interestingly,TP-0184 with venetoclax or cytarabine showed a synergistic effect in FLT3-mutant cells (combination index 0.01; p<0.01)... Our data indicate that ACVR1 causes resistance to FLT3 inhibitors. TP-0184, a dual inhibitor, targets mutant FLT3 and ACVR1 in AML cell lines. TP-0184 sensitizes AML cells with chemotherapy and venetoclax and inhibits AML growth in vivo."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ACVR1 • FLT3 • STAT5

Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic study of oral TP-0184, an activin receptor-like kinase-2 (ALK2) inhibitor, in patients (pts) with advanced solid tumors (ASTs) (AACR 2022) - P1 | "Preliminary data suggest that TP-0184 is tolerated as monotherapy at doses up to 125 mg QW; MTD was not reached. A study in pts with myelodysplastic syndromes is ongoing."

Clinical • P1 data • PK/PD data • Bladder Cancer • Breast Cancer • Hematological Malignancies • Melanoma • Myelodysplastic Syndrome • Oncology • Solid Tumor • ACVR1

AML-326 Novel FLT3-ALK2 Dual Inhibitor TP-0184 Inhibits Leukemia Growth by Targeting Serine Biosynthesis in FLT3-ITD-Positive AML Cells. (PubMed, Clin Lymphoma Myeloma Leuk) - "Our data indicate that ALK2 is a prognostic marker in FLT3-mutated AML. TP-0184 inhibits cell proliferation by inhibiting FLT3 downstream signaling pathways in AML cells. Kinase assays confirmed that TP-0184 is a highly specific FLT3-ALK2 dual inhibitor. TP-0184 inhibits AML growth in FLT3-mutated PDX and xenograft models."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • PI3K • STAT5

Novel FLT3-ALK2 Dual Inhibitor TP- 0184 Inhibits Leukemia Growth by Targeting Serine Biosynthesis in FLT3- ITD-Positive AML Cells (SOHO 2022) - "Our data indicate that ALK2 is a prognostic marker in FLT3-mutated AML. TP-0184 inhibits cell proliferation by inhibiting FLT3 downstream signaling pathways in AML cells. Kinase assays confi rmed that TP-0184 is a highly specifi c FLT3-ALK2 dual inhibitor."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • PI3K • STAT5

A Study of TP-0184 to Treat Anemia in Adults With IPSS-R Low or Intermediate Risk MDS (clinicaltrials.gov) - P1/2 | N=2 | Completed | Sponsor: Sumitomo Pharma Oncology, Inc. | Active, not recruiting ➔ Completed

Trial completion • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Study of TP-0184 to Treat Anemia in Adults With IPSS-R Low or Intermediate Risk MDS (clinicaltrials.gov) - P1/2; N=2; Active, not recruiting; Sponsor: Sumitomo Dainippon Pharma Oncology, Inc; Recruiting ➔ Active, not recruiting; N=90 ➔ 2; Trial completion date: Sep 2023 ➔ Dec 2021; Trial primary completion date: Apr 2023 ➔ Nov 2021

Clinical • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

ALK2/ALK5 Inhibition with TP0184 Improves Hematopoiesis of Primary Low Risk MDS (ASH 2021) - "Prior Vidaza treatment, percent blasts and transformation to AML prevented the work of ALK inhibitors. ALK inhibition with both TP0184 and TP6379 proves to be effective at improving S100A9-induced defective hematopoiesis. This improvement correlated with a decrease in MDSC in the BM. Aged S100A9Tg mice showed similar improvement and reduction of MDSC."

Acute Myelogenous Leukemia • Hematological Disorders • Oncology • CD8 • PAI1 • S100A9 • SF3B1 • SRSF2 • TGFB1

TP-0184, a Novel FLT3-ALK2 Dual Inhibitor, Targets Amino Acid Transport and Biosynthesis in AML Cells and Sensitizes AML Cells to Chemotherapy and BCL2 Inhibition (ASH 2021) - "Interestingly, TP-0184 plus chemotherapy showed a synergistic effect only in FLT3-ITD cell lines, whereas TP-0184 plus the BCL2 inhibitor, venetoclax was synergistic in both FLT3-ITD and FLT3-WT cell lines. Our data indicate that ALK2 is a prognostic marker for AML patients with FLT3-ITD mutations. TP-0184 significantly inhibits cell proliferation by inhibiting signaling pathways downstream of FLT3, including serine biosynthesis, in AML cells. Kinase assays confirmed that TP-0184 is a highly specific FLT3 inhibitor as well as an ALK2 inhibitor."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4EBP1 • FLT3 • MAP2K3 • STAT5

First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Sumitomo Dainippon Pharma Oncology, Inc; Active, not recruiting ➔ Completed; Trial completion date: Sep 2021 ➔ Mar 2021; Trial primary completion date: Sep 2021 ➔ Mar 2021

Clinical • Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A Study of TP-0184 to Treat Anemia in Adults With IPSS-R Low or Intermediate Risk MDS (clinicaltrials.gov) - P1/2; N=90; Recruiting; Sponsor: Sumitomo Dainippon Pharma Oncology, Inc; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Sumitomo Dainippon Pharma Oncology Announces First Patient Dosed in Phase 1/2 Study of TP-0184 for the Treatment of Anemia in Patients with Low or Intermediate Risk Myelodysplastic Syndromes (PRNewswire) - "Sumitomo Dainippon Pharma Oncology, Inc...announced that the first patient has been dosed in a Phase 1/2 study evaluating the investigational agent TP-0184, an activin receptor-like kinase 2 (ALK2) and ALK5 inhibitor, for the treatment of anemia in adult patients with low or intermediate risk myelodysplastic syndromes (MDS)."

Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Sumitomo Dainippon Pharma Oncology, Inc; Recruiting ➔ Active, not recruiting; Trial completion date: Dec 2020 ➔ Sep 2021; Trial primary completion date: Dec 2020 ➔ Sep 2021

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Neutropenia • Oncology • Solid Tumor

A Study of TP-0184 to Treat Anemia in Adults With IPSS-R Low or Intermediate Risk MDS (clinicaltrials.gov) - P1/2; N=90; Not yet recruiting; Sponsor: Sumitomo Dainippon Pharma Oncology, Inc

Clinical • New P1/2 trial • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=20; Recruiting; Sponsor: Tolero Pharmaceuticals, Inc.; N=40 ➔ 20; Trial completion date: Apr 2020 ➔ Dec 2020; Trial primary completion date: Feb 2020 ➔ Dec 2020

Clinical • Enrollment change • Trial completion date • Trial primary completion date

Tolero Pharmaceuticals to present new data evaluating investigational agents TP-0903 and TP-0184 at AACR Annual Meeting 2019 (PRNewswire) - "Tolero Pharmaceuticals...announced that new data from five abstracts on the company's pipeline of investigational agents will be presented at...[AACR 2019]. Data to be presented includes preclinical studies evaluating the anti-tumor activity of TP-0903...in advanced ovarian cancer, colorectal cancer, EGFR positive non-small cell lung cancer and breast cancer models. Additionally, data will be presented on the evaluation of activin A receptor type 1 (ACVR1) gene mutations as potential clinical biomarkers for the small molecule ACVR1 inhibitor TP-0184."

Biomarker • Preclinical