ONCT-216 / Oncternal Therap, Shanghai Pharma - LARVOL DELTA

A predictive 14-gene signature and FLI1 inhibition overcome tumor-infiltrating lymphocyte dysfunction in triple-negative breast cancer. (PubMed, Biochem Biophys Res Commun) - "Although immune checkpoint inhibitors such as pembrolizumab have improved clinical outcomes in a subset of patients, limited response rates and durability highlight the need for alternative strategies. Notably, pharmacological inhibition of FLI1 using TK216 restored the cytotoxic function of non-reactive TILs and reduced expression of immunosuppressive genes. These findings identify a functional gene signature associated with TIL reactivity and suggest that targeting FLI1 may represent a strategy to enhance TIL-based immunotherapy in TNBC."

Gene Signature • IO biomarker • Journal • Tumor-infiltrating lymphocyte • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • FLI1

Exploring Resistance to ETS Targeting Agents in Diffuse Large B-Cell Lymphoma. (PubMed, Cancer Med) - "Venetoclax and selinexor retained activity in resistant models, supporting their potential for rational combinations with TK216. These findings demonstrate that multiple, heterogeneous mechanisms drive resistance to ETS inhibition in DLBCL, highlighting therapeutic strategies to overcome it."

IO biomarker • Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ABCB1 • AURKA • BCL2 • MCL1 • SPI1 • SRSF11

Targeted and molecular therapies in Ewing sarcoma: a comprehensive review of preclinical and clinical advances. (PubMed, Clin Transl Oncol) - "Targeted and molecular therapies in EWS show significant promise, particularly in rational combinations that exploit the tumor's dependence on EWS-FLI1-driven transcriptional dysregulation, DNA damage repair deficiencies, or survival signaling. Future research must prioritize biomarker-driven patient selection, integration of multiomics approaches, and multicenter prospective trials to translate these strategies into clinically meaningful improvements in EWS survival."

IO biomarker • Journal • Preclinical • Review • Ewing Sarcoma • Gene Therapies • Oncology • Sarcoma • Solid Tumor • AURKA • CD99 • EWSR1 • FLI1

The small nucleolar RNA SNORD46 and SNORD72 have tumor suppressor activity in diffuse large B cell lymphoma (AACR 2024) - "Here, we characterized SNORD46 and SNORD72, the two snoRNAs most upregulated cells after YK-4-279 and TK-216 and mapped to the 1p34.1 locus recurrently lost in DLBCL.Methods...Furthermore, the snoRNAs were upregulated in four ABCs and four GCB DLBCLs cell lines exposed to the PI3K/mTOR inhibitor bimiralisib. Bioinformatic analysis indicated the possible binding of SNORD46 and especially of SNORD74 to BCR signaling molecules (SYK, LYN, BTK, PI3Kδ, IRAK4, IRAK1, CARD11), RNA helicases (RHA, DDX21, DDX5) and essential DLBCL proteins (BCL6, IRF4).Conclusions. SNORD46 and SNORD74 exert tumor suppressor activity in DLBCL cells, possibly as negative regulators of the BCR signaling."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL6 • CARD11 • DDX21 • DDX5 • ETS1 • FLI1 • IRAK4 • IRF4 • LYN • PIK3CD • SYK

Using genome-wide CRISPR screening to develop novel combination therapies for high-risk Ewing's sarcoma (AACR 2024) - "In addition, inhibition of USP9X with a small-molecule inhibitor WP1130, led to significant cell death in EWS alone and in combination with TK-216 with wide therapeutic indices. The molecular mechanism of synergy and in vivo efficacy of the novel TK-216 combination will be determined in our study for future clinical translation."

Combination therapy • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • EWSR1 • FLI1 • USP9X

A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov) - P2 | N=15 | Completed | Sponsor: Shanghai Pharmaceuticals Holding Co., Ltd | Recruiting ➔ Completed | N=30 ➔ 15

Enrollment change • Trial completion • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

ETS1 potentiates pancreatic Pyroptosis in mice with acute pancreatitis by regulating the NKIRAS1/NF-κB Axis. (PubMed, Int Immunopharmacol) - "This study reveals that ETS1 transcriptionally suppresses NKIRAS1, activating NF-κB signaling and promoting pyroptosis and pancreatic injury in AP. Targeting ETS1 may represent a promising therapeutic strategy."

Journal • Preclinical • Inflammation • Oncology • Pancreatitis • ETS1

A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Shanghai Pharmaceuticals Holding Co., Ltd | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Sep 2025 ➔ Sep 2026

Trial completion date • Trial primary completion date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

Oncternal Therapeutics Announces Termination of its Clinical Studies and Exploration of Strategic Alternatives (GlobeNewswire) - P1 | N=57 | NCT05588440 | Sponsor: Oncternal Therapeutics Inc. | "Oncternal Therapeutics...announced its decision to discontinue its clinical trials evaluating...ONCT-808, its ROR1-targeting autologous CAR T program for the treatment of patients with aggressive B-cell lymphoma, and to explore strategic alternatives...The results with ONCT-808 at an interim Phase 1 analysis showed anti-tumor activity at every dose tested, including a complete metabolic response lasting eight months and long-term persistence of the CAR-T cells, with expected treatment emergent adverse events for a CAR-T therapy, and one death due to complications of shock at the highest dose tested...Company will discontinue all product development activities....'In light of these data and the challenging financing environment, we intend to explore strategic options with the hope of advancing and realizing value from our pipeline including ONCT-534, ONCT-808, zilovertamab and ONCT-216.'"

Discontinued • P1 data • Pipeline update • Trial termination • Castration-Resistant Prostate Cancer • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Mediastinal B Cell Lymphoma • Metastatic Castration-Resistant Prostate Cancer • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Network Pharmacology Identifies Intersection Genes of Apigenin and Naringenin in Down Syndrome as Potential Therapeutic Targets. (PubMed, Pharmaceuticals (Basel)) - "Moreover, molecular docking studies included positive control drugs, such as lamellarin D, valiltramiprosate, benserazide, and TK216, which exhibited binding affinities ranging from -5.5 to -8.9 kcal/mol. Future studies should focus on in vivo validation, clinical trials, and exploring combination therapies to fully harness the therapeutic potential of these compounds for managing DS. This study underscores the promising role of network pharmacology in identifying novel therapeutic targets and agents for complex disorders like DS."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Genetic Disorders

Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma. (PubMed, J Clin Oncol) - "TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES."

Journal • P1/2 data • Ewing Sarcoma • Febrile Neutropenia • Hematological Disorders • Infectious Disease • Leukopenia • Neutropenia • Oncology • Sarcoma • Solid Tumor • Thrombocytopenia • FLI1

Mechanoresponsive ETS1 causes endothelial dysfunction and arterialization in varicose veins via NOTCH4/DLL4 signaling. (PubMed, Eur J Cell Biol) - "TK216, an inhibitor of ETS-family, prevented the acquisition of arterial molecular identity and loss of endothelial integrity in cells exposed to the ensuing altered shear stress. We conclude that ETS1 senses blood flow disturbances and may promote venous remodeling by inducing endothelial dysfunction. Targeting ETS1 rather than downstream Notch proteins could be an effective and safe strategy to develop varicose vein therapies."

Journal • Varicose Veins • DLL4 • ETS1 • MAP2K1 • NOTCH4

A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Shanghai Pharmaceuticals Holding Co., Ltd | Not yet recruiting ➔ Recruiting

Enrollment open • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

The Small-Molecule E26-Transformation-Specific Inhibitor TK216 Attenuates the Oncogenic Properties of Pediatric Leukemia. (PubMed, Genes (Basel)) - "Priming the leukemic cells with 5-Azacitidine enhanced the cytotoxic effects of TK216 on pediatric leukemia cells...Consistent with this, TK216 also potentiated the cytotoxic effects of Bcl-2 inhibition in venetoclax-resistant cells. The sustained survival benefit provided to leukemic cells in the presence of bone-marrow-derived conditioned media is also found to be modulated by TK216. Taken together, our data indicates that TK216 could be a promising targeted therapeutic agent for the treatment of acute myeloid and B-lymphoid leukemia."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • MCL1

A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Shanghai Pharmaceuticals Holding Co., Ltd | Trial completion date: Dec 2023 ➔ Dec 2025 | Trial primary completion date: Sep 2023 ➔ Sep 2025

Trial completion date • Trial primary completion date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

[VIRTUAL] Phase I study of TK216, a novel anti-ETS agent for Ewing sarcoma (ESMO 2020) - "Notably, TK216 plus vincristine (VCR) was shown to exert synergistic activity (Zollner 2017). Legal entity responsible for the study: Oncternal Therapeutics. Funding: Oncternal Therapeutics."

P1 data • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

TK216 FOR EWING SARCOMA- INTERIM PHASE 1/2 RESULTS (CTOS 2021) - "TK216 plus vincristine (VCR) exerted synergistic activity in non-clinical models. TK216 plus VCR was well tolerated and showed encouraging early evidence of anti-tumor activity at the RP2D in this heavily pre-treated/ high tumor burden ES pt population. Investigations are ongoing to characterize the most responsive pt population and intensify TK216 exposure."

P1/2 data • Anemia • Ewing Sarcoma • Fatigue • Hematological Disorders • Leukopenia • Neutropenia • Oncology • Pediatrics • Sarcoma • Solid Tumor

ETS-Transcription Factor inhibitors are effective in TERT promoter mutated meningioma cells in vitro (EANO 2022) - "Conclusion : In summary, our results indicate that ETS transcription factor inhibition by TK216 exerts antitumour activity in our TERT promoter mutant meningioma cell model. Additionally, the sensitivity against TK216 is superior to YK-4-279 and therefore TK216 may represent a promising new therapeutic option for patients with aggressive, TERT promoter mutated meningioma."

Preclinical • Brain Cancer • Meningioma • Oncology • Solid Tumor • ANXA5 • ARID1A • CDKN2A • CDKN2B • PTEN • TERT

A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Shanghai Pharmaceuticals Holding Co., Ltd | Initiation date: May 2022 ➔ Sep 2022 | Trial primary completion date: Nov 2022 ➔ Sep 2023

Trial initiation date • Trial primary completion date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

TK216 targets microtubules in Ewing sarcoma cells. (PubMed, Cell Chem Biol) - "Using reconstituted microtubule (MT) polymerization in vitro and cell-based chemical probe competition assays, we demonstrate that TK216 acts as an MT destabilizing agent. This work defines the mechanism of cytotoxicity of TK216, explains the synergy observed with vincristine, and calls for a reexamination of ongoing clinical trials with TK216."

Journal • Ewing Sarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • EWSR1 • FLI1

The small molecule TK216 targets microtubules in Ewing sarcoma cells (EACR 2022) - "Conclusion This work defines the mechanism of cytotoxicity of TK216 and explains the synergy observed with vincristine in EWS cells. These results call for a reexamination of ongoing clinical trials using TK216; and additional investigation of potential synergy between colchicine binding pocket agents and vinca alkaloids for cancers sensitive to MT destabilizing agents."

Ewing Sarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • EWSR1 • FLI1

TK216-01: TK216 in Patients With Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov) - P1/2 | N=85 | Terminated | Sponsor: Oncternal Therapeutics, Inc | N=45 ➔ 85 | Trial completion date: Mar 2024 ➔ Jun 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2023 ➔ May 2022

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • EWSR1 • FLI1

Oncternal Therapeutics Deprioritizes Development of ONCT-216 to Focus Resources on Phase 3 Trial for Zilovertamab in the Treatment of Mantle Cell Lymphoma (GlobeNewswire) - "Oncternal Therapeutics, Inc...announced that it has deprioritized further development of ONCT-216 to reallocate resources to zilovertamab, the Company’s investigational anti-ROR1 monoclonal antibody, and its Phase 3 registrational trial that the Company expects to initiate in Q3 2022. As such, the Company has discontinued enrollment in the Phase 1/2 study evaluating ONCT-216 in patients with relapsed or refractory Ewing sarcoma."

Discontinued • Enrollment status • New P3 trial • Ewing Sarcoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Sarcoma • Solid Tumor

TK216-01: TK216 in Patients With Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov) - P1/2 | N=45 | Active, not recruiting | Sponsor: Oncternal Therapeutics, Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • EWSR1 • FLI1

A Clinical Study of TK216 in Patients With Relapsed or Refractory Ewing's Sarcoma (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Shanghai Pharmaceuticals Holding Co., Ltd | Initiation date: Dec 2021 ➔ Mar 2022

Trial initiation date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor