This phase IB/II trial studies the best dose of TP-0903 and how well it works when given alone or with azacitidine in treating patients with FLT3 gene mutated acute myeloid leukemia. TP-0903 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving TP-0903 alone or with azacitidine may kill more cancer cells.

开始日期2020-11-05

申办/合作机构

Ohio State University Comprehensive Cancer Center

[+1]

NCT03572634

/ Terminated临床1/2期

A Combined Phase 1/2 Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of TP-0903 in Patients With Previously Treated Chronic Lymphocytic Leukemia (CLL)

TP-0903 is an inhibitor of AXL kinase. TP-0903 has shown potent inhibition of AXL kinase and other TAM family members in a biochemical kinase assay. TP-0903 demonstrates corresponding activity in cancer cell lines and mouse xenograft efficacy models. TP-0903 is shown to block cancer cell epithelial-to-mesenchymal transitions. AXL was identified as a potential therapeutic target in chronic lymphocytic leukemia (CLL). TP 0903 was shown to induce apoptosis in CLL B-cells taken directly from patients.TP-0903 was equally potent against CLL cells regardless of risk-factor.
TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. TP-0903 has demonstrated profound single agent activity in CLL B cells taken directly from patients even if the patient has high risk factors (ie, 17p/P53 deletions) or progressed on other agents (ie, ibrutinib). TP-0903 is currently being evaluated in patients with refractory solid tumors (TP-0903-101). This proposed study is designed to identify the maximum tolerated dose (MTD), safety profile and recommended Phase 2 dose (RP2D) of TP-0903 in patients with previously treated CLL. Treatment cycles may be repeated if the patient continues to show benefit and if TP-0903 is reasonably well tolerated.
The study will investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of TP-0903.

开始日期2019-06-10

申办/合作机构

Sumitomo Pharma America, Inc.

NCT02729298

/ Completed临床1期

A Phase 1a / 1b, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0903 Administered Daily for 21 Days to Patients With Advanced Solid Tumors

TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. Preclinical studies have shown promising antitumor activity of TP-0903 as a single agent against a variety of tumor types in both in vitro and in vivo studies.
This first-in-human Phase 1a study is conducted to identify the maximum tolerated dose (MTD) of TP-0903 administered orally to patients with advanced solid tumors and to identify the safety profile and Recommended Phase 2 Dose (RP2D) of TP-0903. Once the MTD has been established, additional patients with specific tumor types (advanced solid tumors that have progressed after achieving a best documented response of at least stable disease (ie, SD, PR, or CR documented per iRECIST following at least 2 cycles (8 weeks) of immunotherapy, EGFR+ Non Small Cell Lung Cancer [NSCLC] and have demonstrated recent progression following a best documented response of at least stable disease (ie, SD, PR, or CR documented per RECIST v1.1 on ≤2 lines of oral TKIs (Prior chemotherapy ± immunotherapy is allowed as long as the patient is clearly demonstrating current progression on an EGFR TKI.), BRAF-, KRAS-, or NRAS-mutated Colorectal Carcinoma [CRC] for whom there is no standard therapy remaining, persistent/recurrent Ovarian Cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy, and BRAF-mutated Melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor) will be enrolled at the MTD in the Phase 1b study. Data collected from patients enrolled in each of these additional cohorts will be used for to confirm safety, explore potential biomarkers, and evaluate potential signals of activity when TP-0903 is administered to specific groups of heavily pretreated patients or given in combination with immunotherapy or a tyrosine kinase inhibitor (TKI).
The study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity profiles.

开始日期2016-12-14

申办/合作机构

Sumitomo Pharma America, Inc.

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项与 Dubermatinib 相关的文献（医药）

2025-07-01·Cancer research communications

A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia ≥Age 60 Years

Article

作者: Lin, Tara L. ; Zeidner, Joshua ; Madanat, Yazan F. ; Levine, Ross L. ; Bhatnagar, Bhavana ; Stefanos, Mona ; Eisenmann, Eric D. ; Chen, Timothy L. ; Redner, Robert ; Byrd, John C. ; Druker, Brian J. ; Al-Mansour, Zeina ; Baer, Maria R. ; Huang, Ying ; Burd, Amy ; Baker, Sharyn D. ; Abbott, Nicole ; Mims, Alice S. ; Borate, Uma ; Phelps, Mitch ; Swords, Ronan ; Buelow, Daelynn ; Orwick, Shelley ; Yocum, Ashley O. ; Martycz, Molly ; Foster, Matthew C. ; Druggan, Franchesca ; Kovacsovics, Tibor

Abstract:

Purpose::

Older patients who have acute myeloid leukemia (AML) with mutant TP53 and/or complex karyotype have a dismal prognosis and lack treatment options. Having previously demonstrated that TP-0903, a multikinase inhibitor, has compelling preclinical activity in drug-resistant AML, including TP53-mutated AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.

Patients and Methods::

This was a multicenter, open-label, phase 1b/2 substudy of Beat AML Master Trial (ClinicalTrials.gov: NCT03013998). The phase 1b portion used a 3 + 3 design, and the phase 2 portion used a Simon two-stage design. Eligible patients ages ≥60 years who had newly diagnosed AML with mutations in TP53 and/or complex karyotype (≥3 cytogenetic abnormalities) received either 37 mg (group 1) or 25 mg (group 2) TP-0903 orally on days 1 to 21 with decitabine 20 mg/m2 on days 1 to 10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which decitabine dosing was reduced to days 1 to 5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.

Results::

The overall composite remission rate (CR/CR with incomplete count recovery/CR with hematologic improvement) was 33.3% in group 1 and 50.0% in group 2, with CR rates of 13.3% and 25%, respectively. The median overall survival for groups 1 and 2 was 7.6 and 7.5 months, respectively.

Conclusions::

The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.

Significance::

Treatment options for AML with mutant TP53 and/or complex karyotype are limited. In a phase 1b/2 clinical trial, TP-0903, a multikinase inhibitor, was well-tolerated and had activity comparable with other emerging therapies. Our results suggest that TP-0903 may offer insight and serve as a benchmark for the development of future agents leveraging similar strategies or scaffolds to improve outcomes in these intractable subtypes of AML.

2025-03-18·ANALYTICAL CHEMISTRY

High-Throughput Empirical and Virtual Screening To Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

Article

作者: Shih, Chien-Hung ; Chen, Yu-Chih ; Chen, Hsiao-Chun ; Ma, Yushu ; Brown, Daniel D. ; Zhang, Yuan ; Wang, Li-Ju ; Cheng, Jinxiong ; Tan, Yanhao ; Lee, Adrian V. ; Oesterreich, Steffi ; Chiu, Yu-Chiao

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirical testing of all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacy in silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated five compounds as potent PGCC inhibitors using cell lines and patient-derived models. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer.

2025-03-13·ACS Medicinal Chemistry Letters

A Hybrid Energy-Based and AI-Based Screening Approach for the Discovery of Novel Inhibitors of AXL

Article

作者: Xinglong Chi ; Zhichao Pan ; Xiaojun Ying ; Wenhai Huang ; Xinting Lv ; Jingyi Zhao ; Long Li ; Youlu Pan ; Youkun Kang ; Linjun Wang

AXL, part of the TAM receptor tyrosine kinase family, plays a significant role in the growth and survival of various tissues and tumors, making it a critical target for cancer therapy. This study introduces a novel high-throughput virtual screening (HTVS) methodology that merges an AI-enhanced graph neural network, PLANET, with a geometric deep learning algorithm, DeepDock. Using this approach, we identified potent AXL inhibitors from our database. Notably, compound 9, with an IC₅₀ of 9.378 nM, showed excellent inhibitory activity, suggesting its potential as a candidate for further research. We also performed molecular dynamics simulations to explore the interactions between compound 9 and AXL, providing insights for future enhancements. This hybrid screening method proves effective in finding promising AXL inhibitors, and advancing the development of new cancer therapies.

项与 Dubermatinib 相关的新闻（医药）

2020-12-05

·PR Newswire

Sumitomo Dainippon Pharma Oncology Presents Findings from Phase 2 Zella 201 Clinical Study Evaluating Investigational Agent Alvocidib in Patients with Acute Myeloid Leukemia at 62nd ASH Annual Meeting

CAMBRIDGE, Mass., Dec. 5, 2020 /PRNewswire/ -- Sumitomo Dainippon Pharma Oncology, Inc., a developer of novel cancer therapeutics, today presented new data from the Phase 2 Zella 201 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in patients with MCL-1 dependent acute myeloid leukemia (AML). These results were presented at the 62nd American Society of Hematology Annual Meeting, being held virtually December 5-8, 2020. Preliminary findings from the open-label, randomized, multicenter study indicated that alvocidib was well tolerated with a manageable safety profile in combination with cytarabine and mitoxantrone in an exploratory arm of patients with newly diagnosed, high-risk MCL-1 dependent AML. Alvocidib in combination showed preliminary signs of clinical activity in the study, with 62% (n=8 of 13) of evaluable patients achieving complete remission/complete remission with incomplete count recovery. Of the patients that responded, 75% (n=6 of 8) achieved complete remission after the first treatment cycle. Although all patients included in this cohort were determined to be MCL-1 dependent, there was no association of complete remission with increasing MCL-1 dependence. The most frequently observed treatment-emergent non-hematologic adverse events of Grade 3 or higher were diarrhea, tumor lysis syndrome, hypocalcemia, sepsis and hypotension.1 Sumitomo Dainippon Pharma Oncology (SDP Oncology) will also be presenting details regarding the trial design of a Phase 1 study evaluating TP-3654, a PIM kinase inhibitor, in patients with intermediate-2 and high-risk primary or secondary myelofibrosis. In addition, SDP Oncology and its parent company, Sumitomo Dainippon Pharma Co. Ltd., will be presenting Phase 1 data evaluating alvocidib in combination with cytarabine and mitoxantrone in patients with relapsed/refractory AML or cytarabine and daunorubicin in patients with newly diagnosed AML. Finally, preclinical data evaluating how dubermatinib (TP-0903), an oral AXL kinase inhibitor, modulates CART19 will be presented. "These findings presented at the ASH Annual Meeting represent the first data evaluating the clinical activity of alvocidib in patients with newly diagnosed, high-risk, MCL-1-dependent AML," said Patricia S. Andrews, CEO and Global Head of Oncology, SDP Oncology. "The completion of this study marks a milestone for SDP Oncology as we continue to learn more about the optimal patient population that may benefit from alvocidib. The breadth of updates we presented at ASH 2020 from across our pipeline demonstrate our commitment to advancing purposeful science by transforming new discoveries into meaningful therapeutic options for patients with cancer." Below are the details for the SDP Oncology and Sumitomo Dainippon Pharma presentations: For more information about SDP Oncology's pipeline and clinical trials, please visit the company's virtual booth at the ASH Annual Meeting here. About Alvocidib Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the ongoing Phase 2 Zella 202 study in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacitidine or decitabine (NCT03969420). Alvocidib is also being evaluated in Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with azacitidine or decitabine (NCT03593915) and in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555). About CDK9 Inhibition and MCL-1 MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.2 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.3 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).5,6 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.5 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.2 About TP-3654 TP-3654 is an investigational second-generation selective PIM kinase inhibitor currently under evaluation in a Phase 1 study in patients with myelofibrosis (NCT04176198) and a Phase 1 study in patients with advanced solid tumors (NCT03715504). About PIM Kinase PIM kinases are major effectors of JAK/STAT proliferative signaling downstream of multiple growth factors and cytokines.7 PIM is overexpressed in cancers and it may enhance the ability of fibroblasts to differentiate into myofibroblasts.7 About Dubermatinib (TP-0903) Dubermatinib is an investigational oral AXL receptor tyrosine kinase (RTK) inhibitor under evaluation in a Phase 1a/b study in patients with advanced solid tumors (NCT02729298) and an ongoing study in collaboration with the Leukemia & Lymphoma Society as part of the Beat AML Clinical Trial (NCT03013998). SDP Oncology is exploring parallel clinical development paths for dubermatinib in both solid and hematologic malignancies. About AXL Kinase AXL belongs to the TAM (Tyro3, AXL and Mer) family of receptor tyrosine kinases and is overexpressed in many human cancers.8 It plays a key role in tumor cell proliferation, survival, metastasis, cellular adhesion, and avoidance of the immune response. The overexpression of AXL is associated with a poor patient prognosis and drug resistance.9 About Sumitomo Dainippon Pharma Oncology Sumitomo Dainippon Pharma Oncology, Inc., is a wholly owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd. As a global oncology organization with teams in the U.S. and Japan, SDP Oncology is relentlessly committed to advancing purposeful science by transforming new discoveries into meaningful treatments for patients with cancer. The company's robust and diverse pipeline of preclinical and advanced-stage assets spans multiple areas, including oncogenic pathways, survival mechanisms and novel protein interactions, which aim to address unmet clinical needs in oncology. For more information, visit . About Sumitomo Dainippon Pharma Sumitomo Dainippon Pharma is among the top-10 listed pharmaceutical companies in Japan, operating globally in major pharmaceutical markets, including Japan, the U.S., China and the European Union. Sumitomo Dainippon Pharma aims to create innovative pharmaceutical products in the Psychiatry & Neurology area, the Oncology area and Regenerative medicine/Cell therapy field, which have been designated as the focus therapeutic areas. Sumitomo Dainippon Pharma is based on the merger in 2005 between Dainippon Pharmaceutical Co., Ltd., and Sumitomo Pharmaceuticals Co., Ltd. Today, Sumitomo Dainippon Pharma has more than 6,000 employees worldwide. Additional information about Sumitomo Dainippon Pharma is available through its corporate website at . Disclaimer Regarding Forward-Looking Statements This press release contains "forward-looking statements," as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. The forward-looking statements in this press release are based on management's assumptions and beliefs in light of information presently available and involve both known and unknown risks and uncertainties. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice. References Zeidner, J, Lee, D, Fine, G, et al. Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed by Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm. 62nd American Society of Hematology (ASH) Annual Meeting. 5 December 2020 . Abstract 1045. Thomas D, Powell JA, Vergez F, et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 2013;122(5):738-748. Perciavalle RM, Opferman JT. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29. Glaser SP, Lee EF, Trounson E, et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 2012;26(2):120-125. Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519. Ocana A, Pandiella A. Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies. Oncotarget. 2017;8(13):22218-22234 Zemskova MY, Song JH, Cen B, et al. Regulation of prostate stromal fibroblasts by the PIM1 protein Kinase. Cell Signaling. 2017;27(1):135-146. Soh KK, Bahr BL, Bearss JJ, et al. Inhibition of Axl kinase reverses the mesenchymal phenotype in leukemic cells through the disruption of retinoic signaling [Abstract]. Blood. 2015;126:3253. Park IK, Mundy-Bosse B, Whitman SP, et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29(12):2382-2389. SOURCE Sumitomo Dainippon Pharma Oncology, Inc.

临床1期临床结果临床2期ASH会议ASCO会议

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外链

KEGG	Wiki	ATC	Drug Bank
D11732	-	-	DB15187

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适应症	最高研发状态	国家/地区	公司	日期
慢性淋巴细胞白血病	临床2期	美国	Sumitomo Pharma America, Inc.	2019-06-10
小淋巴细胞淋巴瘤	临床2期	美国	Sumitomo Pharma America, Inc.	2019-06-10
伴有 FLT3/ITD 突变的急性髓系白血病	临床1期	美国	Sumitomo Pharma America, Inc.	2020-11-05
复发性急性髓细胞白血病	临床1期	美国	Sumitomo Pharma America, Inc.	2020-11-05
治疗相关性急性髓系白血病	临床1期	美国	Sumitomo Pharma America, Inc.	2020-11-05
晚期恶性实体瘤	临床1期	美国	Sumitomo Pharma America, Inc.	2016-12-14
BRAF 突变结直肠癌	临床1期	美国	Sumitomo Pharma America, Inc.	2016-12-14
BRAF V600 突变阳性黑色素瘤	临床1期	美国	Sumitomo Pharma America, Inc.	2016-12-14
EGFR阳性非小细胞肺癌	临床1期	美国	Sumitomo Pharma America, Inc.	2016-12-14
复发性卵巢癌	临床1期	美国	Sumitomo Pharma America, Inc.	2016-12-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03013998 (BeatAML, EHA2023)	临床1/2期	急性髓性白血病	27	TP-0903 + decitabine 37 mg	窪願繭襯憲憲範鑰膚築(襯繭蓋壓願齋網糧簾顧) = 艱衊醖餘醖窪願選顧觸鏇鏇繭蓋醖繭鑰齋獵醖 (選築廠壓獵鏇簾網網繭, 11.8–61.6) 更多	-	2023-06-08
				TP-0903 + decitabine 25 mg	窪願繭襯憲憲範鑰膚築(襯繭蓋壓願齋網糧簾顧) = 範選糧鑰鏇衊鬱範築構鏇鏇繭蓋醖繭鑰齋獵醖 (選築廠壓獵鏇簾網網繭, 21.1–78.9) 更多
NCT03013998 (ASCO2022) 人工标引	临床1/2期	急性髓性白血病一线 TP53 Mutation	16	Dubermatinib+Decitabine	範淵獵齋觸艱鑰餘窪艱(淵網築憲繭觸構積顧顧) = 齋齋鬱衊餘鑰鹹餘膚製選獵夢範餘構醖淵顧鹹 (構選艱憲願選窪艱顧餘, 15.2 ~ 64.6) 更多	积极	2022-06-02
NCT03572634 (CTgov)	临床1/2期	慢性淋巴细胞白血病 \| 小淋巴细胞淋巴瘤	3	TP-0903 (TP-0903 Monotherapy (25mg Dose of TP-0903))	獵製網繭鏇構築襯獵選(齋鏇簾選積繭憲壓艱膚) = 糧襯淵餘簾積繭艱範築齋簾鏇繭齋製製夢選範 (構選繭夢鏇鏇齋簾艱憲, 鏇餘醖鏇選餘構構餘廠 ~ 夢餘製願夢構衊積繭衊) 更多	-	2021-02-02
				Ibrutinib+TP-0903 (TP-0903 and Ibrutinib Combination Therapy (20 mg Dose of TP-0903))	獵製網繭鏇構築襯獵選(齋鏇簾選積繭憲壓艱膚) = 蓋壓餘齋壓襯築積願鬱齋簾鏇繭齋製製夢選範 (構選繭夢鏇鏇齋簾艱憲, 繭選獵鬱遞膚製膚遞願 ~ 糧鹹膚淵鏇製鹹艱糧遞) 更多