Evaluating the safety and logistics of Tarloxotinib combined with Stereotactic Body RadiationTherapy (SBRT) in a window of opportunity trial of advanced Human Papilloma Virus (HPV) negative head & neck cancer.

开始日期2023-10-12

申办/合作机构-

NCT03805841 / Terminated临床2期

Phase 2 Study - Evaluate the Clinical Activity of Tarloxotinib in Patients With Non-Small Cell Lung Cancer That Harbors an EGFR Exon 20 Insertion or HER2-Activating Mutation and Other Advanced Solid Tumors With NRG1/ERBB Family Gene Fusions

Open-label, Phase 2, single treatment arm, 3 cohorts

开始日期2019-03-13

申办/合作机构

Rain Oncology, Inc.

NCT02449681 / Terminated临床2期

A Phase 2 Study of Tarloxotinib (TH-4000) in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Skin

This phase 2 study is designed to evaluate the safety and activity of TH-4000, a hypoxia-activated prodrug in participants with recurrent or metastatic squamous cell carcinoma of the head and neck or skin.

开始日期2015-08-01

申办/合作机构

Rain Oncology, Inc.

100 项与 Tarloxotinib Bromide 相关的临床结果

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100 项与 Tarloxotinib Bromide 相关的转化医学

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100 项与 Tarloxotinib Bromide 相关的专利（医药）

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项与 Tarloxotinib Bromide 相关的文献（医药）

2024-03-01·Archives of toxicology

TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2+ breast cancer

Article

作者: Ding, Yongbin ; Li, Lei ; Tang, Jinhai ; Xu, Di ; Shao, Xinyi ; Sun, Yidan ; Zhou, Honglei ; Shan, Liuqun ; Yang, Dawei ; Yan, Xueqin ; Yu, Qiang

Human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer is correlated with poor prognosis, the current treatment of which is still based on surgery and adjuvant targeted therapy with monoclonal antibody. Problems of drug resistance hinder the use of monoclonal antibodies. Subsequently, tyrosine kinase inhibitors (TKIs) have been noticed, TKIs have the advantages of multi-targets and reduced drug resistance. However, TKIs that target HER family proteins often cause adverse effects such as liver damage and diarrhea. Thus, TKIs with high selectivity are being developed. TH-4000, a prodrug that generated an active form TH-4000Effector (TH-4000E) under hypoxic condition, was evaluated in this research. We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2⁺ breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. TH-4000E activated Caspase-3 and induced apoptosis through a reactive oxygen species (ROS)-dependent pathway. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2⁺ breast cancer.

2022-08-01·INVESTIGATIONAL NEW DRUGS3区 · 医学

A phase II study of tarloxotinib (a hypoxia activated prodrug of a pan-erb tyrosine kinase inhibitor) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or skin

3区 · 医学

Article

作者: Gramza, Ann ; Liu, Stephen ; Khan, Saad A ; McLean, Luke S ; Pearce, Tillman ; Rischin, Danny ; Colevas, A Dimitrios ; Morris, Tessa A

BACKGROUND:

Tarloxotinib, a hypoxia-activated prodrug of an irreversible pan-ErbB tyrosine kinase inhibitor, represents a novel therapeutic which exploits the tumor-specific hypoxic environment as a mechanism for tumor-specific targeting. This study evaluated the safety and activity of tarloxotinib in recurrent or metastatic (R/M) cutaneous (CSCC) or head and neck squamous cell carcinoma (HNSCC).

METHODS:

This was a phase II two-stage multi-centre study for patients with R/M HNSCC or CSCC. All patients received tarloxotinib 150 mg/m2 on days 1,8,15 and 22 in a 28-day cycle. Stage 1 enrolled patients in three cohorts: p16-negative HNSCC, p16-positive oropharyngeal SCC, and CSCC. In order for a cohort to proceed to stage 2 a minimum response rate of 5% was required.

RESULTS:

30 patients were enrolled: 23% were female with median age of 63.3 years. The median duration of follow-up was 20 weeks. The median progression-free survival was 2.0 months (95%CI 1.8-3.4) and median overall survival 5.7 months (95%CI 3.6-8.0). Treatment was well tolerated. The objective response rate was 3% with one patient with CSCC having a partial response.

CONCLUSIONS:

Hypoxia-activated prodrugs represent a novel approach to cancer treatment, however, no clinically meaningful benefit for tarloxotinib in R/M HNSCC or CSCC was identified in this study.

TRIAL REGISTRATION NUMBER:

NCT02449681 (May 20, 2015).

2021-08-01·Translational lung cancer research2区 · 医学

Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study

2区 · 医学

Article

作者: Koga, Takamasa ; Fujino, Toshio ; Ohara, Shuta ; Mitsudomi, Tetsuya ; Tirunagaru, Vijaya ; Vellanki, Avanish ; Doebele, Robert C ; Suda, Kenichi ; Soh, Junichi ; Hamada, Akira ; Nishino, Masaya

BACKGROUND:

HER2 (ERBB2) activating mutations are present in 2-3% of lung adenocarcinomas; however, no targeted therapy is approved for HER2-altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the in vitro activity of tarloxotinib-E in HER2-mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells.

METHODS:

Growth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six HER2 mutations or wild-type (WT) HER2, in addition to H1781 cells with HER2 exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated HER2-mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E.

RESULTS:

Tarloxotinib-E showed potent activity against HER2-mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC₅₀) of tarloxotinib (inactive form) for WT HER2 was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of HER2 by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased HER3 expression was the molecular mechanism of tarloxotinib-E resistance.

CONCLUSIONS:

Tarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.

项与 Tarloxotinib Bromide 相关的新闻（医药）

2021-04-23

·Endpoints

April showers bring more biotechs to Nasdaq, as Rain and Impel bump 2021's total raise above $6B

Editor’s note: Interested in following biopharma’s fast-paced IPO market? You can bookmark our IPO Tracker here. What’s that in the sky — is it a bird? Is it a plane? No, it’s another handful of biotech IPOs. Two more biotechs priced their public offerings late Thursday, coming just one day after Zymergen blew folks away with its $500 million pricing. This week’s winners are Rain Therapeutics and Impel Neuropharma, who raised $125 million and $80 million, respectively. Rain priced at $17 and Impel’s shares debuted at $15 apiece. Combined, the sector has now raised more than $6 billion among nearly three dozen debuts, according to the Endpoints News tally. That’s on pace to top last year’s record raise of $16.5 billion and 91 IPOs, per Nasdaq. Also on Thursday came the F-1 filing of Swiss biotech Molecular Partners, which is penciling in $100 million for its leap to Nasdaq. The company is already publicly traded in its home country. Rain stock price could bring company’s valuation to $427 million After a 2020 that led to a significant expansion of its pipeline, Rain Therapeutics has priced its IPO. The biotech that specializes in oncology has priced its 7,352,941 shares of its stock at $17 a share, and is expected to raise $125 million. In a release Monday, the company stated that price would command a market cap of $457 million. Rain’s pipeline tripled in a single week around Labor Day last year, when it licensed a research program from Drexel University and grabbed a Phase II-ready drug from Daiichi Sankyo. That program has become RAIN-32. That is the company’s lead program now, and should see the majority of IPO funds funneled toward it. RAIN-32 is a small molecule inhibitor of MDM2 taken orally to reduce tumors activity in liposarcoma and other solid tumors. In 2018, the company launched the experimental drug tarloxotinib with its $18 million in Series A fundraising. Last year, it raised $63 million. Rain will trade under the ticker $RAIN. — Josh Sullivan Impel announces IPO to launch migraine treatment Impel NeuroPharma is going public a little more than two years after its crossover raise, and Thursday, the company announced that it would be priced at $15 a share. Impel is expected to take home $80 million in proceeds with the public offering of 5,333,334 shares of its stock. The biotech from Seattle will use that money to commercially launch its migraine treatment Trudhesa, delivered through an upper nasal formulation of dihydroergotamine. The proceeds will also help its INP105 program, which is designed for treatment of agitation and aggression associated with autism spectrum disorder. This candidate, like many of the company’s drugs, is delivered to the brain through the nose, as it’s a nasal reformulation of olanzapine. Shares of Impel’s stock — which will be listed as $IMPL — will begin trading today. — Josh Sullivan Swiss biotech looking to hop across the pond with its protein therapies Molecular Partners is ostensibly seeking to capitalize on last month’s news that one of their antiviral programs will participate in an NIH-run Covid-19 trial. Molecular Partners teamed up with Novartis for the candidate, which is what they’re calling a “trispecific” DARPin antiviral known as ensovibep. Researchers will evaluate the antiviral as part of the NIH’s ACTIV-3, the hospitalized mild-to-moderate patient arm of their ACTIV protocol against Covid-19. If the medicine hits all its milestones, Novartis will be on the hook for up to $231 million. But Molecular Partners is also focusing on eye diseases, oncology and AML. The company has a Phase III program for wet AMD where they’ve partnered with Allergan/AbbVie and a lead cancer program for FAP-positive cancers in collaboration with Amgen. The biotech has three programs it expects to fund with its IPO: a Phase I trial for its second oncology program seeking to bind FAP and CD40, to complete a Phase I study for the second Novartis-partnered Covid-19 program known as MP0423, and to advance their liquid tumor portfolio in AML through Phase I as well. Once the IPO is closed, Molecular Partners will trade on the ticker $MOLN, which is also their Swiss ticker. — Max Gelman

合作小分子药物IPO

2021-04-07

·BioSpace

Rain Plans $100 Million IPO, Phase III Trial for Lead Precision Cancer Therapy

Newark, California-based cancer company Rain Therapeutics filed Friday for a $100 million IPO to advance its lead MDM2 inhibitor RAIN-32 into Phase III testing. The news comes months after the company closed a $63 million Series B and inlicensed RAIN-32 from Daiichi Sankyo. Rain licenses and develops precision cancer therapies. The new lead program, RAIN-32, previously completed Phase I testing in patients with solid tumors or lymphomas. The influx of cash will support a pivotal Phase III trial in liposarcoma, which Rain intends to launch this year, plus two more Phase II trials in solid tumors and intimal sarcoma, respectively. Preclinical data published by independent French researchers last year suggested MDM2 inhibitors had therapeutic potential for treating liposarcomas, where MDM2 amplification is common. MDM2 is an inhibitor of tumor-suppressive p53, a notoriously challenging drug target. Several companies are developing MDM2 inhibitors to act upstream of p53, with limited success, which Rain attributes to dose-limiting hematological toxicities. Last year, Roche ended development of its MDM2 inhibitor, idasanutlin, then in Phase II testing for patients with acute myeloid leukemia (AML). The most advanced anti-MDM2 therapy is APG-115, which Ascentage Pharma has in multiple Phase Ib/II trials for solid tumors and hematologic malignancies, plus a Phase II combination trial with checkpoint inhibitor Keytruda (pembrolizumab) for anti-PD-1 refractory or relapsed cancers. At least two other companies–Novartis and Aileron–also have MDM2 inhibitors in early clinical testing for several cancers. According to Rain, the safety and tolerability data from Daiichi Sankyo’s trial suggest RAIN-32 can be dosed longer than other MDM2-targeting programs in development. Rain also has a preclinical RAD52 inhibitor program, licensed from Drexel University in August 2020. RAD52 plays a role in DNA damage response and the company is exploring therapies for breast and ovarian cancers characterized by BRCA1/2 mutations. The company is aiming to select a lead clinical RAD52 inhibitor candidate in 2022. There are no known RAD52 inhibitors in clinical trials. As recently as last year, its previous lead candidate tarloxotinib, licensed from the University of Auckland, was in Phase II testing for patients with EGFR and ErbB Exon 20 insertion mutations in solid tumors. The company has not announced an end to the trial but tarloxotinib is not named in Rain’s Securities and Exchange Commission (SEC) forms or listed on the company’s website. Rain did not respond to a request for clarification in time for publication.

IPO

2015-12-09

·Pm Live

Merck abandons evofosfamide as two trials fail

Merck KGaA has said it will no longer seek approval for its solid tumour candidate evofosfamide after two phase III trials failed to show efficacy. The decision was taken after evofosfamide (TH-302) failed to show any improvement in overall survival in the trials, which involved patients with metastatic pancreatic cancer and soft tissue sarcoma who received the drug in combination with chemotherapy. The revelation - coming less than a month after Merck finalised a co-promotion deal for the drug - had a dramatic impact on evofosfamide's original developer Threshold Pharmaceuticals. The US biopharma company saw its share price fall 85% on the day of the announcement, with chief executive Barry Selick telling investors that it will make a decision on ongoing and pending evofosfamide trials in the near future. Evofosfamide is an investigational hypoxia-activated prodrug, designed to be inert in the body until it comes into contact with the low-oxygen environment in solid tumours. Merck first took a license to the drug in 2012 in a $525m deal. "Despite seeing signs of activity in pancreatic cancer, pre-specified primary endpoints were not met in both studies and therefore the data do not support filing in these indications," said Merck's head of global R&D Luciano Rossetti in a statement. "We will be making a quick decision on the future of the ongoing evofosfamide clinical programme," he added, noting that Merck will redeploy resources into other projects such as Pfizer-partnered immuno-oncology drug avelumab. If evofosfamide is deemed terminal, Threshold will focus on tarloxotinib, a prodrug designed to selectively release an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor under severe hypoxia conditions, which is in two phase II trials. The big question now is whether the strategy of harnessing hypoxia as a delivery trigger for cancer therapies adopted by Threshold is undermined by the results or whether the disappointing results with evofosfamide are compound-specific. Preliminary data on tarloxotinib are due in the first half of next year, said Selick, but in the meantime "we will be thoughtfully evaluating strategic options pertaining to the future of the company".

临床2期临床3期引进/卖出

100 项与 Tarloxotinib Bromide 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14944

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床2期	美国	Rain Oncology, Inc.	2019-03-13
晚期恶性实体瘤	临床2期	加拿大	Rain Oncology, Inc.	2019-03-13
晚期恶性实体瘤	临床2期	中国香港	Rain Oncology, Inc.	2019-03-13
转移性非小细胞肺癌	临床2期	美国	Rain Oncology, Inc.	2019-03-13
转移性非小细胞肺癌	临床2期	加拿大	Rain Oncology, Inc.	2019-03-13
转移性非小细胞肺癌	临床2期	中国香港	Rain Oncology, Inc.	2019-03-13
非小细胞肺癌IIIB期	临床2期	美国	Rain Oncology, Inc.	2019-03-13
非小细胞肺癌IIIB期	临床2期	加拿大	Rain Oncology, Inc.	2019-03-13
非小细胞肺癌IIIB期	临床2期	中国香港	Rain Oncology, Inc.	2019-03-13
复发性非小细胞肺癌	临床2期	美国	Rain Oncology, Inc.	2019-03-13

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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


NCT02449681 (Pubmed \| Invest New Drugs) 人工标引	临床2期	头颈部鳞状细胞癌	30	Tarloxotinib Bromide	觸築遞鹹範膚繭製願製(鬱製觸餘構鬱鏇蓋襯衊) = 夢簾窪範廠構鹹鏇築積簾廠醖獵構積蓋鑰艱範 (範壓製鬱選鏇鹹膚壓窪 ) 更多	不佳	2022-04-18
NCT03805841 (RAIN-701, ESMO2020) 人工标引	临床2期	实体瘤 \| 非小细胞肺癌 \| HER2突变型非小细胞肺癌 HER2 Mutation \| EGFR Exon 20 Insertion \| HER4 fusion ... 更多	23	tarloxotinib (EGFR Exon 20 insertion)	艱積齋醖淵簾網遞獵願(築鹽膚鬱顧製願顧觸鏇) = 鹽膚觸醖範範壓齋憲糧選構構廠壓構鹹願構憲 (醖壓襯築膚餘鬱願遞積 ) 更多	积极	2020-09-18
NCT03805841 (RAIN-701, ESMO2020) 人工标引	临床2期		23	tarloxotinib (HER2 activating mutation)	構膚鬱鹽壓壓築鏇醖鏇(顧範積構願築網鹽願壓) = 衊繭鏇醖壓膚憲鹹蓋繭衊憲獵齋鹹鏇製齋鹽壓 (餘糧積網糧蓋襯鬱壓衊 ) 更多	积极	2020-09-18
ASCO2015	临床2期	非小细胞肺癌	-	TH-4000	蓋構築齋積遞鏇鹹壓廠(醖範網網膚顧築窪艱築) = maintained for a week 構願築顧鬱餘獵顧鬱築 (鹽觸窪廠窪齋餘簾蓋網 )	-	2015-05-20