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.

Start Date12 Oct 2023

Sponsor / Collaborator-

NCT05313009 / TerminatedPhase 1/2IIT

A Phase Ib / II Trial of Tarloxotinib and Sotorasib in Patients With KRAS G12C Mutations

This is a Phase IB dose expansion trial with safety lead-in evaluating the safety, clinical activity/efficacy of the combination of tarloxotinib and sotorasib in patients with KRAS G12C mutation who have progressed on any small molecule targeting KRAS G12C mutant Non-Small Cell lung cancer.

Start Date07 Mar 2022

Sponsor / Collaborator

Medical University of South Carolina

[+1]

NCT03805841 / TerminatedPhase 2

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

Start Date13 Mar 2019

Sponsor / Collaborator

Rain Oncology, Inc.

100 Clinical Results associated with Tarloxotinib Bromide

100 Translational Medicine associated with Tarloxotinib Bromide

100 Patents (Medical) associated with Tarloxotinib Bromide

Literatures (Medical) associated with Tarloxotinib Bromide

01 Aug 2022·Investigational New DrugsQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: 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).

01 Aug 2021·Translational lung cancer researchQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Ohara, Shuta ; Fujino, Toshio ; Koga, Takamasa ; Mitsudomi, Tetsuya ; Tirunagaru, Vijaya ; Vellanki, Avanish ; Doebele, Robert C ; Soh, Junichi ; Suda, Kenichi ; 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.

01 May 2021·Thoracic cancerQ3 · MEDICINE

Activity of tarloxotinib‐E in cells with EGFR exon‐20 insertion mutations and mechanisms of acquired resistance

Q3 · MEDICINE

ArticleOA

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

Abstract:

Background:

Approximately 10% of non‐small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in‐frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR‐tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia‐activated prodrug that releases a potent, irreversible pan‐ERBB TKI (tarloxotinib‐E) under solid tumor hypoxia.

Methods:

We examined the efficacy of tarloxotinib‐E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib‐E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib‐E by establishing cells with resistance to tarloxotinib‐E via chronic drug exposure after N‐ethyl‐N‐nitrosourea mutagenesis treatment.

Results:

Among all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib‐E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib‐E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR‐TKIs. As acquired resistance mechanisms to tarloxotinib‐E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation.

Conclusions:

These findings indicate that tarloxotinib‐E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib‐E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.

News (Medical) associated with Tarloxotinib Bromide

23 Apr 2021

·endpts.com

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

CollaborateSmall molecular drugIPO

07 Apr 2021

·www.biospace.com

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

09 Dec 2015

·www.pmlive.com

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".

Phase 2Phase 3License out/in

100 Deals associated with Tarloxotinib Bromide

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14944

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	US	Rain Oncology, Inc.	13 Mar 2019
Advanced Malignant Solid Neoplasm	Phase 2	CA	Rain Oncology, Inc.	13 Mar 2019
Advanced Malignant Solid Neoplasm	Phase 2	HK	Rain Oncology, Inc.	13 Mar 2019
metastatic non-small cell lung cancer	Phase 2	US	Rain Oncology, Inc.	13 Mar 2019
metastatic non-small cell lung cancer	Phase 2	CA	Rain Oncology, Inc.	13 Mar 2019
metastatic non-small cell lung cancer	Phase 2	HK	Rain Oncology, Inc.	13 Mar 2019
Non-small cell lung cancer stage IIIB	Phase 2	US	Rain Oncology, Inc.	13 Mar 2019
Non-small cell lung cancer stage IIIB	Phase 2	CA	Rain Oncology, Inc.	13 Mar 2019
Non-small cell lung cancer stage IIIB	Phase 2	HK	Rain Oncology, Inc.	13 Mar 2019
Recurrent Non-Small Cell Lung Cancer	Phase 2	US	Rain Oncology, Inc.	13 Mar 2019

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02449681 (Pubmed \| Invest New Drugs) Manual	Phase 2	Squamous Cell Carcinoma of Head and Neck	30	Tarloxotinib Bromide	ipybbkewje(qqujupserw) = qvscqdwqen dsmsnbdtfs (wfvbxayetz ) View more	Negative	18 Apr 2022
NCT03805841 (RAIN-701, ESMO2020) Manual	Phase 2	Solid tumor \| Non-Small Cell Lung Cancer \| HER2 mutant non-small cell lung cancer HER2 Mutation \| EGFR Exon 20 Insertion \| HER4 fusion ... View more	23	tarloxotinib (EGFR Exon 20 insertion)	ufyarfzkin(behhyenkva) = rsafojulkv glkrxhvmjr (jvjemykbus ) View more	Positive	18 Sep 2020
NCT03805841 (RAIN-701, ESMO2020) Manual	Phase 2		23	tarloxotinib (HER2 activating mutation)	zjxwogikgm(wqdnixnrqh) = hxbtghuxcg srlmujfqjo (dgqavisluk ) View more	Positive	18 Sep 2020
ASCO2015	Phase 2	Non-Small Cell Lung Cancer	-	TH-4000	zynrrzqyfw(zwesfowlye) = maintained for a week xtxxinlawy (idszzcwtrx )	-	20 May 2015

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