A Phase 1b, Open Label, Dose Escalation Study of IOA-289, an Orally Bioavailable, Selective Autotaxin (ENPP2) Inhibitor Alone and in Combination with Gemcitabine/nab-paclitaxel in Patients with Metastatic Pancreatic Cancer

The objective of study IOA-289-102 is to evaluate the safety and tolerability of escalating doses of IOA-289 in patients with metastatic pancreatic cancer in combination with standard chemotherapy consisting of gemcitabine and nab-paclitaxel. Blood and tumour samples for PK and PD will be collected and assessments for determination of any clinical efficacy will be completed.

开始日期2022-10-10

申办/合作机构

iOnctura SA初创企业

NCT05027568

/ Completed临床1期

Randomized, Double-blind, Placebo-controlled, Dose Escalation Study for the Assessment of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Oral Doses of IOA-289 in Healthy Male Volunteers

The purpose of Part 1 of this First-in-Human trial is to evaluate the safety and tolerability after single ascending oral doses of IOA-289 given to healthy male subjects, compared to placebo. After the oral dose administrations, the amount of IOA-289 present in serum will be determined for pharmacokinetic characterisation. Also the reduction of LPA in plasma will be determined as a pharmacodynamic biomarker.
Part 2 is optional and its conduct will be dependent on the pharmacokinetic data generated in Part 1. Part 2 will be a randomized, crossover, open label, single oral dose administration of IOA-289 to healthy male subjects either in a fasted state, or after a high-fat meal.

开始日期2021-06-28

申办/合作机构

iOnctura SA初创企业

100 项与 Cambritaxestat 相关的临床结果

登录后查看更多信息

100 项与 Cambritaxestat 相关的转化医学

登录后查看更多信息

100 项与 Cambritaxestat 相关的专利（医药）

登录后查看更多信息

项与 Cambritaxestat 相关的文献（医药）

2025-02-04·MOLECULAR CANCER THERAPEUTICS

Pancreatic CAF-Derived Autotaxin Drives Autocrine CTGF Expression to Modulate Protumorigenic Signaling

Article

作者: Deken, Marcel A. ; Pacheco, Natalia ; Sandig, Hilary ; Di Conza, Giusy ; Taylor-Smith, Ewan ; Sousa, Bebiana C. ; Sharpe, Hayley J. ; Farrow, Stuart ; Rudge, Simon A. ; Lopez-Clavijo, Andrea F. ; van der Veen, Lars ; Maggs, Lauren Z. ; Shah, Pritom ; Taylor, Diane ; Clark, Jonathan ; Carruthers, Alan ; Volat, Fanny ; Price, Alice ; Medhi, Ragini ; Johnson, Zoë ; Andrews, Lauren ; Fraser, Amy

Abstract:

Autotaxin (ATX), encoded by ENPP2, is a clinical target in pancreatic ductal adenocarcinoma (PDAC). ATX catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME), yet the protumorigenic action of the ATX/LPA axis in PDAC remains unclear. In this study, by interrogating patient samples and cell line datasets, we show that the PDAC TME, rather than cancer cells, is responsible for the majority of ENPP2 expression and highlight a key role for cancer-associated fibroblast (CAF)-derived ATX in autocrine and paracrine protumorigenic signaling. Using the clinical-stage ATX inhibitor, IOA-289, we identified connective tissue growth factor (CTGF), also known as CCN2, as a downstream mediator of ATX signaling in the PDAC CAF-derived cell line, 0082T. Genetic ablation or pharmacologic inhibition of ATX in 0082T CAFs reduced CTGF secretion via modulation of LPA/LPA receptor signaling. Despite the loss of ATX function, extracellular levels of LPA were paradoxically increased, indicating a role for ATX beyond its enzymatic activity and suggesting a role for its LPA chaperone function in the LPA/LPA receptor signaling in CAFs. As CAFs are the main source for CTGF in the PDAC TME, these findings suggest a role for ATX in promoting a protumorigenic microenvironment via modulation of CAF secretion not only via its LPA-producing activity but also via its LPA chaperone function, providing a potential mechanism for the antitumor effects of ATX inhibition.

2024-01-02·Cancer research

Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma

Article

作者: De Vita, Veronica ; Di Conza, Giusy ; Fazzini, Federica ; Sabbadini, Fabio ; Bertolini, Monica ; Lahn, Michael ; Casalino, Simona ; Zecchetto, Camilla ; Merz, Valeria ; Scarlato, Enza ; Melisi, Davide ; Quinzii, Alberto ; Pietrobono, Silvia ; Mangiameli, Domenico ; Lunardi, Giulia

Abstract:

The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression-free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared with those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

Significance::

TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response.

2023-06-01·Immuno-oncology technology

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors

Article

作者: Niewola-Staszkowska, K ; Pergher, M ; Mikulčić, N ; Johnson, Z ; Di Conza, G ; Shah, P ; Ziviani, L ; Pickering, C ; van der Veen, L ; Peyruchaud, O ; Deken, M A ; Lahn, M ; Tagliavini, A ; Nizzardo, A ; Milleri, S ; Cheasty, A ; Antolić, M

Background:

Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile.

Materials and methods:

In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose.

Results:

In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA.

Conclusions:

Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

项与 Cambritaxestat 相关的新闻（医药）

2024-12-11

·PRNewswire

iOnctura reaches new clinical milestones in uveal melanoma

Completed Phase I DIONE-01 study demonstrates clinical activity and long-term safety of roginolisib, a unique allosteric modulator of PI3Kδ Patients with uveal melanoma showed a doubling of overall survival compared to historical controls Site activation ongoing for randomized Phase II OCULE-01 study in uveal melanoma GENEVA and AMSTERDAM, Dec. 11, 2024 /PRNewswire/ -- iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, today provides a clinical update on its lead asset, roginolisib. Results from the completed Phase I DIONE-01 study are due to be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) annual congress tomorrow, 12 December at 12:30 CET (presentation 164P). Allosteric modulator of PI3Kδ, roginolisib, has a unique chemical structure and binding mechanism which makes it highly specific for PI3Kδ, giving it an advantageous pharmacology profile and an unprecedented safety profile compared to previous generations of PI3Kδ inhibitors. Roginolisib is being investigated in solid and hematological malignancies including uveal melanoma (UM), a rare cancer of the eye. Eye melanoma is a rapidly growing market which is projected to be worth USD 9.56B by 2032[1]. The two-part Phase I study DIONE-01, firstly evaluated continuous daily dosing of roginolisib [at 10, 20, 40 and 80 mg] in 24 patients with pretreated solid tumors and follicular lymphoma (FL), and secondly evaluated a dose confirmation cohort in 20 UM patients. Results from DIONE-01 show: Study met its primary objective to determine the safety of the anticipated optimal biologically effective dose (BED): Roginolisib was well tolerated at the recommended Phase II dose (RP2D) of 80mg, with <7% Grade 3/4 treatment-emergent adverse events (TEAEs) considered to be related to roginolisib. TEAEs did not result in immune-related toxicity, or dose-limiting toxicity, in either solid tumor or hematological patients. In contrast to prior PI3Kδ inhibitors, roginolisib dosing did not require dose modifications. Roginolisib is well tolerated over long periods of treatment, up to 4.5 years. Median overall survival (OS) was 16 months for the 29 patients with UM treated with roginolisib, who had previously received a median of two prior therapies. This exceeds the median OS of 7 months observed in historical controls in patients receiving immunotherapies as second line treatment[2]. Median progression free survival (PFS) was 5 months for patients treated with roginolisib versus less than 3 months for historical controls2. Clinical findings validate the mechanism of action of roginolisib: roginolisib reduces immune-suppressive immune cells and chemokines, UM-related tumor clones (ctDNA) and PI3K-related signaling indicating a rebalancing of the immune system. Catherine Pickering, Chief Executive Officer of iOnctura, said: "The Phase I DIONE-01 data highlight the benefits of roginolisib for patients with uveal melanoma and advanced cancers. Roginolisib's unique allosteric binding mechanism has translated into a differentiated beneficial clinical profile, including a doubling of overall survival compared to historical controls in uveal melanoma. We are delighted to announce these data support progression of roginolisib into a randomized Phase II study." Professor Michele Maio, University of Siena and Principal Investigator of the roginolisib studies, added: "Being able to continue to investigate roginolisib in a randomized Phase II study is a positive step to understand more about this already well tolerated molecule. Roginolisib has given prolonged disease stabilization to patients with uveal melanoma who have exhausted all other therapeutic options. So far, these patients have maintained a good quality of life without major limitations. I'm looking forward to seeing what the Phase II trial delivers over the coming months." Activation of trial sites for the Phase II OCULE-01 study (NCT06717126) investigating roginolisib versus investigator's choice in the second-line+ treatment of uveal melanoma is ongoing. About iOnctura iOnctura is a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers with precision oral small molecules that target cancers in novel ways. The bold new treatments extend lives and improve healthspans, changing the outlook for patients and their families. Two therapeutic candidates have progressed into mid-stage clinical development: roginolisib is the first allosteric modulator of PI3Kδ; and cambritaxestat is the only autotaxin inhibitor in clinical development to treat cancer. iOnctura BV is headquartered in Amsterdam, The Netherlands with its wholly owned Swiss subsidiary, iOnctura SA, located in Geneva, Switzerland. iOnctura is backed by specialist institutional investors including Syncona, EIC Fund, M Ventures, Inkef Capital, VI Partners and Schroders Capital. About roginolisib Roginolisib is an allosteric modulator of PI3Kδ with a unique chemical structure and binding mode. The PI3K signaling pathway is one of the most commonly dysregulated pathways in cancer and the precise targeting of the PI3Kδ isoform delivers substantial anti-tumor effects with a low-toxicity profile. Clinical data have demonstrated roginolisib's excellent safety profile and sustained clinical activity in uveal melanoma (UM), a rare eye cancer with few available treatments. Site activation for the randomized Phase II OCULE-01 study in uveal melanoma is ongoing, and Phase II studies in other cancers, including non-small cell lung cancer and myelofibrosis, are in planning. [1] Emergen Research, Jan 2024 [2] Rantala et al., Melanoma Res., 2019 Dec 29(6):561-568 SOURCE iOnctura WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床1期临床2期临床结果免疫疗法

2024-07-09

·PRNewswire

iOnctura announces expansion of roginolisib clinical trial program to NSCLC

Phase II study in non-small-cell-lung-cancer (NSCLC) to be run in collaboration with the ETOP IBCSG Partners Foundation across sites in Europe Study will investigate dostarlimab + roginolisib +/- docetaxel in patients with NSCLC resistant to first-line checkpoint inhibitor therapy GENEVA and AMSTERDAM, July 9, 2024 /PRNewswire/ -- iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, today announces expansion of the clinical trial program for lead pipeline asset, roginolisib. Via clinical collaboration agreements with the ETOP IBCSG Partners Foundation and GSK, roginolisib will be evaluated in combination with dostarlimab in NSCLC. Roginolisib is an allosteric modulator of PI3Kδ, widely recognized as a 'master switch' of cancer. Inhibition of PI3Kδ unleashes a multi-pronged anti-tumor and immune response to combat the tumor1 . Roginolisib has demonstrated an unprecedented clinical profile in solid and liquid cancers2, with 44 patients treated to date. Emerging clinical and translational biomarker data supports the hypothesis that combining roginolisib with a programmed death receptor-1 (PD-1) targeting agent, with or without docetaxel, may prevent or reverse drug resistance in NSCLC and may show synergistic anti-tumor immune activity without significant addition of toxicity3. Dostarlimab is a PD-1-blocking antibody approved for certain patients with endometrial cancer, which has also demonstrated clinical activity in combination with chemotherapy in NSCLC4. Under the terms of the agreement with iOnctura, GSK will supply dostarlimab for use in a randomized Phase II clinical trial in NSCLC patients resistant to first-line checkpoint inhibitor therapy, with or without docetaxel. iOnctura will retain worldwide rights to roginolisib. The ETOP IBCSG Partners Foundation is a leading organization performing international clinical and translational research in thoracic malignancies and breast cancer. Through the clinical collaboration, iOnctura will be provided access to a network of highly experienced investigators for the Phase II study. Professor Solange Peters, MD, PhD, Chair of Medical Oncology and the Thoracic Malignancies Programme in the Department of Oncology at the University Hospital of Lausanne will be the primary coordinating investigator of the study. Catherine Pickering, Chief Executive Officer of iOnctura, said: "As iOnctura moves into the next phase of clinical development, we are thrilled to be able to assess the effectiveness of roginolisib in combination with dostarlimab for the treatment of NSCLC. The successful uveal melanoma data reported so far, combined with a rich preclinical data package, support the rationale to expand our development program with potentially synergistic combinations in NSCLC." Solange Peters, Professor and Chair of Medical Oncology & Thoracic Malignancies Programme in the Department of Oncology at the University Hospital of Lausanne in Lausanne, Switzerland, commented: "On behalf of the ETOP IBCSG Partners Foundation, we are intrigued by the benefit/risk profile of roginolisib. In patients who no longer respond to current therapies, we wish to investigate whether roginolisib in combination with dostarlimab provides a novel treatment option. ETOP IBCSG Partners Foundation is committed to investigate novel treatment options to help our patients." About iOnctura iOnctura is a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers with precision oral small molecules that target cancers in novel ways. The bold new treatments extend lives and improve healthspans, changing the outlook for patients and their families. Two therapeutic candidates have progressed into mid-stage clinical development: roginolisib is the first allosteric modulator of PI3Kδ and cambritaxestat is the only autotaxin inhibitor in clinical development to treat cancer. iOnctura BV is headquartered in Amsterdam, The Netherlands with its wholly owned Swiss subsidiary, iOnctura SA, located in Geneva, Switzerland. iOnctura is backed by specialist institutional investors including Syncona, EIC Fund, M Ventures, Inkef Capital, VI Partners and Schroders Capital. About roginolisib Roginolisib is the first allosteric modulator of PI3Kδ with a unique chemical structure and binding mode. The PI3K signalling pathway is one of the most commonly dysregulated pathways in cancer and the precise targeting of the PI3Kδ isoform delivers substantial anti-tumor effects with a low-toxicity profile. Clinical data have demonstrated roginolisib's excellent safety profile and sustained clinical activity in uveal melanoma (UM), a rare eye cancer with few available treatments. Randomized Phase II trials are planned to start in late 2024 in UM and other cancers, including non-small cell lung cancer and primary myelofibrosis. About the ETOP IBCSG Partners Foundation The ETOP IBCSG Partners Foundation was established through the merger of the European Thoracic Oncology Platform (ETOP) and the International Breast Cancer Study Group (IBCSG) (ETOP IBCSG Partners Foundation). The foundation, with its legal seat in Bern, Switzerland, has become a leading organization in performing international clinical research in thoracic malignancies and breast cancer. The ETOP IBCSG Partners Foundation is sponsoring and managing an increasing number of clinical trials and translational research projects in Europe and beyond. 1 AACR Volume 3, Issue 4, April 2023, Poster presentation, SITC 2022 2 Poster presentation, ESMO-IO 2023 3 Poster presentation, ESMO-IO 2023, Poster presentation EACR 2023 4 Lim, S.M. et al., Nat Commun 14, 7301 (2023) SOURCE iOnctura

临床2期引进/卖出

2024-07-09

·Pharmaceutical Technology

iOnctura expands PI3K inhibitor programme to NSCLC

The expansion to roginolisib’s clinical programme is via collaborations with ETOP IBCSG Partners Foundation and GSK. Image credit: Shutterstock/tomertu. Fresh from raising nearly $86m in financing last month, iOnctura will now start evaluating lead asset roginolisib in non-small cell lung cancer (NSCLC). The expansion to roginolisib’s clinical programme is via clinical collaboration agreements with the ETOP IBCSG Partners Foundation and GSK , iOnctura said in a 9 July press release. The Swiss biopharma iOnctura outlined plans for a Phase II study that will investigate roginolisib in combination with GSK’s PD-1 inhibitor Jemperli (dostarlimab). The combo therapy will be evaluated in NSCLC patients resistant to first-line checkpoint inhibitor therapy, with or without docetaxel. Roginolisib is an allosteric modulator of phosphoinositide 3-kinase-δ (PI3Kδ), which iOnctura says is “widely recognised as a ‘master switch’ of cancer.” Inhibition of the protein elicits an anti-tumour effect, which induces immune system activity against cancer cells. In January this year, roginolisib received an orphan drug designation from the US Food and Drug Administration (FDA). iOnctura is basing the combination with GSK’s programmed death receptor (PD-1) on “emerging clinical and translational biomarker data,” adding that it may prevent or reverse drug resistance in NSCLC. This enhanced anti-tumour immune activity would also be without significant addition of toxicity, according to the biopharma. See Also: Dupixent “addresses current gap” in COPD biologics landscape Peltopepimut-s by ISA Pharmaceuticals for Cervical Cancer: Likelihood of Approval Roginolisib is being evaluated in a Phase I clinical trial (NCT04328844) as a monotherapy and in combination with chemotherapy in patients with advanced or metastatic cancers, including metastatic uveal melanoma . The biopharma reported positive efficacy results at the 80mg dose, with grade 1 and 2 adverse events observed in the continuous daily dosing portion of the trial for patients with solid tumors. iOnctura’s CEO Catherine Pickering said: “The successful uveal melanoma data reported so far, combined with a rich preclinical data package, support the rationale to expand our development program with potentially synergistic combinations in NSCLC.” P13K inhibitors faced a setback in recent years after the FDA’s Oncologic Drugs Advisory Committee (ODAC ) lost confidence in the safety profile of the drugs. The agency recommended that future approvals of PI3K inhibitors for haematologic malignancy indications should require randomised trial data, as per a vote in 2022. The decision was based on high levels of fatal adverse events (AEs) and toxicity observed in patients taking the drug class. Roche made a recent advancement in the space, securing FDA priority review in breast cancer for the PI3K inhibitor inavolisib as a combination therapy with fulvestrant and Pfizer ’s Ibrance (palbociclib). iOnctura raised €80m ($85.8m) in Series B financing earlier this year, helping to fund Phase II activity for roginolisib and its other candidate cambritaxestat, autotaxin inhibitor.

临床1期临床结果孤儿药优先审批临床2期

100 项与 Cambritaxestat 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
转移性胰腺癌	临床2期	意大利	iOnctura SA初创企业	2022-10-10
转移性胰腺癌	临床2期	英国	iOnctura SA初创企业	2022-10-10
不能切除性胰腺癌	临床2期	意大利	iOnctura SA初创企业	2022-10-10
不能切除性胰腺癌	临床2期	英国	iOnctura SA初创企业	2022-10-10
胰腺导管腺癌	临床1期	英国	iOnctura SA初创企业	-
胃癌	临床1期	英国	iOnctura SA初创企业	-

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05586516 (ASCO2024) 人工标引	临床1/2期	转移性胰腺导管腺癌	13	IOA-289 (100 mg + Cohort 1)	獵窪顧襯膚鹹範鬱膚鏇(鬱網壓鹽獵獵遞鏇壓遞) = None 窪艱鹹衊構積壓構蓋選 (窪廠襯廠襯餘餘製積觸 ) 更多	积极	2024-05-24
NCT05586516 (ASCO2024) 人工标引	临床1/2期	转移性胰腺导管腺癌	13	IOA-289 (200 mg + Cohort 2)	獵窪顧襯膚鹹範鬱膚鏇(鬱網壓鹽獵獵遞鏇壓遞) = None 窪艱鹹衊構積壓構蓋選 (窪廠襯廠襯餘餘製積觸 ) 更多	积极	2024-05-24
ATS2021	N/A	肺纤维化	-	IOA-289	夢積壓鏇艱願願鹽窪糧(獵夢鹽鬱衊齋艱齋鹹衊) = 衊膚憲膚築淵築壓範築範壓糧繭艱鹹鬱獵醖鹽 (鹽鹹鹹淵憲獵糧壓繭築 )	-	2021-05-03