A Multicenter, Open-Label, Dose-Escalation, Phase 1 Study of TAK-441, an Oral Hedgehog Signaling Pathway Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

This is the first study in which TAK-441 is administered to humans. The patient population will consist of adults aged 18 or older who have advanced nonhematologic malignancies and for whom standard treatment is no longer effective or does not offer curative or life-prolonging potential. Following completion of the dose escalation study, patients will be enrolled as part of 2 expansion cohorts.

开始日期2010-10-01

申办/合作机构

Millennium Pharmaceuticals, Inc.

100 项与 TAK-441 相关的临床结果

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100 项与 TAK-441 相关的转化医学

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100 项与 TAK-441 相关的专利（医药）

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项与 TAK-441 相关的文献（医药）

2022-10-01·JOURNAL OF INVESTIGATIVE DERMATOLOGY1区 · 医学

Aberrant Wnt Signaling Induces Comedo-Like Changes in the Murine Upper Hair Follicle

1区 · 医学

Article

作者: Tan, Alvin Yong Quan ; Shang, Wei ; Lim, Xinhong ; van Steensel, Maurice A M

Stem cell proliferation and differentiation must be carefully balanced to support tissue maintenance and growth. Defective stem cell regulation may underpin diseases in many organs, including the skin. LRIG1-expressing stem cells residing in the hair follicle junction zone (JZ) support sebaceous gland homeostasis. An emerging hypothesis from observations in both mice and human holds that imbalances in key stem cell regulatory pathways such as Wnt signaling may lead to abnormal fate determination of these LRIG1^+ve cells. They accumulate and form cystic structures in the JZ that are similar to the comedones found in human acne. To test the possible involvement of Wnt signals in this scenario, we used the Lrig1-CreERT2 mouse line to modulate Wnt signaling in JZ stem cells. We observed that persistent activation of Wnt signaling leads to JZ cyst formation, with associated sebaceous gland atrophy. The cysts strongly express stem cell markers and can be partially reduced by all-trans retinoic acid treatment as well as by Hedgehog signaling inhibition. Conversely, loss of Wnt signaling leads to enlargement of JZ, infundibulum, and sebaceous glands. These data implicate abnormal Wnt signaling in the generation of mouse pathologies that resemble human acne and respond to acne treatments.

2022-04-01·Journal of the American Academy of Dermatology

Notes & Comments on “Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and analysis”

Letter

作者: Vogt, Meagan ; Brocato, Jason ; Sethi, Anirudh ; Squittieri, Nicholas

Meta-anal. of.Several sonic hedgehog inhibitors (SHHis) in basal cell carcinomas.However, utility in meta-analyses remains limited for some such as sonidegib, itraconazole, and TAK-441 because of fewer studies compared with others such as vismodegib.Data were derived from varying numbers of studies: 14 for vismodegib, 2 for sonidegib, and 1 each for itraconazole and TAK-441.The authors state that response in the Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment (BOLT) trial was assessed using central Response Evaluation Criteria In Solid Tumor (RECIST) criteria.Adverse events and discontinuations were more frequent in the 800-mg group, resulting in a lower median duration of exposure (6.5 mo) vs patients receiving 200 mg.

2020-10-02·Cancer biology & therapy3区 · 医学

The use of hedgehog antagonists in cancer therapy: a comparison of clinical outcomes and gene expression analyses

3区 · 医学

Article

作者: Steg, Adam D. ; Kovac, Stefan ; Booker, Burthia E. ; Amm, Hope M. ; Landen, Charles N.

Hedgehog (HH) signaling, a critical developmental pathway, has been implicated in cancer initiation and progression. With vismodegib and sonidegib having been approved for clinical use, increasing numbers of HH inhibitors alone and in combination with chemotherapies are in clinical trials. Here we highlight the clinical research on HH antagonists and the genetics of response to these compounds in human cancers. Selectivity of HH inhibitors, determined by decreased pathway transcriptional activity, has been demonstrated in many clinical trials. Patients with advanced/metastatic basal cell carcinoma have benefited the most, whereas HH antagonists did little to improve survival rates in other cancers. Correlation between clinical response and HH gene expression vary among different cancer types. Predicting response and resistance to HH inhibitors presents a challenge and continues to remain an important area of research. New approaches combine standard of care chemotherapies and molecularly targeted therapies to increase the clinical utility of HH inhibitors.

100 项与 TAK-441 相关的药物交易

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