A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations Review
| Authors: | Rodón, J.; Funchain, P.; Laetsch, T. W.; Arkenau, H. T.; Hervieu, A.; Singer, C. F.; Murciano-Goroff, Y. R.; Chawla, S. P.; Anthony, K.; Yamamiya, I.; Liu, M.; Halim, A. B.; Benhadji, K. A.; Takahashi, O.; Delaloge, S. |
| Review Title: | A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations |
| Abstract: | PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations. Signaling paths control growth and activities inside cells. Overactivity in these paths can encourage many types of cancers to develop. Tumor suppressor proteins can inhibit cell signals that promote cancer. This protection can be lost if there are errors in any gene coding for a tumor suppressor protein. We are carrying out a clinical study to test TAS-117, a potential new oral medicine, in people who have solid tumors and whose cells have changes in their genes that inactivate a tumor suppressor protein called PTEN. TAS-117 targets part of a signaling path that may be overactive due to loss of PTEN activity. In early research, TAS-117 has shown promising activity against certain tumor types. Our trial will explore if TAS-117 can provide a new treatment for rare forms of cancer where genetic changes have led to a loss of PTEN activity. Clinical Trial Registration: NCT04770246 (ClinicalTrials.gov). |
| Keywords: | protein kinase b; genetics; clinical trial; neoplasm; neoplasms; metabolism; germ cell; phosphatidylinositol 3 kinase; germ cells; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; clinical trials, phase i as topic; clinical trials, phase ii as topic; pten protein, human; cowden syndrome; germ-line mutation; phase 2 clinical trial (topic); phase 1 clinical trial (topic); hamartoma syndrome, multiple; phosphatidylinositol 3-kinases; germline mutation; advanced solid tumor; humans; human; germline pten mutation; pten hamartoma tumor syndrome; pten inactivation; tas-117; 3-amino-1-methyl-3-(4-(3-phenyl-5h- imidazo(1,2-c)pyrido(3,4-e)(1,3)oxazin-2-yl)phenyl)cyclobutanol |
| Journal Title: | Future Oncology |
| Volume: | 18 |
| Issue: | 30 |
| ISSN: | 1479-6694 |
| Publisher: | Future Medicine |
| Date Published: | 2022-09-01 |
| Start Page: | 3377 |
| End Page: | 3387 |
| Language: | English |
| DOI: | 10.2217/fon-2022-0305 |
| PUBMED: | 36039910 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- Export Date: 1 December 2022 -- Source: Scopus |
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