A phase I study of AZD8186 in combination with docetaxel in patients with PTEN-mutated or PIK3CB-mutated advanced solid tumors Journal Article
| Authors: | Schram, A. M.; Takebe, N.; Chen, A.; Zhou, Q.; Iasonos, A.; Silber, J.; Reynolds, M.; Hussain, S.; Gavriliuc, M.; Smyth, L. M.; Garrison, D.; Dumbrava, E. E. |
| Article Title: | A phase I study of AZD8186 in combination with docetaxel in patients with PTEN-mutated or PIK3CB-mutated advanced solid tumors |
| Abstract: | <p>Background: Loss of PTEN activity is common in solid tumors and promotes cancer growth through activation of the PI3K pathway. PTEN-deficient tumors have increased dependence on PI3Kf and are sensitive to PI3Kf inhibition in preclinical models. Efficacy is further enhanced by the addition of taxane chemotherapy. We conducted a phase I trial of AZD8186, a small molecule inhibitor of PI3Kf and PI3K8, in combination with docetaxel (Taxotere) Material and methods: Patients with advanced PTEN- or PIK3CB-mutated solid tumors identified through local testing were eligible. Treatment included docetaxel intravenously every 21 days and AZD8186 orally twice daily, 5 days on and 2 days off. Primary objectives were safety, tolerability, and maximum tolerated dose (MTD) as determined by a 3 + 3 dose-escalation design. Secondary objectives included assessment of antitumor activity. Results: Twenty-three patients were enrolled with 11 distinct tumor types across 5 dose levels. Clinically significant neutropenia led to dose-level adjustment and the addition of prophylactic growth factor. The MTD was not reached and AZD8186 120 mg twice daily with docetaxel 75 mg/m2 was named the recommended phase II dose. The most common treatment-emergent adverse events (TEAEs) were anemia (57%), diarrhea (43%), and fatigue (43%). The most common grade >= 3 TEAE was neutropenia (30%). One patient with docetaxel-naive prostate cancer had a prolonged partial response (overall response ratio 5.6%); clinical benefit rate was 22.2%. Conclusions: The combination of AZD8186 and docetaxel was generally well tolerated, with the exception of neutropenia, which was effectively managed with the use of growth factor. Limited clinical activity was observed.</p> |
| Keywords: | neutropenia; solid tumor; breast; docetaxel; pten; pharmacokinetics; activation; pathway; trastuzumab resistance; selective inhibitor; cancer; basket trial; tensin homolog; pik3cb; azd8186; p110-beta isoform |
| Journal Title: | ESMO Open |
| Volume: | 10 |
| Issue: | 9 |
| ISSN: | 2059-7029 |
| Publisher: | European Society for Medical Oncology |
| Date Published: | 2025-09-01 |
| Language: | English |
| ACCESSION: | WOS:001571210800001 |
| DOI: | 10.1016/j.esmoop.2025.105569 |
| PROVIDER: | wos |
| Notes: | Article -- 105569 -- Source: Wos |
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