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| Ref Type | Journal Article | ||||||||||||
| PMID | (40939237) | ||||||||||||
| Authors | Schram AM, Takebe N, Chen A, Zhou Q, Iasonos A, Silber J, Reynolds M, Hussain S, Gavriliuc M, Smyth LM, Garrison D, Dumbrava EE | ||||||||||||
| Title | A phase I study of AZD8186 in combination with docetaxel in patients with PTEN-mutated or PIK3CB-mutated advanced solid tumors. | ||||||||||||
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| Abstract Text | 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 PI3Kβ and are sensitive to PI3Kβ 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 PI3Kβ and PI3Kδ, in combination with docetaxel (Taxotere) (NCI 10131; NCT03218826).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.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%.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. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| PTEN inact mut | Advanced Solid Tumor | no benefit | AZD8186 + Docetaxel | Phase I | Actionable | In a Phase I trial, treatment with the combination of AZD8186 and Taxotere (docetaxel) was generally well tolerated but demonstrated limited efficacy with an overall response rate of 5.6% (1/18), clinical benefit rate of 22.2% (4/18), and median progression-free survival of 3 months in patients with advanced solid tumors harboring PTEN inactivating mutations (n=21) or PIK3CB activating mutations (n=3) (PMID: 40939237; NCT03218826). | 40939237 |