A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid
Atish D Choudhury1, Celestia S Higano2, Johann S de Bono3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib.
Patients And Methods:
This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non-small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses.
Results:
In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction.
Conclusions:
AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway-dependent cancers.
Insights
The PI3Kβ inhibitor AZD8186 showed good safety and tolerability in patients with advanced solid tumors. Early results suggest limited antitumor activity when used alone or with abiraterone acetate or vistusertib.
Area of Science:
- Oncology
- Pharmacology
Background:
- The PI3K/AKT/mTOR pathway is crucial in cancer development.
- PI3Kβ is implicated in various solid tumors, including prostate and breast cancer.
- Targeting PI3Kβ offers a potential therapeutic strategy for specific cancers.
Purpose of the Study:
- To evaluate the safety and tolerability of AZD8186, a selective PI3Kβ inhibitor.
- To determine the recommended phase II dose (RP2D) of AZD8186.
- To assess the preliminary efficacy of AZD8186 in combination with abiraterone acetate or vistusertib.
Main Methods:
- Phase I open-label study in patients with advanced solid tumors (prostate, triple-negative breast, squamous NSCLC).
- Four study arms: AZD8186 monotherapy (dose finding and expansion), and combinations with abiraterone acetate or vistusertib.
- Primary endpoints: safety, tolerability, RP2D. Secondary endpoints: pharmacokinetics, pharmacodynamics, tumor response, PSA levels.
Main Results:
- 161 patients enrolled; AZD8186 was well tolerated with mainly gastrointestinal adverse events.
- Recommended phase II doses identified: 60-mg BID (5:2) and 120-mg BID (continuous and 5:2).
- Dose-proportional pharmacokinetics observed; preliminary antitumor activity and PSA reduction noted in prostate cancer.
Conclusions:
- AZD8186 monotherapy and combination therapies demonstrated acceptable safety and tolerability.
- Preliminary evidence of antitumor activity supports further investigation of AZD8186.
- AZD8186 warrants further study in PI3Kβ pathway-dependent cancers.
