A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Abstract

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.

Figure 1.

Summary of treatment-related AEs* by maximum reported CTCAE grade in the monotherapy (A) dose-finding and (B) dose-expansion arms (safety analysis set). *, AEs considered by the investigator to be related to AZD8186 treatment occurring in ≥10% of patients in the dose-finding or dose-expansion arms, respectively. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; ECG QT, electrocardiogram QT interval

Figure 2.

Assessment of PD biomarkers after treatment with AZD8186 (PD analysis set; pooled data for 60-mg and 120-mg BID cohorts). Mean ratio of (A) pAKT (S473):tAKT(S473); (B) pAKT (T308):tAKT (T308); and (C) pGSK3β:tGSK3β over time in platelet-rich plasma (AZD8186 monotherapy arms). Total H-scores (top) and the percentage of change from baseline (bottom) are shown for (D) membranous pAKT (S473) and (E) pPRAS40 in individual patients*. Examples of membrane (F) pAKT scoring by DIA and (G) pPRAS40 scoring pre-treatment and 4 hours after dose at C1W2^† (PD analysis set). C1D1, cycle 1 day 1; C1W2, cycle 1 week 2; DIA, digital image analysis; p, phosphorylated; t, total. ^*, Data for individual patients shown as different colors; ^†, On-treatment tumor biopsies were collected in week 2, after dose on days 11 or 12 for 5 days on/2 days off schedule or after dose on days 11–14 for continuous schedule.

Figure 3.

Best response for (A) target lesions, based on RECIST (n = 12 with measurable disease), and (B) PSA concentration (n = 30 evaluable for response) by patient and dose in the efficacy-evaluable analysis set (AZD8186/abiraterone acetate combination arm). *, Response was not confirmed at follow-up scan.