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AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20)

Background: Loss of PTEN function leads to increased PI3Kβ signaling. AZD8186, a selective PI3Kβ/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss.

Methods: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II.

Results: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility.

Conclusion: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.

 

Comments:

Based on the provided background and methods, the study aimed to evaluate the efficacy and safety of combining the selective PI3Kβ/δ inhibitor AZD8186 with paclitaxel in patients with advanced gastric cancer who had loss of PTEN function. PTEN loss leads to increased PI3Kβ signaling, and AZD8186 has shown promising results in preclinical models with PTEN deficiency.

The phase Ib part of the study involved patients with advanced solid tumors who received escalating doses of oral AZD8186 (60 mg or 120 mg, twice daily; 5 days on/2 days off) along with intravenous paclitaxel (70 mg/m2 or 80 mg/m2; on days 1, 8, and 15) in a 4-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination.

Based on the phase Ib results, both the MTD and RP2D were determined to be paclitaxel at a dose of 80 mg/m2 and AZD8186 at a dose of 120 mg BID.

In the phase II part of the study, patients with metastatic or recurrent gastric cancer (MRGC) and PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received the RP2D of AZD8186 plus paclitaxel. The primary endpoint in this phase was the 4-month progression-free survival (PFS) rate.

Eighteen patients were enrolled in the phase II part, with 17 having PTEN loss and 1 having a PIK3CB mutation. However, the 4-month PFS rate was found to be only 18.8% (3 out of 16 evaluable patients). Due to this limited clinical efficacy, further enrollment in the phase II part was stopped due to futility.

In conclusion, although the combination of AZD8186 and paclitaxel was well tolerated, it did not show significant clinical efficacy in patients with advanced gastric cancer and PTEN loss.

Related Products

Cat.No. Product Name Information
S7694 AZD8186 AZD8186 is a potent and selective inhibitor of PI3Kβ and PI3Kδ with IC50 of 4 nM and 12 nM, respectively. Phase 1.

Related Targets

PI3K