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First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors
Xiao-Li Wei1, Fu-Rong Liu2, Ji-Hong Liu3
1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
Abstract:
PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.
Insights
A phase Ia study of CYH33, a PI3Kα inhibitor, in advanced solid tumors found a manageable safety profile. The recommended dose for further trials was established, showing preliminary anti-tumor efficacy in patients with PIK3CA mutations.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- PIK3CA mutations are common in solid tumors, making PI3Kα a therapeutic target.
- CYH33 is a selective inhibitor of PI3Kα developed for cancer treatment.
Purpose of the Study:
- To assess the safety, tolerability, and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33.
- To evaluate the pharmacokinetics, preliminary efficacy, and pharmacodynamic biomarkers of CYH33 in patients with advanced solid tumors.
- To explore the correlation between CYH33 efficacy and tumor biomarker status, particularly PIK3CA mutations.
Main Methods:
- A phase Ia, open-label, dose-escalation and -expansion study (NCT03544905) was conducted.
- 51 patients with advanced solid tumors received CYH33 at doses ranging from 1-60 mg.
- Safety, tolerability, MTD, RP2D, pharmacokinetics, pharmacodynamics, and preliminary efficacy were assessed.
Main Results:
- The MTD and RP2D of CYH33 were determined to be 40 mg once daily.
- Common grade 3/4 adverse events included hyperglycemia, rash, and fatigue.
- The confirmed objective response rate was 11.9% in all evaluable patients and 14.3% in patients with PIK3CA mutations.
Conclusions:
- CYH33 demonstrates a manageable safety profile in patients with advanced solid tumors.
- The study established the MTD and RP2D for CYH33, supporting its further investigation.
- Preliminary anti-tumor activity was observed, particularly in patients with PIK3CA-mutated tumors, warranting further clinical development.
