WX390, a high-potent PI3K-mTOR dual inhibitor, first-in-human (FIH) phase I study in advanced relapsed or refractory solid tumor, and lymphoma.

Abstract

3106 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. WX390 exhibited anti-tumor activity and high potency in xenograft models with inhibition of AKT phosphorylation. Methods: Patients (pts) with advanced lymphoma and solid tumors who have failed standard therapies were enrolled in dose escalation cohorts and received WX390 administered daily orally in 28-day cycles until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma samples were collected up to 7 days after the first dose and up to 24 hours at C1D28. Results: As of the cut-off date 2021 Feb 10, 25 patients (median age 52 years) were enrolled in 6 dose levels (0.1mg, 0.2mg, 0.4mg, 0.7mg, 1.1mg and 1.4mg) of the dose-escalation cohorts. Cohorts 0.1 mg to 1.1 mg were completed without dose-limiting toxicities (DLT), cohort 1.4 mg was completed with 1 DLT (Diabetic ketoacidosis combined with grade 3 hyperglycemia) out of 4 evaluable patients. Common treatment-related adverse events (TRAEs) (all grades, ≥20%) included hyperglycemia (20 pts, 80%), proteinuria (10 pts, 40%), creatinine increased (11 pts, 44%), hypophosphatemia (10 pts, 25%), anemia (8 pts, 33.3%), thrombocytopenia (7 pts, 29.2%), and aspartate aminotransferase increased (25%). Grade≥3 TRAEs were hyperglycemia (7 pts, 28%, 1 pt combined with diabetic ketoacidosis), hypophosphatemia (2 pts, 8%), neutropenia (2 pts, 8%), dermatitis (1 pt, 4%), and maculopapular rash (1 pt, 4%). PK showed fast absorption (Tmax 0.5-4 h) and dose proportionality for Cmax and AUC0-∞. The mean multiple dose T1/2 was approximately 12.4 hours across all cohorts with minimum accumulation. Among 14 tumor response evaluable patients, there were 3 patients with confirmed PIK3CA mutation. All 3 patients experienced tumor shrinkage and were still on treatment by the cut-off date. 2 (1 pt with head and neck cancer and 1 pt with cervical cancer) of them have achieved partial response (PR). The head and neck cancer patient (PR) was treated with WX390 0.7mg/day without any severe AE and the duration of response was beyond 15 months. Stable disease (SD) was observed in 6 patients (n = 5 with unknown PIK3CA mutation status and n = 1 with confirmed PIK3CA mutation). Of note, 1 patient (follicular lymphoma) treated with 0.1mg experienced SD for 14 months. Another patient (SD, head and neck cancer with PIK3CA mutation) experienced tumor shrinkage for more than 8 months and was still receiving WX390 treatment by the cut-off date. Conclusions: the PI3K-mTOR dual inhibitor WX390 was well tolerated with manageable safety profile, and showed encouraging antitumor activity. A RP2D of 1.1 mg qd is selected to be explored for different indications in solid tumor clinical studies. Clinical trial information: NCT03730142.