A phase i study of a selective PI3Kδ inhibitor YY-20394 in patients with relapsed or refractory B-cell malignancies

Background: YY-20394, an oral highly selective PI3Kδ inhibitor was studied in a phase I trial for patients with relapse or refractory B-cell malignancies. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YY-20394. Methods: YY-20394 was given orally once daily (QD) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Only 1 subject was treated with starting dose 20 mg once daily, then subsequent cohorts used a 3+3 design and evaluated doses of 40, 80, 140 and 200 mg QD. Once a recommended Phase II (RP2D) dose is determined, a separate dose expansion part will enroll up to 12 patients at the RP2D. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria.Results: 22 patients were enrolled as of Jan 14th 2019. The patients including diffuse large B-cell lymphoma (DLBCL), n=2; follicular lymphoma (FL), n=8; follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL), n=3; mantle cell lymphoma (MCL), n=3; lymphoplasmacytic lymphoma (LPL), n=1; marginalzone B-cell lymphoma (MZBL), n=1 and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), n=4, received YY-20394 20 mg (n=1), 40 mg (n=3),80 mg (n=11),140 mg/day (n=3) or 200 mg/day (n=4) respectively. All the patients had heavy treatment and had received an average of 3.5 lines of therapy before participating in the current study including BTK inhibitor therapy and CAR-T treatment. All the patient have completed cycle 1 safety observation and no dose-limiting toxicities occurred. The most common nonhematologic TEAEs (all grades/grade≥3) were LDH elevation (36.4%/0%), pneumonia (18.2%/18.2%) and hyperuricemia (13.6%/4.5%). Gr≥3 hematologic TEAEs were neutropenia (13.6%), lymphocythaemia (9.1%), leukocytosis (4.5%) and leukopenia (4.5%). Of 19 patients evaluable for response, the overall objective response rate was 68% ((4CR + 9 PR)/19), with 86% ((3CR + 3PR)/7) in FL. The median duration of response is not available so far, the treatment for 11 subjects was still ongoing. The duration of response in 4 subjects with ongoing treatment has already over 8 months. PK parameters AUC0-24h and Cmaxwere dose proportional with median Tmax 2 hours. Conclusions:YY-20394 is well tolerated and with promised objective response rates in patients with relapsed or refractory B-cell malignancies.