Preliminary Results from a Phase I, First-in-Human Study of YY-20394, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies

Introduction: Aberrant activation of the PI3Kδ pathway is associated with increased malignant B-cell proliferation and survival. Recently, several PI3Kδ inhibitors have been reported to play a role in B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL) by mediating abnormal B-cell growth and survival. YY-20394, a novel small molecule, is a highly selective and highly potent PI3Kδ inhibitor. The current study is a phase I, first-in-human, dose escalation study to assess the safety, tolerability, and efficacy of YY-20394 in patients with relapse or refractory B-cell malignant hematological tumor (Chinadrugtrials.org.cn ID: CTR20170995).

Methods: Adult patients were eligible for study participation if they had relapsed or refractory lymphoid B-cell malignancies, ECOG ≤2, normal hepatic and renal function, and no autologous hematopoietic stem-cell transplant (HSCT) within 3 months of screening. YY-20394 was given orally once daily until disease progression, unacceptable toxicity, or withdrawal from the study. The protocol was initiated with a single-patient cohort, treated with oral YY-20394 20 mg once daily (QD). Subsequent cohorts used a 3+3 design and evaluated doses of 40-320mg QD. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria.

Results: The study enrolment is still ongoing. As of Jul. 14, 2018, total of 10 patients were enrolled. The patients including diffuse large B-cell lymphoma, n=1; follicular lymphoma, n=5; mantle cell lymphoma, n=1; lymphoplasmacytic lymphoma, n=1 and CLL , n=2, received YY-20394 20 mg (n=1), 40 mg (n=3), 80 mg (n=3) or 140 mg/day (n=3) respectively; All the patients had heavy treatment before participating in the current study including BTK inhibitor therapy (n=3) and CAR-T treatment (n=2). All the patient have completed cycle 1 safety observation and no dose-limiting toxicities occurred.

The most common nonhematologic TEAEs (all grade [Gr]; Gr ≥3) were LDH elevation (30%; 0%), dizzy (10%; 0%), pneumonia (10%; 10%), alopecia (10%; 0%), and hyperuricemia (10%; 0%). Gr ≥3 hematologic TEAEs were neutropenia (10%) and lymphocythaemia (20%). 1 Serious AEs were reported as grade 3 pulmonary infection after the patient received 2 cycles treatment, it is still unknown if the SAE is related with the study drug. The pulmonary infection has been improved after anti-inflammation treatment.

Of 10 patients treated, 71.4% of overall response rate and 100% of disease control rate were achieved in 7 patients who were available for efficacy evaluation, including 1 CR (80 mg, FL) , 4 PR (40 mg, n=2 with FL and CLL respectively; 80 mg, n=2 with FL and DLBCL respectively and 2 SD ( 20 mg with MCL, n=1 and 40 mg with CLL ,n=1 respectively. The PK results demonstrated dose-proportional increase in plasma concentrations.

Conclusion: YY-20394 is well tolerated and with promised objective response rates in patients with relapsed or refractory B-cell malignancies. The current first-in-human study for dose escalation and dose expansion is still ongoing.