To the editor

The selective PIP2 3-kinase δ (PI3Kδ) inhibitor idelalisib in combination with rituximab [1,2,3] and the PI3K-δ/γ inhibitor duvelisib (IPI-145) [4] have been approved to treat B-cell malignancies. In addition, a selective PI3Kδ inhibitor parsaclisib (INCB050465) is undergoing phase 2 trials [5, 6]. We report the first-in-human clinical investigation of YY-20394, a novel PI3Kδ-selective inhibitor, in a dose escalation study in patients with relapsed or refractory B-cell malignancies to evaluate its safety, pharmacokinetic (PK) parameters and efficacy.

YY-20394 [N-[5-[6-fluoro-8-[[4-(1-hydroxy-1-methylethyl)-1-piperidinyl]methyl]-2-(4-morpholinyl)-4-quinazolinyl]-2-methoxy-3-pyridinyl]-methanesulfonamide] is structurally different from idelalisib, and is a potent PI3Kδ inhibitor (IC50: 4.6 nM) with less activity against PI3Kγ giving a kinase inhibition profile that is more PI3Kδ-selective by nearly 2 orders of magnitude (Additional file 1: Table S1).

Patients ≥ 18 years old with refractory or relapsed B-cell malignancies were enrolled from November, 2017 to completion of the trial in November, 2019. Inclusion and exclusion criteria are listed in Additional file 2 and baseline patient characteristics in Additional file 3: Table S2.

Of the 27 enrolled patients, 25 were evaluable including 10 follicular lymphoma (FL), 4 mantle cell lymphomas (MCL), 4 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 2 diffuse large B-cell lymphoma (DLBCL), 3 DLBCL/FL, 1 marginal zone lymphoma (MZL) and 1 lymphatic plasma cell lymphoma (LPL) patients. During dose escalation, patients received YY-20394 tablets q.d. at dosages of 20, 40, 80, 140 or 200 mg. The maximum tolerated dose (MTD), dose escalation phase and dose-limiting toxicity (DLT) as well as hematological toxicity classifications are described in Additional file 4. The primary endpoints were safety, tolerability and the MTD of YY-20394. Secondary endpoints were PK parameters and efficacy. Response criteria followed the revised International Research Working Group (IRWG) for non-Hodgkin lymphomas (NHL) [7], and the International Working Group on Chronic Lymphocytic Leukemia (IWCLL) criteria for CLL [8]. Efficacy determinations were the objective response rate (ORR), disease control rate (DCR), complete remission (CR), partial remission (PR), stable disease (SD), progressive disease (PD) and progression-free survival (PFS).

The safety evaluation of YY-20394 included adverse events (AEs) and serious AEs (SAEs) by standard categorizations. All 25 patients had at ≥ 1 AE. Thirteen (52.0%) and 9 (36.0%) patients experienced SAEs and drug-related AEs. The drug-related AEs that occurred in ≥ 20% of patients were neutropenia (68.0%), leukopenia (44.0%), elevated lactate dehydrogenase (44.0%), elevated α-hydroxybutyrate dehydrogenase (24.0%), thrombocytopenia (20.0%) and hyperuricemia (20.0%). Those that occurred in ≥ 5% of patients are also listed (Table 1). Among 32 ≥ grade III AEs, most were grade III; 3 cases of grade IV hyperuricemia and 4 grade IV neutropenia, but no grade V AEs occurred. Overall, YY-20394 had a manageable safety profile. It is noteworthy that unlike other PI3K inhibitors, the incidence of diarrhea, colitis, and hepatotoxicities [9] was very low.

Table 1 Drug-related adverse events occurring in ≥ 5% of evaluable patients at grade III or greater
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After single administrations of YY-20394 (20 to 140 mg), terminal elimination was consistent and in vivo exposure increased proportionally in a dose-dependent manner (Cmax, AUC0-t, AUC0-∞) (Additional file 5: Table S3). Also, the PK parameters after multiple administrations revealed that the exposure of YY-20394 (Cmax, AUC0-t, AUC0-∞) increased with dosage (20 to 200 mg) (Additional file 6: Table S4). The 80 mg dose level produced a serum concentration of YY-20394, corresponding to 90% inhibition of basophil activation in vitro.

YY-20394 treatment produced an overall 64.0% ORR (16/25) (95%confidence interval (CI): 45.2, 82.8%) and a 72.0% DCR (18/25) (95%CI: 54.4, 89.6%) in B-cell malignancies, including 5 CR, 11 PR, 2 SD and 7 PD cases. Notably, in the FL patients, a 90% ORR (9/10) (95%CI: 71.4, 100.0) and 90% DCR (9/10) (95%CI: 71.4, 100.0) were found (Fig. 1a), with 3 CR (80 mg), 6 PR (1/40 mg and 5/80 mg) and 1 PD (200 mg) (Fig. 1b), with a median PFS time of 300 days. The median PFS was 255 days when all evaluable patients data were combined, with the longest treatment duration being 36 months (40 mg, CLL/ SLL patient) (Fig. 1c).

Fig. 1
figure 1

Efficacy evaluation of YY-20394 treatments in the dose escalation study of B-cell malignancies. a Overall efficacy chart of YY-20394. b Waterfall plot of overall tumor changes from baseline #indicates transient staging with ongoing treatment at the end of the study period. c PFS curve (days) in the 5 patient dosing groups. Note: CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LPL, Lymphatic plasma cell lymphoma; MCL, mantle cell lymphoma; MZL marginal zone lymphoma; PD, progressive disease; PR, partial remission; SD, stable disease

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From the combination of safety, PK, ORR and DOR data, the recommended phase 2 dose for YY-20394 monotherapy was established at 80 mg q.d.

With its excellent efficacy and tolerability in aggressive lymphomas the clinical development of YY-20394 as a novel treatment for relapsed or refractory hematological malignancies is warranted.