Parsaclisib in Japanese patients with relapsed or refractory B‐cell lymphoma (CITADEL‐111): A phase Ib study

Abstract Parsaclisib, a potent, selective, next‐generation PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory B‐cell lymphoma. We undertook a phase Ib study (CITADEL‐111) evaluating safety, pharmacokinetics, and efficacy of parsaclisib in Japanese patients with relapsed or refractory B‐cell malignancies. Patients received oral parsaclisib daily for 8 weeks then once weekly (10‐mg dose, n = 3; 20‐mg dose, n = 14). Pharmacokinetic samples were collected on days 1, 8, and 15, and efficacy was monitored according to Lugano criteria. At data cut‐off (August 14, 2020), 6 patients (35.3%) remained on study treatment and 11 (64.7%) discontinued due to progressive disease (9 [52.9%]) or adverse events (2 [11.8%]). Median duration of treatment was 8.3 (range, 0.3–24.4) months. The most commonly reported nonhematologic adverse events were constipation (6 [35.3%]), nausea, and pyrexia (each 4 [23.5%]). Five patients (29.4%) experienced treatment‐emergent new or worsening decreased neutrophils to grade 3 or 4. No treatment‐emergent worsening in aminotransferase elevations to grade 3 or 4 were observed. Ten patients (58.8%) required dose interruption and 5 (29.4%) dose reduction. Body weight–normalized parsaclisib exposure was comparable between Japanese and Western patients. Objective response rate was 100% in follicular lymphoma (9 of 9 patients, including complete response in 2 patients [22.2%]) and marginal zone lymphoma (2 of 2 patients), and 16.7% in diffuse large B‐cell lymphoma (1 of 6 patients). Results observed in Japanese patients with relapsed or refractory follicular or marginal zone lymphoma support further clinical development of parsaclisib in these patient populations.

Parsaclisib is a next-generation PI3Kδ-selective inhibitor that is structurally different from early-generation PI3Kδ inhibitors, and has demonstrated activity in preclinical models of B-cell malignancy. 14 Results of the phase I/II CITADEL-101 study in a US patient population with relapsed or refractory B-cell malignancies indicated a differentiated safety profile from early-generation PI3K inhibitors with reduced hepatotoxicity observed when parsaclisib was given at a dose of 20 mg QD for 9 weeks, followed by 20 mg QW. 16 Parsaclisib has subsequently been investigated in phase II studies in patients with relapsed or refractory DLBCL, 17 FL, 18 MCL, 19,20 and MZL. 21 Here, we describe the results of a multicenter, open-label, phase Ib dose-escalation study of parsaclisib in Japanese patients with previously treated B-cell lymphoma (CITADEL-111).

| Study design
The purpose of this phase Ib study was to evaluate the safety and tolerability, including DLT and MTD, and pharmacokinetics of parsaclisib in Japanese patients with relapsed or refractory B-cell malignancies including DLBCL, FL, MZL, or MCL (CITADEL-111 study; NCT03314922; JapicCTI-184219). Eligible patients were enrolled between August 2018 and August 2020 at five centers in Japan.
The study was carried out according to the ethical principles of the Declaration of Helsinki and local regulatory requirements. All patients provided written informed consent prior to participation in any study-specific procedures.
The administration regimen consisted of initial daily doses of parsaclisib for 8 weeks followed by weekly administration of the same dose until disease progression or unacceptable toxicity. Patients were hospitalized for the first 28 days of treatment (DLT period).
To be considered evaluable for tolerability and MTD, patients must have received parsaclisib on a minimum of 23 out of 28 days or have experienced a DLT; patients who received fewer than 23 doses were permitted to be replaced to complete the cohort. Up to 18 patients were to be enrolled.
The starting dose of parsaclisib was 10 mg QD, which was half of the targeted starting dose for phase II studies based on the prior phase I/II CITADEL-101 study in a US patient population. 16 Dose escalation followed a 3 + 3 design and if no DLTs were observed in the initial three patients during the first 28 days of treatment, then the 20-mg dose cohort was initiated and at least 12 patients were treated at this dose to confirm safety if the MTD was not exceeded.
If a DLT was observed at the initial dose of 10 mg, then deescalation may be considered.
Dose-limiting toxicities were assessed by the investigator according to NCI Common Terminology Criteria for Adverse Events version 4.03 criteria, and included nonhematologic toxicity of grade 3 or above (with the exception of grade 3 or above nausea, vomiting, or diarrhea adequately controlled with medical therapy within 48 hours); any-grade anemia or thrombocytopenia requiring transfusion, grade 3 thrombocytopenia with bleeding; grade 4 anemia, neutropenia, or thrombocytopenia; febrile neutropenia; and general toxicity requiring dose interruption for more than 1 week or any dose reduction during the first 28 days of treatment. Maximum tolerated dose was defined as one dose level below the dose at which one-third or more of patients (two of six patients) in a cohort reported a DLT. If this lower dose level only had three patients treated, then an additional three patients would be enrolled to confirm a DLT rate at one or fewer of six patients to confirm this dose as the MTD.

K E Y W O R D S
B-cell lymphoma, Japan, non-Hodgkin lymphoma, parsaclisib, phosphatidylinositol 3-kinase Patients continued receiving parsaclisib treatment until disease progression, death, unacceptable toxicity, or consent withdrawal.

| Study cohort
Key eligibility criteria of this study were as follows: Japanese (can trace maternal and paternal Japanese ancestry) patients 20 years of age or older with histologically confirmed B-cell NHL (DLBCL, FL, MZL, or MCL); documented disease progression on at least one prior systemic therapy, with no further standard therapy available (as determined by the investigator); an ECOG performance status of no more than 2; adequate hematologic, hepatic, and renal function; life expectancy of more than 3 months; and willingness to undergo lymph node or tissue biopsy (or provide the most recent archival tissue).
Key exclusion criteria included allogeneic HSCT within the past 6 months or autologous HSCT within the past 3 months, active graft-versus-host disease, or prior treatment with a PI3K inhibitor.
Patients with a history of central nervous system lymphoma were also excluded.

| Study end-points and assessments
Primary study end-points were safety and tolerability, and phar-

| Statistical analysis
All treated patients comprised the full analysis set and the safety population, which included all patients enrolled in the study who re- All statistical analyses were undertaken using SAS ® software version 9 or later (SAS Institute).

| Patients
Seventeen patients were enrolled in this phase Ib study. Three patients were treated in the 10-mg QD + 10-mg QW dose group and 14 patients in the 20-mg QD + 20-mg QW dose group. The median age (range) was 71 (57-79) years, the majority of patients were women

| Pharmacokinetics and pharmacodynamics
At cycle 1 day 15, following 10-mg and 20-mg oral administration in the fasted state, the mean ± SD maximum plasma drug concentration of parsaclisib was 1440 ± 502 nM and 2630 ± 530 nM, achieved at a median time to maximum plasma drug concentration of 0.97 and 0.55 hours, respectively, with subsequent biexponential decay. The overall parsaclisib steady-state geometric mean t ½ was 9.9 hours and dose-independent, with a systemic accumulation ratio of approximately 1.3 with daily dose ( Table 3). The apparent oral dose clearance at steady state and volume of distribution were 2.2 ± 0.7 L/h and 31.2 ± 9.8 L, respectively. Mean ± SD Prior systemic therapies  (Table S1).
To assess the pharmacodynamic activity of parsaclisib, plasma samples collected from 15 patients were analyzed for changes in proteins associated with PI3Kδ inhibition. Analysis of approximately 1000 proteins in samples from patients with FL and MZL (n = 11) identified a set of 23 plasma proteins that were significantly changed following 4 weeks or 8 weeks of QD parsaclisib dosing (Table S2).
Among the set were multiple proteins previously reported as bio- whereas a subset of proteins showed significant fold-changes that were equivalent to FL and MZL patients (eg, MMP9, X-C chemokine ligand 1, and CD160).

| Safety
As of the data cut-off date, all patients experienced at least one with pyrexia being the most frequent, experienced by 2 patients

| Efficacy
The ORR was 100% in FL (9 of 9 patients) and MZL (2 of 2 patients), including 22.2% complete responses (2 of 9 patients) in FL; the ORR was 16.7% (1 of 6 patients) in DLBCL ( Table 6). The best percentage change of target lesions size from baseline for individual patients is shown in Figure 1

| DISCUSS ION
Parsaclisib is a next-generation PI3Kδ inhibitor that has been inves- Proteomic analysis of plasma samples confirmed pharmacodynamic response in a set of proteins enriched for factors involved in lymphocyte activation and immune response, including previously described pharmacodynamic biomarkers of PI3Kδ inhibition. 24,25 The majority of parsaclisib-responsive proteins were decreased in Japanese patients receiving treatment, with mean expression levels that were essentially unchanged between week 4 and week 8.
A majority of the same parsaclisib-responsive proteins were also identified in the earlier phase I/II CITADEL-101 study 16