Phase I study of duvelisib in Japanese patients with relapsed or refractory lymphoma

Duvelisib is a novel dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ. This single-arm, multicenter phase I study investigated its safety, pharmacokinetics, and preliminary efficacy in Japanese patients with relapsed or refractory lymphoma. Duvelisib was administered orally twice daily at 25 mg in 28-day cycles. Seven patients, comprising 4 with follicular lymphoma (FL), 2 with diffuse large B-cell lymphoma, and 1 with mantle cell lymphoma (MCL) were enrolled. No dose-limiting toxicity occurred in any patient. The most commonly experienced treatment-related adverse events of any grade were neutropenia and thrombocytopenia, occurring in 3 patients each (42.9%); followed by lymphopenia, diarrhea, enterocolitis, stomatitis, hepatic function abnormal, ALT increased, and AST increased, occurring in 2 patients each (28.6%). The most common grade ≥ 3 treatment-related adverse events were neutropenia, which occurred in 3 patients (42.9%), and thrombocytopenia, lymphopenia, and hepatic function abnormal, which occurred in 2 patients each (28.6%). One patient with FL achieved a complete response; the remaining 3 with FL and the 1 with MCL achieved a partial response. The overall response rate was 71.4% (5/7 patients). Duvelisib was well tolerated in Japanese patients with relapsed or refractory lym- phoma. Safety and preliminary efficacy data support further development of duvelisib in Japanese patients.
Keywords Clinical trial · PI3K · Japanese · Lymphoma · Duvelisib

Duvelisib is a novel dual inhibitor of phosphoinositide-3-ki- nase (PI3K)-δ and -γ. Phosphoinositide-3-kinase is a lipid kinase involved in intracellular signal transduction in many types of cell. The isoforms of its catalytic subunit (p110) exist as α, β, δ, and γ, with the δ and γ isoforms being pref- erentially expressed in leukocytes and involved in innate and adaptive immune function [1–4]. The pathways medi- ated by PI3K-δ and -γ contribute to survival, proliferation, and differentiation of cancer cells in patients with advanced hematologic malignancies.Phosphoinositide-3-kinase-δ and -γ are also involved in the establishment and maintenance of the tumor microenvi- ronment (TME), which plays an important role in the devel- opment and maintenance of cancer cells [5, 6]. Accordingly, we presumed that inhibition of PI3K-δ and -γ would disrupt tumor progression. One in vivo study demonstrated that dual inhibition of PI3K-δ and -γ using isoform-selective inhibi- tors reduced tumor growth more than inhibition of either PI3K-δ or -γ alone [7].These data indicate that duvelisib inhibits tumor growth synergistically, suggesting that it is superior to other isoform-selective inhibitors.In a phase I study in advanced hematologic malignan- cies in the US, the dose of duvelisib was escalated from 8 mg to 100 mg twice daily (BID) and the maximum tol- erated dose (MTD) determined to be 75 mg. Biological activity was not dose-dependent, and maximized at 25 mg. In addition, no notable difference was seen in the safety profile of duvelisib by dose level [8]. The biological effec- tive dose, which was one third of the MTD (75 mg BID), was well tolerated and showed efficacy in patients with chronic lymphocytic leukemia (CLL) or indolent non- Hodgkin’s lymphomas [8].
The purpose of the present phase I study was to inves- tigate the safety, pharmacokinetics (PK), and efficacy of duvelisib 25 mg BID in Japanese patients with relapsed or refractory (r/r) lymphoma.

This was an open-label, single-arm, multicenter study. The primary endpoints were safety and PK; the second- ary endpoint was efficacy. Duvelisib was administered orally at 25 mg BID in 28-day cycles. No dose escalation was planned. In patients in whom duvelisib 25 mg BID was not tolerated, the dose was reduced to 15 mg BID (reduction level-1) or 10 mg once daily (reduction level-2). Patients received a concomitant Pneumocystis prophylaxis in accordance with institutional guidelines.The study treatment was continued until disease pro- gression, adverse events that require discontinuation of duvelisib, voluntary withdrawal by patient, or decision by the investigator or sponsor.All patients signed informed consent to participate in the study. The study was approved by the institutional review boards of investigators sites. This study was regis- tered at ClinicalTrials.gov (NCT02598570).All the patients were Japanese and aged 20 years or older. The key inclusion criteria included the following: diagno- sis of lymphoma of any subtype (excluding lymphoblas- tic lymphoma); an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2; measurable disease with a lymph node or tumor mass > 1.5 cm in at least 1 dimension; progression during, refractory to, or intolerant of established therapies, or the presence of a disease for which there was no standard treatment (no limit on maximum number of prior treatment regimens). The key exclusion criteria included the following: any prior treatment with a PI3K or Bruton’s tyrosine kinase (BTK) inhibitor; ongoing treatment with chronic immune sup- pressants (e.g., cyclosporine; or prednisone at > 20 mg/day or equivalent of other systemic steroid); inadequate bone marrow function (absolute neutrophil count (ANC) < 1000 cells/mm3, platelet count < 100,000 cells/mm3, or hemo- globin < 8 g/dL without transfusion or cytokine support).Severity of adverse events (AEs) and laboratory values were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. Dose-limiting toxicities (DLTs) were evaluated in all patients who completed cycle 1 with ≥ 80% duvelisib adherence. Any of the following treatment-related events occurring during the first cycle were considered as a DLT: grade 3 febrile neutropenia with an elevated temperature (≥ 38.6 °C) confirmed on 2 occasions within a 12-h period; grade ≥ 3 thrombocytope- nia with grade ≥ 2 hemorrhage; grade 4 thrombocytopenia of any duration requiring transfusion support or any other hematologic toxicity of grade ≥ 4 and of > 7-day duration; grade 3 diarrhea, nausea, and vomiting for ≥ 24 h despite optimal treatment; grade ≥ 3 QTcF prolongation; grade ≥ 2 pneumonitis or pneumonia; and grade ≥ 3 of any other non-hematologic toxicity. Other AEs considered related to the study drug were also considered a DLT if it limited the administration of duvelisib, and were considered on a case by case basis by the investigator and the medical monitor. If ≤ 1 of 6 patients (or < 33% of the patients if beyond 6 patients were enrolled) experienced DLT, the dose was considered to be tolerable and the recommended phase II dose.On day 1 of cycles 1 and 2, plasma samples were obtained from patients at pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 24 (cycle 1 only) hours after the morning dose of duvelisib for PK analyses. On days 8, 15, and 22 of cycle 1, and day 1 of cycles 3 and 5, plasma samples were obtained at pre-dose. Plasma concentrations of duvelisib were determined using validated liquid chromatography and tandem mass spec- trometry. The PK parameters of duvelisib were derived using non-compartmental methods and comprised maxi- mum plasma concentration (Cmax), time to Cmax (Tmax), area under the time–concentration curve (AUC0–8 and AUC 0–t), and the accumulation ratio.Disease response was assessed in accordance with the revised International Working Group (IWG) criteria [9]. Bone marrow aspirates and biopsies were only obtained to confirm a suspected complete response (CR). The number, proportion, and 2-sided 95% confidence interval (CI) in patients responding to treatment (best over- all response of CR or partial response [PR]) were sum- marized in total and by disease types. The exact binomial method (Clopper–Pearson) was used to construct the CI.Progression-free-survival (PFS) was defined as the time from the first dose of the study drug to the first documenta- tion of progressive disease or death due to any cause. Overall survival (OS) was defined as the time from the first dose of the study drug until death. PFS and OS were estimated using the Kaplan–Meier method.This study was designed to enroll at least 6 patients. No formal sample size calculations were performed. Results Seven patients were enrolled at 3 institutions in Japan between November 2015 and December 2016. All were evaluable for DLTs. Patient demographics and baseline characteristics are summarized in Table 1. The median age was 61 years (range 54–74 years). The patients comprised 4 (57.1%) male and 3 (42.9%) female, 6 of whom (85.7%) had an ECOG PS of 0 or 1. The diagnoses were comprised of 4 patients with follicular lymphoma (FL, 57.1%), 2 with diffuse large B-cell lymphoma (DLBCL, 28.6%), and 1 withNo. of prior treatment regimens, median (range) 3 (1–5) Prior rituximab-containing regimens, n (%) 7 (100%) mantle cell lymphoma (MCL, 14.3%). Six patients (85.7%) had stage III or IV disease. All had received a median of 3 (range 1–5) prior treatment regimens, and all had received a rituximab-containing regimen.Three patients discontinued the study treatment due to progressive disease; 2 due to study termination by the spon- sor; and 2 due to AEs.SafetyNo DLT occurred in any patient. Five of the 7 patients com- pleted 6 or more cycles of the study drug (range 6–11); 2 received only 2 cycles of the study drug due to progressive disease. The dose was reduced from 25 mg BID to 15 mg BID in 3 patients. All enrolled patients experienced at least 1 treatment- related AE (TRAE, listed in Table 2) during the study period. The most commonly experienced TRAEs were neu- tropenia and thrombocytopenia, occurring in 3 patients each (42.9%); followed by lymphopenia, diarrhea, enterocolitis, stomatitis, hepatic function abnormal, ALT increased, and AST increased, occurring in 2 patients each (28.6%). Com- mon grade ≥ 3 TRAEs comprised neutropenia (3 patients, 42.9%), and thrombocytopenia, lymphopenia and hepatic function abnormal (2 patients each, 28.6%). All other TRAEs occurred in no more than 1 patient each (14.3%). Two of the 7 patients (28.6%) experienced a total of 5 treatment-emergent serious adverse events (TESAEs) dur- ing the study period. Enterocolitis, which occurred in both, was the only TESAE experienced by more than 1 patient. Other TESAEs experienced by 1 patient each (14.3%) com- prised stomatitis, cholecystitis, and Pneumocystis jirovecii pneumonia. Three of the 5 TESAEs were grade 3 according to the Investigator (enterocolitis, stomatitis, and Pneumo- cystis jirovecii pneumonia), and 1 each were grade 2 and 1 (cholecystitis and enterocolitis, respectively). The Investi- gator judged that all the TESAEs were possibly due to the study drug.Tdrug. The grade 3 Pneu- mocystis jirovecii pneumonia and enterocolitis occurred in 7.5 and 8.6 months after initiation of the study treat- ment, respectively. The Pneumocystis pneumonia occurred in spite that the patient received inhaled pentamidine as Pneumocystis prophylaxis monthly. There was 1 death during the study period, which was attributed to progres- sive disease. No duvelisib-related death was noted.A summary of the PK parameters is shown in Table 3. Duvelisib was rapidly absorbed after single and multiple doses, with median Tmax values of 1.0 and 2.0 h, respec- tively. The accumulation of the AUC0–8 was observed after multiple dosing with a mean accumulation ratio of2.15. The mean pre-dose (trough) levels collected during cycle 1 of the study showed that steady state was generally achieved by day 8 of cycle 1.All 7 patients were evaluable for response according to the revised IWG criteria. The overall response rate was 71.4% (95% CI: 29.0, 96.3). One patient (14.3%) withFL achieved a best overall response of CR. Four patients (57.1%), 3 with FL and the 1 with MCL achieved PR. No patient had stable disease, and 2 patients (28.6%), both with DLBCL, had progressive disease (Table 4). At a median follow-up duration of 10.4 months (range 9.9–14.9 months), median PFS was 8.7 months (90% CI: 1.0, not estimable; NE) and median OS was NE (90% CI: 1.6, NE). Discussion In this open-label, single-arm, multicenter phase I study, the safety, PK, and efficacy of duvelisib 25 mg BID were evaluated in Japanese patients with r/r lymphoma. Seven patients, comprising 4 with FL, 2 with DLBCL, and 1 with MCL, were enrolled.No DLT was observed in this study. The safety profile was consistent with those in previously reported clinical trials of duvelisib [10, 11]. Neutropenia and thrombocy- topenia were the most frequently occurring TRAEs, and diarrhea and enterocolitis, which have been suggested to be immune-related adverse events associated with PI3K-δ inhibition [2], were also observed in this trial. Five of the 7 patients continued duvelisib treatment for 6 or more cycles. In addition, it was possible to continue treatment without discontinuation by means of a dose reduction or interruption with or without supportive measures, as nec- essary, even in patients that experienced diarrhea, neu- tropenia, or abnormal hepatic function. Pneumocystis jirovecii pneumonia and enterocolitis led to discontinua- tion, however, indicating that patients should be carefully monitored for signs of these TRAEs when duvelisib is administered in a Japanese population. Overall, duvelisib 25 mg BID was well tolerated in this Japanese population. In the present study and the phase I study in advanced hematologic malignancies conducted in the US [8], duvel- isib 25 mg was rapidly absorbed after administration, with a median Tmax of 1.0–2.0 h in both trials. The mean Cmax (coefficient of variation (CV)) on day 1 of cycles 1 and 2 in the present study was 1700 (32.8%) and 2480 (29.3%) ng/mL, respectively, while that in the phase I study in the US was 1062 (69.9%) ng/mL and 1511 (63.6%) ng/mL, respectively. Although the Cmax in the present Japanese population was slightly higher than that in non-Japanese.In the present study, a response was observed in all 4 patients with FL and the 1 patient with MCL, and 1 out of 4 patients with FL achieved CR. Although all FL patients had undergone prior rituximab-containing therapy, the response was observed in all of them. This preliminary efficacy data of the present study was in line with the earlier results of the study by Flinn et al. [10]. Since the present study included only small number of patients and not designed to evaluate efficacy as the primary objective, future clinical studies to evaluate efficacy are warranted. In conclusion, the present study demonstrated tolerability of duvelisib 25 mg BID and its preliminary efficacy in Japa- nese patients with r/r lymphoma, including FL. PK profile obtained with the present study was consistent with that in the phase I study in the US [8], suggesting there is no eth- nic differences in the PK profile of duvelisib. Duvelisib was approved for CLL/small lymphocytic lymphoma (SLL) in the US in September 2018 [10, 11], and also received accel- erated approval IPI-145 for FL at 25 mg BID at the same time [10]. A clinical trial for CLL/SLL (JapicCTI-194871) is currently underway in Japan, and the results are awaited.