Idelalisib

Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia

Noriko Fukuhara1,*, Tomohiro Kinoshita2, Kazuhito Yamamoto 2, Hirokazu Nagai3, Koji Izutsu 4,5, Go Yamamoto5, Pankaj Bhargava6, Nishan Rajakumaraswamy6, Rita Humeniuk6, Anita Mathias6, Guan Xing6, Masato Fukui6 and Kensei Tobinai4

Abstract

Objective Idelalisib is an orally administered, highly selective inhibitor of phosphatidylinositol 3-kinase-δ. In this phase 1b study, the safety, tolerability and pharmacokinetics of idelalisib, an oral inhibitor of phosphatidylinositol 3-kinase-δ, were evaluated in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma.
Methods In total, six patients (follicular lymphoma: n= 3, chronic lymphocytic leukemia: n= 3) were enrolled to receive idelalisib 150 mg twice daily.
Results No dose-limiting toxicities were reported. The most common adverse events were diarrhea (n = 5), gastritis (n = 3), insomnia (n = 3) and pyrexia (n = 3). The most common ≥grade 3 adverse events were diarrhea (n= 2), increased transaminase levels (n= 2) and decreased appetite (n= 2). The maximum idelalisib plasma concentrations (Cmax) were achieved at 2.50 h (range: 1.50– 4.00 h). The mean idelalisib plasma concentrations decreased over time but remained detectable in most patients at 12 h. All enrolled patients underwent efficacy evaluation by investigators, and five patients (follicular lymphoma: n= 2, chronic lymphocytic leukemia: n= 3) achieved partial response. The median duration of partial response was 14.5 months (range: 3.7–31.3 months). Conclusion Idelalisib 150 mg twice daily was considered tolerable in Japanese patients with follicular lymphoma or chronic lymphocytic leukemia. (Clinical trial registration: NCT02242045)

Key words: idelalisib, phase 1 study, follicular lymphoma, chronic lymphocytic leukemia, safety

Introduction

Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions, including motility, proliferation and survival (1). PI3K signaling is mediated by four catalytic isoforms: α, β, γ and δ. Although potentially important in multiple cell types, PI3Kδ shows an expression pattern that is particularly prominent in cells of hematopoietic origin (2). In lymphoid cancers, sustained activation of the PI3K/AKT pathway has been shown to promote malignant B-cell survival via mechanisms that are dependent on the PI3Kδ isoform (3–5).
Idelalisib is a potent, oral, highly selective inhibitor of PI3Kδ (5). In primary tumor samples and in cell lines derived from patients with lymphoid malignancies, idelalisib induces a dose-dependent decrease inAKTphosphorylation(4,5,6).Inaddition,idelalisibdisruptsPI3Kδ activation, and the supportive intercellular signaling observed when chronic lymphocytic leukemia (CLL) cells are co-cultured with stromal cells (6,7). In multiple primary lymphoid tumors and malignant cell lines, idelalisib enhances apoptosis; moreover, it demonstrates a concentration-dependent cell-killing effect when applied as a single agent and increases the therapeutic efficacy of other antineoplastic agents when administered in combination (7,8). In phase 3 studies of relapsed/refractoryCLL,acombinationofidelalisibandrituximabas well as idelalisib and ofatumumab was shown to be superior to rituximab and placebo,with an acceptable safety profile (9,10).Moreover, in a phase 2 study, idelalisib monotherapy showed efficacy with an acceptable safety profile in heavily pre-treated patients with indolent B-cell non-Hodgkin lymphoma (iNHL) (11). Idelalisib is approved in the United States for the treatment of CLL, small lymphocytic leukemia (SLL) and follicular lymphoma (FL).Regional variations to the label and the clinical practice exist between the United States and European Union; overall, in clinical practice, idelalisib monotherapy is used as an option for the treatment of third-line FL patients and idelalisib in combination with rituximab is used as a second-line option for CLL patients.
This phase 1b study was designed to confirm the safety profile of idelalisib in Japanese patients with iNHL. The primary objectives were to evaluate the 28-day safety and tolerability of idelalisib in Japanese subjects with relapsed or refractory iNHL and to determine the pharmacokinetics (PK) of idelalisib in Japanese patients with relapsed or refractory iNHL.

Methods

Study population

Japanese patients with iNHL aged ≥20 years were eligible. The iNHL included FL, CLL, SLL, lymphoplasmacytic lymphoma and marginal zone lymphoma. Other key inclusion criteria were previous treatment with at least one regimen for iNHL, discontinuation of all therapy for the treatment of iNHL at ≥4 weeks before Day 1, regression of all acute toxic effects of any prior antitumor therapy to grade ≤ 1 before Day 1 and European Cooperative Oncology Group performance status of 0 or 1. Key exclusion criteria were as follows: known histological transformation to an aggressive histology,known presence of myelodysplastic syndrome, history of iNHL with central nervous system involvement, history of a non-lymphoid malignancy or pneumonitis including interstitial lung disease and evidence of ongoing systemic bacterial, fungal or viral infection on Day 1.
The study protocol and informed consent form were reviewed and approved by the Institutional Review Board of each participating site. The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonization guidelines and the laws and regulations in Japan, including the Ministerial Ordinance on Good Clinical Practice. All patients provided written informed consent before participating in the study.

Study design

This was a phase 1b, open-label study of continuous daily administration of idelalisib in Japanese patients with relapsed or refractory iNHL. The study utilized a 6 + 6 design with four cohorts (Cohorts A1, A2, B and C). This design was adopted because no dose-limiting toxicity (DLT) was observed after treatment with up to 350 mg twice daily and the maximum tolerated dose was not determined in an overseas phase 1 study (12). Therefore, up to six patients were allowed to be enrolled continuously into this Japanese phase 1 study.
Cohort A1 was planned to include six patients treated with idelalisib 150 mg twice daily. This dose regimen was considered to be appropriate for Japanese patients because it had been determined as the recommended dose based on overseas phase 1 and phase 2 studies (11, 12), and there was no clinically meaningful difference in PK between Japanese and Caucasian volunteers at this dose (13).
The safety and tolerability of idelalisib were evaluated after the sixth patient had been enrolled in the study for at least 28 days. No additional patients were planned to be enrolled if the safety and tolerability were confirmed in Cohort A1.
Cohort A2 was planned to enroll an additional six patients for treatment with idelalisib 150 mg twice daily. This cohort would be opened for enrollment only if an unexpected treatment-related adverse event (AE) was observed in Cohort A1. The safety and tolerability of idelalisib would be evaluated after the sixth patient had been enrolled in the study for at least 28 days. In the event of an unexpected treatment-related AE at the 150 mg BID dose, dose deescalation to idelalisib 100 mg twice daily was planned in the next cohort, Cohort B.
Cohort B would enroll an additional six patients for treatment with idelalisib 100 mg twice daily. The safety and tolerability of idelalisib would be evaluated after the sixth patient had been enrolled in the study for at least 28 days.
Cohort C was planned to include six patients with CLL treated with idelalisib 150 mg twice daily. This cohort would be opened for enrollment only if Cohort A1 enrolled ≤2 CLL patients or if Cohorts A1 and A2 enrolled ≤4 CLL patients combined. If Cohort B was open for enrollment, Cohort C would not be opened to prevent dose discrepancies. If Cohort C was opened and there was an unexpected treatment-related AE, Cohort B would not be opened.
For all cohorts, treatment with idelalisib was planned to be continued until one of the following occurred: unacceptable toxicity, disease progression, substantial non-compliance, pregnancy, initiation of another anticancer or experimental therapy, or as per an investigator’s discretion.

Safety and tolerability

Safety and tolerability were evaluated based on DLTs within the first 28 days after the initiation of idelalisib treatment. The dose was considered to be safe and tolerable if <33% of all evaluable patients experienced DLTs in each cohort. The DLTs were defined as any of the following events: grade 4 hematological toxicities persisting for >14 days, grade ≥ 3 non-hematological toxicities, laboratorygrade > 3 abnormalities, red cell transfusion owing to disease or treatment, and therapeutic platelet transfusion for the treatment of severe thrombocytopenia-related bleeding or excessive bruising. The safety of continuous daily administration of idelalisib was evaluated over the entire duration of the study.
The safety analysis set consisted of all patients receiving at least one dose of study treatment. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 20.1), and the severity of the AEs was graded by an investigator according to the Common Terminology Criteria for Adverse Events (version 4.03). The relationship between the AEs and the study drug was categorized as related or unrelated.A treatment-emergent laboratory abnormality was defined as an abnormality that, compared with the baseline, worsened by ≥1 grade.

Efficacy

The response and progression of iNHL were evaluated based on the standardized response criteria (14–16).

Pharmacokinetics

Plasma samples were collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post-dose on Days 1 and 29 as well as pre-dose and at 1.5 h post-dose on Days 8, 15 and 22. Plasma concentrations of idelalisib were determined using validated bioanalytical assays. PK parameters were estimated by standard non-compartmental methods using WinNonlin software (Certara, NJ).
Individual patient concentration data and PK parameter data (Cmax, Tmax, AUC and Ctau) were summarized using descriptive statistics. Summary statistics consisted of the sample size (n), mean, standard deviation (SD), coefficient of variation (CV), median, minimum, maximum, first quartile (Q1) and third quartile (Q3). The PK dataset included all the six patients enrolled in the study.

Results

Patients and treatment

In total, six patients from five Japanese sites were enrolled in Cohort A1, with the study duration ranging from October 2014 to October 2017.Although patients with FL,CLL,SLL,lymphoplasmacytic lymphoma and marginal zone lymphoma were eligible as patients with iNHL in this study,only patients with FL and CLL were enrolled.The demographics and disease characteristics of each patient are shown in Table 1.

Time course of idelalisib treatment

The time course of idelalisib treatment in each patient is summarized in Fig. 1. Patient 001 experienced grade 1 pneumonitis on Day 562, which led to idelalisib dose interruption since Day 588. Idelalisib was resumed at a reduced dose of 100 mg twice daily on Day 787, and no recurrence of pneumonitis occurred. When idelalisib was interrupted since Day 853 owing to grade 1 gastritis, the patient was judged to have progressive disease (PD); thus, idelalisib treatment was terminated.
Patient 002 experienced grade 2 otitis media on Day 181, which led to immediate idelalisib dose interruption. With supportive care, the AE disappeared, and idelalisib was resumed without dose reduction on Day 197. Idelalisib was interrupted since Day 219 owing to grade 3 pneumonia and grade 3 anorexia; the pneumonia disappeared after 2-week administration of both an antibiotic drug and an antifungal drug. Idelalisib was resumed at a reduced dose of 100 mg twice daily on Day 239, and no recurrence of pneumonia occurred. Idelalisib was interrupted since Day 293 owing to grade 3 diarrhea, which then disappeared and led to the readministration of idelalisib on Day 345. However, the patient relapsed to grade 4 diarrhea on Day 387, and idelalisib was then permanently discontinued.
Patient 003 experienced grade 3 diarrhea on Day 67, which led to immediate idelalisib dose interruption. After the AE disappeared, idelalisib was resumed at the same dose on Day 98. Idelalisib was interrupted from Day 260 owing to grade 3 diarrhea, which disappeared after dose interruption. Idelalisib was then resumed at a reduced dose of 100 mg twice daily on Day 308, and the patient judged to have PD on Day 588.
Patient 004 received idelalisib 150 mg twice daily for 35 months and showed partial response (PR) and no major issues.
Patient 005 experienced grade 4 increase in transaminase levels (grade 4 increased ALT level and grade 3 increased AST level) on Day 73, which disappeared after dose interruption. Idelalisib was then resumed at a reduced dose of 100 mg twice daily on Day 105. Grade 3 increase in transaminase levels (grade 3 increased ALT level and grade 3 increased AST level) occurred again on Day 197, which led to idelalisib dose interruption. Idelalisib was resumed on Day 227; however, 5 days later, grade 3 increase in transaminase levels (grade 3 increased ALT level and grade 3 increased AST level) occurred,and idelalisib was thus permanently discontinued.
Patient 006 experienced grade 3 appetite loss. In this patient, oxycodone had been started before idelalisib to control lymphomarelated pain. After initiation of idelalisib, it was substituted with tramadol/acetaminophen combination tablet due to oxycodone-related nausea and constipation. Then, decreased appetite associated with nausea was developed and was further aggravated to grade 3 on Day 14. However, decreased appetite was improved with the change of analgesic agents without interrupting idelalisib. Thus, we consider that this decreased appetite was caused by analgesic agents and not related to idelalisib. According to the study protocol, as this was grade3non-hematologicaltoxicitynotrelatedtoidelalisib,itwasnot considered to be DLT. This patient was confirmed as stable disease on Day 40.
In this study protocol, prophylaxis for opportunistic infections was not mandatory. However, all patients had prophylaxis for Pneumocystis jirovecii pneumonia.

Safety and tolerability

All enrolled patients in Cohort A1 met the primary objective for safety evaluation, with no DLTs reported in these patients. Cohorts A2, B and C did not meet the criteria for opening, and this study was completed with only Cohort A1 opened. The median duration of exposure to the study drug was 16.0 months (range: 1.3–35.0 months).
Within the first 28 days of treatment, AEs were reported in four patients (66.7%), which, by an investigator, were judged not to be idelalisib-related. Of the reported AEs, the only ≥grade 3 AE was decreased appetite (grade 3).Over the entire treatment duration,AEs were reported in all six patients. The most commonly reported AEs were diarrhea (n = 5, 83.3%), gastritis, insomnia and pyrexia (each n = 3, 50%). The most commonly reported ≥grade 3 AEs were diarrhea, increased transaminase levels and decreased appetite, all of which were reported in two patients (33.3%) (Table 2). Four AEs, which occurred in three patients, were determined to be idelalisibrelated: grade 4 diarrhea, which occurred in one patient and led to idelalisib discontinuation on Day 498; grade 3 pneumonia, which also occurred in the previously mentioned patient; grade 3 diarrhea, which occurred in one patient and led to idelalisib interruption and, later on, to idelalisib dose reduction (this patient also experienced grade 3 infection); grade 1 pneumonitis, which occurred in one patient and led to idelalisib dose reduction.
Within the first 28 days of treatment, one patient (16.7%) experienced a serious adverse event (SAE) of decreased appetite, which was judged by the investigator as not idelalisib-related but caused by disease progression.Over the entire duration of treatment,SAEs were reported in five patients (83.3%). The most commonly reported SAE was diarrhea (three patients, 50.0%). All other SAEs (pneumonia, increased transaminases, decreased appetite, pyrexia and infection) were reported in no more than one patient each. Three patients (50.0%) experienced SAEs that were judged by the investigator as idelalisib-related: one patient with pneumonia and diarrhea, one patient with increased transaminases and one patient with diarrhea and infection.

Pharmacokinetics

Following the administration of the 150 mg idelalisib tablet,the maximum idelalisib plasma concentration (Cmax) was achieved at 2.50 h (range: 1.50–4.00 h). The mean plasma idelalisib concentrations decreased over time and remained detectable in most patients at 12 h, i.e. the last sampling time point (Fig. 2A and B). Following 150 mg twice daily administration of idelalisib for 28 days, the mean (%CV) Cmax, area under the curve at steady state (AUCtau) and trough concentration (Ctau) were 2651.7 ng/ml (16.4), 13310.2 h∗ng/ml (38.1) and 403.0 ng/ml (78.3), respectively (Table 3). No accumulation of idelalisib was observed based on the Cmax or AUC, but modest accumulation of the trough concentration was noted between Day 1 and Day 28.In summary,the PK observed in this study was consistent with that reported in previous studies of idelalisib (17).

Efficacy

All six enrolled patients underwent efficacy evaluation by the investigators, and five patients [83.3% (FL: 2, CLL: 3)] were determined to achieve PR. These patients achieved PR at the first pre-specified radiological assessment,with a median time to response of 3.6 months (range: 3.6–3.8 months). The median duration of PR was 14.5 months (range: 3.7–31.3 months).

Discussion

This is the first study of idelalisib conducted in Japanese patients with hematologic malignancies. No DLTs were reported. Within the first 28 days of the DLT evaluation period, the only ≥grade 3 AE was decreased appetite, which was judged as not idelalisib-related.
Of the six patients enrolled, two experienced grade 3 diarrhea and one experienced grade 1 pneumonitis, which could be related to immune-related AEs (irAEs). These irAEs were manageable and reversible with idelalisib dose interruption for 1–2 months and supportive care. However, a patient with grade 4 diarrhea who underwent idelalisib interruption for more than 3 months was unable to resume the study drug. Of the six patients in this study, five experienced diarrhea; all of these patients recovered without steroids. One FL patient experienced grade 4 increased transaminase levels (grade 4 increased ALT level and grade 3 increased AST level), which was managed with idelalisib dose interruption for 1 month and supportive care, with steroid therapy as an available option.
All five patients who achieved PR received alkylating agents as prior therapy; four of them were heavily pre-treated, receiving more than two regimens of chemotherapy plus an anti-CD20 antibody. Nevertheless, these patients achieved PR at the first pre-specified radiological assessment. Idelalisib dose interruption or dose reduction or both were required for four patients with PR owing to AEs.
The plasma concentrations of idelalisib observed in this study were similar to those reported in other idelalisib studies. It has also been reported that there were no relationships between idelalisib exposure and the safety and efficacy endpoints in iNHL patients (17).
However, this study had several limitations. This study had a small sample size and evaluated only one dose level. Moreover, there was no comparator, and only Japanese patients were enrolled in this study.
In conclusion, this phase 1b study revealed that idelalisib 150 mg twice daily was tolerable in Japanese patients with relapsed/refractory FL and CLL.

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