Oral Inhibitor Of PI3Kδ Research Articles

Phase Ib study of the oral PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

Patients with advanced solid tumors have a suboptimal prognosis. This study investigated the safety and feasibility of linperlisib, a selective phosphatidylinositol 3-kinase delta isoform (PI3Kδ) inhibitor, for treating patients with advanced solid tumors. In this phase Ib, single-arm, open-label, multi-center clinical trial, patients with histologically confirmed advanced solid tumors from eight centers in China were enrolled to receive oral linperlisib (80mg/day). The primary endpoint was safety. Between August 2019 and June 2022, 94 patients were enrolled in the trial and received the study treatment. The most common (≥ 20%) treatment emergent adverse events (TEAEs) of all grades irrespective of causality were increased aspartate aminotransferase (AST) (26.6%), proteinuria (26.6%), decreased appetite (25.5%), increased alanine aminotransferase (ALT) (22.3%), weight loss (21.3%), and anemia (21.3%). The most common grade ≥ 3 TEAEs were diarrhea (4.3%), increased AST (3.2%), increased ALT (3.2%), neutropenia (3.2%), anemia (3.2%), increased blood alkaline phosphatase (3.2%). The objective response rate (ORR) was 1.1% (95% confidence interval [CI] 0.0-5.8), and the disease control rate (DCR) was 37.2% (95% CI 27.5-47.8). As of the data cutoff, the median follow-up time was 4.2months (95% CI 2.8-6.9). The median progression-free survival (PFS) was 1.85months (95% CI 1.79-1.88). The median overall survival (OS) was not reached. Linperlisib showed an acceptable safety profile and preliminary clinical benefit in patients with a range of advanced solid tumors. Further studies of linperlisib safety and efficacy are warranted.

A Phase II Clinical Study Exploring the Safety and Efficacy of the Oral PI3Kδ Inhibitor, Linperlisib, in Relapsed Refractory T Cell Lymphoma

A Phase II Clinical Study Exploring the Safety and Efficacy of the Oral PI3Kδ Inhibitor, Linperlisib, in Relapsed Refractory T Cell Lymphoma

Subgroup Analysis from a Phase 2, Single-Arm Trial of the Oral PI3Kδ Inhibitor Linperlisib in Patients with Relapsed or Refractory Follicular Lymphoma

Background In our previous phase 2 trial (NCT04370405), linperlisib, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, demonstrated encouraging activity and manageable safety in adult patients with relapsed/refractory (R/R) follicular lymphoma (FL) who had received at least 2 prior systemic therapies. It's crucial to note that FL patients with bone marrow involvement (BMI) generally present more unfavorable prognosis. Here, we present a subgroup analysis from this phase 2 study, which is specifically focused on BMI at baseline. Methods Details of the trial design and study population have been previously reported. In brief, eligible patients (age > 18 years; histologically confirmed relapsed or refractory FL; disease progression post at least 2 prior systemic therapies) received 80 mg linperlisib tablets daily in a 28-day cycle, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC); secondary endpoints included the duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety profile. For this subgroup analysis, patients were grouped based on the presence or absence of BMI at baseline. For those with baseline BMI, biopsies were evaluated to confirm complete responses. Evaluations of antitumor response were conducted every 2 treatment cycles, following the guidelines of the International Research Working Group. Results As previously reported, 84 patients included in the full analysis set (FAS). By subgroup, 25 had baseline BMI and 59 did not. Baseline characteristics by subgroup are shown in Table 1. In this subgroup analysis, a trend toward higher response rate was seen in R/R FL patients with BMI compared to those without such involvement: ORR based on IRC assessment was 88.0% vs 76.3%; best overall response (BOR) of CR was 24.0% vs 11.9%; BOR of PR was 64.0% vs 64.4%. Patients with BMI had DCR that was consistent with those without BMI (92.0% vs 93.2%). The median DOR and PFS were similar across this subgroup (DOR: 11.7 months vs 13.0 months; PFS: 13.3 months vs 13.7 months) (Table 2). Although the median OS was not reached, 12-month OS rates for patients with and without BMI was 91.7% and 91.5%, respectively (Table 2). Safety was evaluated in all R/R FL patients who had received ≥1 dose of linperlisib. Rates of any-grade treatment-related adverse events (TRAEs) were similar across this subgroup and comparable with the overall population (Table 2). When compared to the overall population, patients without BMI experienced fewer grade ≥3 TRAEs, while a marginally higher incidence of grade ≥3 TRAEs was observed in patients with BMI (Table 2). Conclusions This subgroup analysis indicated that linperlisib is an effective and well-tolerated treatment option for patients with R/R FL, irrespective of BMI. Although minor differences were observed in this subgroup, their significance is limited due to the small sample sizes and probably do not alter the overall clinical benefit of linperlisib. Nevertheless, these findings warrant further investigation.

Dose Adjustments of Linperlisib in Relapsed or Refractory Follicular Lymphoma: A Post-Hoc Analysis of a Pivotal Phase II Study

Background: The oral PI3Kδ inhibitor linperlisib has proven to be a significant therapeutic option for patients with relapsed or refractory follicular lymphoma (FL) in a phase II study. As a result, linperlisib was approved in China for the management of adult patients with relapsed or refractory FL who had undergone at least two prior systemic treatments. In addition to linperlisib, several PI3K inhibitors were approved by Food and Drug Administration for relapsed or refractory FL. Despite their confirmed efficacy, these drugs encountered substantial tolerability issues, leading to the rescission from indications for FL. In response to these challenges, we undertook a post-hoc analysis of the phase II linperlisib study to evaluate its safety profile in treating FL, as well as assessing the impact of dose adjustments on prognosis of patients. Methods: In the single-arm, open-label, multicenter phase II study, eligible patients (adults with histologically confirmed relapsed or refractory FL showing disease progression post at least two prior systemic therapies) were administered daily doses of 80mg linperlisib until disease progression or the emergence of unacceptable toxicity. The primary endpoint was the objective response rate (ORR). For this post-hoc analysis, patients were stratified into three groups: the dose-adjusted group (patients who had dose adjusted or interrupted due to adverse events [AEs]); the treatment-terminated group (patients who ceased treatment for a variety of reasons, which included AEs, withdrawal of informed consent, and the investigator's judgment); and the dose-unadjusted group (patients who experienced neither dose adjustment nor interruption). Results: Of 84 patients in the study, dose adjustments or interruptions due to AEs were required for 26 patients, while 34 patients terminated their treatment (15 due to AEs, 6 as per the investigator's discretion, and 14 due to withdrawal of informed consent). A remaining subset of 24 patients experienced no dose modifications. Notably, the dose-adjusted and treatment-terminated groups contained more patients aged 60 and above (19.2% and 29.4% respectively), compared to only 4.2% in the dose-unadjusted group. Other baseline characteristics appeared comparable across all three groups. Among 26 patients in the dose-adjusted group, 25 had dose adjustments due to AEs, and 11 experienced dose interruptions. Infectious pneumonia and interstitial pneumonia were reported in 20.2% (17 cases) and 4.8% (4 cases) of patients, and represent the primary AEs causing treatment termination (9 cases and 4 cases, respectively). Thirteen patients experienced diarrhea during the study, with six requiring dose adjustments, and one patient ceasing treatment due to autoimmune colitis combined with a fungal infection. Rashes, which had an incidence of 11.9% (10 cases), necessitated dose interruptions in four patients but did not require any dose reductions. The ORR was comparable among the three groups (84.6% in dose-adjusted group, 79.4% in treatment-terminated group, and 75.0% in dose-unadjusted group). However, the dose-adjusted and dose-unadjusted groups demonstrated superior duration of response (median DOR, 15.9 months in dose-adjusted group, 9.7 months in treatment-terminated group, and 14.8 months in dose-unadjusted group) and progression-free survival (median PFS, 19.4 months in dose-adjusted group, 11.5 months in treatment-terminated group, and 16.6 months in dose-unadjusted group) than the treatment-terminated group (Figure 1). The median overall survival was not reached in three groups. Conclusion: Our post-hoc analysis reveals that elderly patients (≥60 years old) have reduced tolerance to linperlisib, necessitating more frequent dose adjustments due to AEs. Notably, treatment discontinuation results in inferior DOR and PFS, while dose adjustments or suspensions yield comparable DOR and PFS to full-dose treatment, suggesting that tolerability-guided dose modification effectively reduces AEs without sacrificing therapeutic efficacy.

Safety Results of a Phase I Study of Zandelisib + R-CHOP in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL)

Introduction: Emerging data have identified distinct genetic subtypes of DLBCL based on the diverse oncogenic molecular drivers with varying clinical outcomes when treated with standard R-CHOP. Relapse post frontline treatment could be curbed by integrating novel agents upfront. The phosphatidylinositol 3 kinase (PI3K) signalling pathway contributes to the oncogenesesis of both germinal center derived and activated B-cell (ABC) DLBCL subtypes (Wright, et al Cancer Cell, 2020). Zandelisib, a highly selective oral PI3Kδ inhibitor has proven efficacy in B cell lymphoma with a favorable toxicity profile when administered in intermittent dosing schedule (Pagel, et al Lancet Oncol 2022). We conducted a phase I/2 trial to evaluate the safety and efficacy of zandelisib in combination with R-CHOP chemotherapy in newly diagnosed DLBCL. The study enrollment was closed in 12/2022 after the development of zandelisib was discontinued. We present the results of the phase I (P1) trial. Methods: In this investigator-initiated trial, patients (pts) with untreated DLBCL with ECOG performance status (PS) ≤ 2, adequate bone marrow (BM) and organ function were enrolled from 08/2021-12/2022 at Cleveland Clinic (NCT04517435). ECOG PS 3 was allowed if it was attributed to the lymphoma diagnosis. The study was supported by the MEI Pharma. The P1 study had 2 dose escalation cohorts in combination with standard doses of R-CHOP every 21 days for 6 cycles; zandelisib was dosed 60 mg daily on days 1-4 in cohort 1 and daily on days 1-7 in cohort 2. If the 3 subjects in dose level 1 (D1) did not experience any dose limiting toxicity (DLT) during cycle 1 (C1), pts were enrolled into D2. In phase 2 (P2), a cycle of R-CHOP prior to the study treatment was allowed, if clinically deemed. All pts received pneumocystis jirovecii (PJP) and viral prophylaxis. Disease response was assessed after C3 and C6. Primary end point for P1 was to assess safety and tolerability of the combination and to determine recommended P2 dose (RP2D) of zandelisib. Pts who received at least 1 cycle of study treatment were included in the safety analysis. Primary objective of P2 is progression free survival (PFS) at 1 year. Pt and disease characteristics were analyzed using descriptive statistics. Results: We enrolled a total of 13 pts (P1: 9 and P2: 4) in the study prior to termination. The median age was 67 (range 46-79) years, with majority being female (53.8%), with an ECOG PS of 0-2 (100%). Most pts had stage III-IV disease 10/13 (77%), IPI ≥3 in 8/15 (62%), elevated LDH 9/13 pts (69%), and extranodal involvement 7/13 (54%). 3 pts had BM involvement. DLBCL was germinal center (GC) subtype in 77% of the pts. FISH studies revealed translocations in BCL2 (46%), BCL6 (8%) and c-myc (0%). There was no DLT observed in cohort 1 and zandelisib 60 mg daily on D1-7 was the RP2D. 12 of 13 enrolled pts completed 6 cycles of the study regimen prior to study closure. Of the 12 evaluable pts, the ORR was 100% with 9 pts (75%) achieving CR and 3 PR (25%). No pt experienced disease progression prior to study closing. Median time from treatment start to response was 165 (range 48-189) days. The most common adverse events were diarrhea (38%), neutropenia and anemia (31% each), fatigue, constipation, leukopenia and thrombocytopenia (23% each). Other AEs include colitis, nausea, hypoalbuminemia and hypokalemia (15% each). Of the 2 pts who developed colitis, 1 pt had G1 colitis which resolved, while the other pt discontinued the study after 2 cycles due to G3 colitis and bowel obstruction. Another pt experienced G3 jejunal perforation after completing cycle 6. Other G≥3 AE observed were neutropenia and leukopenia each (23% each), lung infection and lymphopenia (8% each). All pts were alive at the time of study closure. Conclusion: In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP.

Efficacy and Safety of Single-Agent Zandelisib Administered By Intermittent Dosing in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Final Results of the Tidal Phase 2 Study

Introduction: Zandelisib is a novel, highly selective, structurally differentiated, oral PI3Kδ inhibitor. Its on-target residence time (≥5 hours) and high volume of distribution lead to higher tumor exposure relative to plasma over time. In a dose optimization Phase 1b study in various B-cell malignancies, zandelisib was evaluated initially by continuous dosing (CD), and then by intermittent dosing (ID) to allow regulatory T-cell repopulation, thereby reducing immune-related adverse events (AEs) (Pagel et al. Lancet Oncol 2022). The TIDAL trial (NCT03768505) started as a randomized, double-blind, 2-arm study to evaluate the safety and efficacy of zandelisib CD (n=16) vs. ID (n=121) in R/R FL and marginal zone lymphoma (MZL) patients (pts). Here we present results from the final analysis of the FL cohort in the ID arm. Methods: Eligible pts ≥18 years with FL Grade I-IIIA, ECOG performance status 0-1, progressive disease after ≥2 prior therapies including an anti-CD20 antibody and chemotherapy, and no prior PI3K inhibitor, provided consent and subsequently received zandelisib 60 mg orally once daily for two 28-day cycles, then ID (days 1-7 of 28-day cycles). The study arm evaluating zandelisib 60 mg daily CD closed early to enrollment after maturing data from the Ph 1b study showed pts on ID having fewer discontinuations due to treatment-emergent AEs and a high rate of durable responses. Study treatment was administered until disease progression or intolerance. The primary efficacy endpoint was objective response rate (ORR) as assessed by blinded independent central review (BICR) using modified Lugano Classification. Secondary endpoints were duration of response (DOR), complete response (CR) rate, median progression-free survival (mPFS), safety and tolerability. Prophylaxis for Pneumocystis jirovecii pneumonia was not mandatory in this single agent trial. Results: Between June 2019 and September 2021, 121 FL pts were enrolled in the ID arm, intent-to-treat (ITT) population, with the initial 91 pts representing the primary efficacy population (PEP). The median number of prior therapies was 3 (range 2-8), 28 pts (23.1%) had prior stem cell transplant, 54 pts (44.6%) were refractory to last therapy, 42 pts (34.7%) had bulky disease (≥5 cm), and 68 pts (56.2%) were POD24. Efficacy data overall and by subgroup (POD24, prior therapy, refractoriness) are shown in the Table. The ORR (CR rate) in the PEP and ITT were 72.5% (36.3%) and 70.2% (34.7%). With median follow-up of 11.3 months in PEP and 9.3 months in ITT, median DOR was estimated at 16.4 and 16.4 months, respectively. Preliminary PFS in the ITT population is shown in the Figure. With a median follow-up of 14.3 months (range: 1.0-30.5) among 121 pts, the most common AEs (all grade/Gr ≥3) were diarrhea (37.2%/5.8%), neutropenia (28.9%/21.5%), nausea (22.3%/0), fatigue (19.0%/0), pyrexia (19.0%/1.7%), and abdominal pain (15.7%/0.8%). 15 pts (12.4%) discontinued therapy due to treatment-related AE. Gr ≥3 AEs of special interest (AESI) in the ID arm were diarrhea in 7 pts (5.8%), lung infection/pneumonia in 6 (5.0%), noninfectious colitis in 4 (3.3%), rash in 4 (3.3 %), stomatitis in 3 (2.5%), and 1 (0.8%) each for ALT and AST increased and noninfectious pneumonitis. In 16 pts in the CD arm, 5 (31.3%) discontinued therapy due to drug-related AE, and 4 (25%) had Gr ≥3 diarrhea/colitis. Gr 5 AEs in the ID arm, excluding COVID-19, were tumor lysis syndrome (1 pt) and pneumonia (1 pt). There were 17 pts with COVID events, fatal in 5. Conclusions: Single agent zandelisib on ID was associated with high rate of durable responses (72.5% ORR, 36.3% CR rate in PEP) in heavily pretreated R/R FL pts, including those with POD24 and refractory disease, and was associated with a relatively lower incidence of Gr ≥3 AESI and AE-related discontinuations, compared with CD. Based on the safety and efficacy profiles observed in this study, these results support further evaluation of zandelisib ID, alone or in combinations, in various B-cell malignancies. Zandelisib plus rituximab vs. chemoimmunotherapy is being evaluated in the randomized phase 3 study COASTAL in R/R FL and MZL (NCT04745832). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 5453: FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies

Abstract Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway plays critical roles in cell growth, differentiation, motility, survival, and intracellular trafficking, and is one of the most frequently dysregulated pathways in human cancers including B-cell malignancies. There are 3 classes of PI3K, among which Class I PI3Ks including PI3Kα, β, γ, and δ isoforms are the mostly studied and plays key roles in physiological functions. PI3Kα has a role in insulin-dependent signaling, PI3Kβ functions in platelet aggregation, thrombosis and insulin signaling, and PI3Kγ/δ are expressed mainly in leukocytes and regulate lymphocyte activation, mast cell degranulation, and chemotaxis. Early PI3K inhibitors such as idelalisib are effective against B-cell malignancies such as chronic lymphocytic leukemia, but their clinical use is largely limited due to intolerable toxicities. More selective PI3Kδ inhibitors such as umbralisib (TGR-1202) demonstrates improved clinical efficacy and safety profile compared to current standard of care and was recently approved as a monotherapy for follicular lymphoma and marginal zone lymphoma. However, there is still unmet medical need for novel PI3Kδ inhibitors with improved safety profile and better efficacy to be used as monotherapy and in suitable combination strategies. Here we introduce FCN-289, a novel and oral next-generation PI3Kδ inhibitor. FCN-289 demonstrates potent kinase activity against PI3Kδ with single-digit nanomolar IC50 and remarkably improved selectivity over other PI3K isoforms compared with TGR-1202. FCN-289 exhibits significant anti-proliferating activity against various human diffuse large B-cell lymphoma (DLBCL)-derived cancer cell lines (OCI-LY10, TMD-8 and WSU-NHL) with superior activity compared with TGR-1202. Consistently, FCN-289 shows dose-dependent anti-tumor growth activity superior to that of TGR-1202 at the same and higher dose in TMD-8 DLBCL xenograft models. FCN-289 shows significantly improved anti-tumor activity when combined with BTK inhibitor ibrutinib in TMD-8 and OCI-LY10 DLBCL xenograft models. In non-clinical settings, FCN-289 exhibits good pharmacokinetic (PK) and safety properties with shorter Tmax and higher bioavailability in both rats and dogs, higher exposure in rats, improved CYP450 inhibition profile, and less plasma protein bound ratio compared with TGR-1202.Together, FCN-289 is a novel PI3Kδ inhibitor that possesses more potent in vitro and in vivo anti-cancer activities in B-cell malignancies-derived models with improved selectivity against other PI3K isoforms compared with TGR-1202. Combination with ibrutinib further improves anti-tumor activity compared with monotherapy. FCN-289 shows favorable PK and safety profiles compared with TGR-1202. Our findings highlight the therapeutic potential of FCN-289 as a novel targeted approach as monotherapy or in combination for treating B-cell malignancies. Citation Format: Shu Lin, Zuwen Zhou, Rui Tan, Hua Xu, Huajie Zhang, Weipeng Zhang, Ling Chen, Lijun Yang, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5453.

Coastal: A Phase 3 Study of the PI3Kδ Inhibitor Zandelisib with Rituximab (R) Versus Immunochemotherapy in Patients with Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Coastal: A Phase 3 Study of the PI3Kδ Inhibitor Zandelisib with Rituximab (R) Versus Immunochemotherapy in Patients with Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

A Phase1b Clinical Study of the Oral PI3Kδ Inhibitor, Linperlisib, in Patients with B-Cell Lymphomas

IntroductionThe PI3Kδ inhibitor, linperlisib, is a structurally distinctive oral agent demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma (FL) and peripheral T-cell lymphoma (PTCL). Here we report initial results of a phase1b study (NCT04279405) evaluating the activity and safety of linperlisib across B-cell lymphoma types, namely DLBCL, MCL, MZL, FL and SLL/CLL.MethodsEnrollment initiated in Jan 2020 at 11 clinical sites in China for patients (pts) of DLBCL, MCL, MZL, FL and SLL/CLL having received at least one standard anti-tumor systemic therapy and at least 2 cycles of each prior treatment. Linperlisib tablets were administered orally, 80mg once daily under fasted conditions for 28 days as a cycle, until disease progression, unacceptable toxicity or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was evaluated every 2 cycles using the IWG 2007 criteria.ResultsAs of Jul 22, 2021, 43 r/r lymphoma patients were enrolled, including DLBCL (20 pts), MCL (9 pts), FL (8 pts), MZL (3 pts) and SLL/CLL (3 pts). With a median of 2 prior therapies, the majority (93%) of pts previously received first line immunochemotherapy including anti-CD20 targeted therapies. One pts withdrew consent before study treatment began. Three pts withdrew consent in first cycle without post baseline imaging assessment. Forty two pts and 39 patients were evaluable for safety and efficacy, respectively.Linperlisib was well-tolerated in this study. The safety profile observed was consistent to that observed in the clinical studies with FL and PTCL patients, with no new toxicities reported. The most frequent TRAE (all Grade >10%) were neutropenia (54.8%), lymphopenia (40.5%), thrombocytopenia (28.6%), anemia (23.8%), alanine aminotransferase increased (21.4%), aspartate aminotransferase increased (21.4%), blood triglycerides increased (16.7%), blood uric acid increased (14.3%), diarrhoea (11.9%), proteinuria (11.9%) and rash (11.9%). The most frequent Grade ≥3 TRAEs were neutropenia (26.2%) and lymphopenia (9.5%). Thirteen (31.0%) pts experienced SAE considered to be drug related, including pneumonia, thrombocytopenia, pancreatitis, and febrile neutropenia. SAE leading discontinuation from study occurred in 7 pts .Three pts experienced AE that lead to dose modification. No death happened due to any TRAE. No specific associations were observed between B-cell lymphoma types and adverse events on linperlisib treatment.An overall response rate (ORR) and overall disease control rate (DCR) of 53.8% and 79.5% were observed in the evaluable patients. Table1 The 17 evaluable DLBCL pts contained 1 unconfirmed CR (GCB) and 3 PR (GCB, N-GCB, and DLBCL transformed from MZL). The DOR for the 4 DLBCL responders were 56 days, 56 days, 56 days and 196 days. The 8 evaluable FL pts were 3 unconfirmed CR plus 5 PR, and a median DOR of 112days. The 8 evaluable MCL pts contained 2 unconfirmed CR, 3 PR, and 2 SD. The median DOR of the 5 MCL responders were 56 days. The 3 evaluable MZL pts and 3 evaluable SLL/CLL pts were both consisted of 1 unconfirmed CR, 1 PR and 1 SD .The DOR for the 2 MZL responders were 196 days and 56 days, the DOR for the 2 SLL/CLL responders were both 196 days. At the data cutoff date, 16 pts were still treatment ongoing, 19 pts had received exceeding 6 months of treatment, and 1 pt had received exceeding 12 months of treatment, supporting a durable benefit of linperlisib monotherapy.ConclusionsLinperlisib demonstrated broad anti-tumor activities in several r/r B -cell malignancies, including DLBC, MCL, MZL, FL and SLL/CLL. Furthermore, linperlisib showed a favorable safety profile with respect to the previously reported information from approved agents in the class of PI3K inhibitors. Further clinical studies of linperlisib in B-cell malignancies and in combination therapies are warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

An Integrated Safety Analysis of the Next Generation PI3Kδ Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

An Integrated Safety Analysis of the Next Generation PI3Kδ Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

Results from the Phase 3 DUOTM Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Results from the Phase 3 DUOTM Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Multicentre Retrospective Analysis of Chronic Lymphocytic Leukaemia Patients Treated with Idelalisib, “Real World” Data from the UK and Republic of Ireland - a Cohort of 68 Patients

INTRODUCTIONIn 2014, idelalisib, an oral PI3Kδ (phosphoinositide 3-kinase delta) inhibitor, was approved in combination with rituximab for refractory/relapsed (RR) Chronic Lymphocytic Leukaemia (CLL). Idelalisib has significant activity in the treatment naïve and RR setting, including those with poor prognostics (17p-/TP53 mutated). In published trials idelalisib has a manageable adverse event profile. However, there have been subsequent safety concerns pertaining to infection-related mortality, Cytomegalovirus (CMV) reactivation, Pneumocystis jiroveci pneumonia (PJP), hepatitis, pneumonitis, intestinal perforation and colitis. There is a paucity of real life data.AIMSTo present “real world” data, detailing Event Free Survival (EFS) and treatment-related toxicities, in patients receiving idelalisib based therapy.METHODSData was collected retrospectively via a standardised data capture form. All prescribing centres (n=112) within the United Kingdom (UK) and Republic of Ireland (ROS) were contacted by email. Trial patients were included. Poor prognostic disease was defined as 17p-, TP53 mutated, 11q- or ATM deleted. It was not possible to document IWCLL response due to selective re-staging. Minimum duration of treatment for inclusion was 3 months.RESULTSSixty-eight patients were analysed, treated between April 2013 to July 2017. Median age was 77 years (range: 50 - 91), 46/68 being male. Median number of prior therapies was 2 (range: 0-7; 9 first line), including rituximab, fludarabine, alemtuzumab and bendamustine. The majority (51/68) had good performance status (Eastern Cooperative Oncology Group 0/1). TP53 mutated/17p- disease accounted for 26/68 (38%), and 11q-/ATM mutated 9/68 (13%; 3 additional TP53 mutations).Median duration of treatment was 12 months (range 3-49), of which 24% (16/68) completed ≥24 months of treatment. Three patients (4%) had no response.Disease-related cytopenias, irrespective of a persisting lymphocytosis, resolved in 78% (51/65), 82% (51/62) and 88% (42/48) at 3, 6 and 12 months. Radiological CR/PR was reported in 71% (PR 10/21; CR 5/21), 70% (11/27 PR; 8/27 CR) and 69% (4/16 PR; 7/16 CR) at 3, 6 and 12 months respectively. Only 1 patient progressed radiologically within the first 6 months. Bone marrow CR/PR was reported in 64% (7/14 PR; 2/14 CR), 69 % (6/17 PR; 5/16 CR) and 75% (3/8 PR; 3/8 CR) at 3, 6 and 12 months.Median EFS (defined as progression, death [including post-Idelalisib discontinuation] or treatment discontinuation) was 15 months (low risk 14 months; high risk 16 months; p=0.3). Sixty-five percent (44/68) of the cohort remained on therapy at 12 months, 22% (15/68) ≥24 months.Diarrhoea/colitis was the commonest toxicity, 22/68 patients (32%), of which half were grade ≥3. Toxicities include haematological 28% (5/19 grade≥3), rash 19% (3/13 grade≥3), hepatotoxicity 19% (4/13 grade≥3), pneumonitis 14% (n=10), PCP infection 7% (n=5, prophylaxis regime unclear) and CMV reactivation 4% (n=3; no CMV infection pre-Idelalisib).Treatment interruption due to drug toxicity was reported in 32/68 patients (diarrhoea/colitis n=10; infections n=11). The median number of drug interruptions was 1 (range: 1-4), median duration off therapy 30 days (range: 7 - 180). In 37/68 patients (54%) idelalisib was discontinued (n=12 progression; n=13 diarrhoea/colitis; n=6 recurrent infection; pneumonitis n=4; hepatotoxicity n=2). Twenty deaths (29%) were recorded but only 3 occurred on Idelalisib (1 therapy-related). Nine of 12 patients that had progressed died at time of analysis.CONCLUSIONWe report one of the first “real-world” cohorts treated with idelalisib. This was a relatively elderly multiply treated population, although with good performance status, 51% had poor prognostics which did not confer an inferior outcome. Median number of cycles was 12 (admixed - first line/relapsed) with an EFS of 15 months. Median treatment duration has been reported up to 22.4 months in the up-front setting (O'Brien et al. 2015; Blood). Thirty seven percent of patients discontinued therapy due to toxicity, mostly due to diarrhoea/colitis, comparable to other publications (Thompson et al. 2016; Cancer). Risk profile can be reduced with PCP prophylaxis, CMV surveillance and following consensus guidelines on toxicity management. Idelalisib remains an efficacious treatment for CLL, with 22% of the cohort continuing on therapy at 24 months. [Display omitted] DisclosuresPatten:Gilead Inc: Honoraria, Research Funding; Roche: Honoraria; Abbvie: Honoraria. Gohil:UCL Business: Patents & Royalties. Iyengar:Gilead Inc: Honoraria; Janssen: Honoraria. Nathwani:UCL Business: Patents & Royalties. Heath:Gilead Inc: Honoraria. Ayto:Gilead Inc: Honoraria.

Efficacy Results of a Phase 2 Trial Evaluating Idelalisib Plus Ofatumumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia

Efficacy Results of a Phase 2 Trial Evaluating Idelalisib Plus Ofatumumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia

Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL).

TPS7573 Background: Patients (pts) with iNHL treated with front-line immunochemotherapy may benefit from an alternative, chemotherapy-free regimen at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3Kδ inhibitor, achieved an 87% response rate, with median duration of response not reached in iNHL when given as a monotherapy or in combination with R. A low rate ( < 10%) of Grade ≥ 3 immune-mediated adverse events of special interest associated with PI3kδ inhibitors is observed in patients administered zandelisib on an intermittent schedule (IS) (JCO 2020 38:15_suppl, 8016). An open-label, phase 2 study (TIDAL, NCT03768505) of zandelisib as monotherapy is ongoing in pts with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: The COASTAL study is a randomized, open-label, controlled multicenter phase 3 trial to investigate the safety and efficacy of zandelisib in combination with R versus standard immunochemotherapy in pts with iNHL. Key eligibility criteria: adults with relapsed or refractory FL or MZL who received ≥1 prior lines of therapy which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion > 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. Key exclusion criteria: histologically confirmed diagnosis of FL grade 3b or transformed disease; administration of 2 prior immunochemotherapy regimens; prior PI3K inhibitor therapy; known lymphomatous involvement of the central nervous system. Subjects will be randomized 1:1 to receive R-zandelisib or immunochemotherapy (R-CHOP or R-B) and stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy. Zandelisib will be given in a 28-day cycle comprising of daily dosing for 2 cycles followed by IS dosing on days 1-7 of each 28-day subsequent cycle for a duration of 2 years. Rituximab or immunochemotherapy will be given for a total of 6 cycles. Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter. The primary efficacy endpoint is progression-free survival. The major secondary endpoints include ORR, complete response rate, overall survival, and safety. The trial will enroll approximately 534 pts in ̃200 sites globally and will begin enrollment in mid-2021. Clinical trial information: NCT04745832.

Initial results of the combination of PI3Kδ inhibitor zandelisib (ME-401) and the BTK inhibitor zanubrutinib in patients (pts) with relapsed or refractory (R/R) B-cell malignancies.

7553 Background: Dual inhibition of PI3Kδ and BTK pathways may overcome existing or acquired monotherapy resistance. Dual inhibition of these pathways displays synergistic activity in cell lines that is evident even at suboptimal concentrations [Blood 2015;125(14):2306-09]. Zandelisib is a potent, selective, and structurally differentiated oral PI3Kδ inhibitor (i), and zanubrutinib is an oral BTKi. Based on their efficacy as monotherapy, we hypothesized that the combination of zandelisib and zanubrutinib can be well tolerated and may improve the depth and durability of responses. We evaluatedthis combination therapy in pts with R/R B-cell malignancies to determine the optimal dose and schedule for further evaluation in disease-specific expansion cohorts (NCT02914938). Methods: This is a multi-cohort Phase 1b study enrolling pts with FL, CLL, MZL, MCL, DLBCL, or high grade B-cell lymphoma (HGBCL), ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3Ki or BTKi therapy. For this combination therapy, two dose levels were evaluated in 28-day cycles: Cohort 10A: zandelisib 60 mg once daily for 2 cycles followed by an intermittent schedule (IS) on days 1-7 of subsequent 28-day cycles and zanubrutinib 160 mg twice daily (bid). Cohort 10C: zandelisib 60 mg on days 1-7 starting in Cycle 1 and zanubrutinib at 80 mg bid. Dose limiting toxicity (DLT) observation period was 28 days for cohort 10A and extended to 56 days for cohort 10C. Response was assessed at month 3, 7, 13 and then every 6 months until progression. Results: 20 pts treated, 7 in cohort 10A and 13 in cohort 10C: 8 FL, 5 CLL, 2 DLBCL, 2 HGBCL, 2 MZL, and 1 MCL. Median age 70 years (range, 44-85) and median prior therapies 2 (1-8). Median follow-up of 2.9 months (0.5-17.4+). There were no DLT in cohort 10A, grade (Gr) ≥3 adverse events (AE) occurred after day 28 in 4 pts, including Gr 4 neutropenia (1 pt), Gr 3 neutropenia, fatigue and CMV colitis (1 pt), Gr 3 AST/ALT and rash (1 pt) and Gr 3 AST/ALT (1 pt). In cohort 10C, 2 pts had DLT with Gr 3 AST/ALT in Cycle 2, with 1 pt successfully resuming both drugs and 1 discontinued treatment due to recurrence of Gr 3 AST/ALT upon rechallenge.. Other Gr 3 AE were all laboratory findings: 1 pt (CLL) had laboratory TLS, neutropenia and thrombocytopenia and 2 pts (FL, DLBCL) had neutropenia. Response rate was 100% (2 CR 14 PR) in the following 16 pts with indolent NHL and MCL evaluable for response: FL (2 CR, 6 PR), CLL (5 PR), MCL (1 PR) and MZL (2 PR). No pt with aggressive B-cell lymphomas has responded. Conclusions: The combination of zandelisib 60 mg on IS from Cycle 1 and zanubrutinib 80 mg bid is well tolerated and achieves a high ORR in R/R indolent B-cell malignancies. This schedule is being evaluated in expansion cohorts in R/R FL and MCL. Clinical trial information: NCT02914938.

Efficacy and safety of the PI3Kδ inhibitor zandelisib (ME-401) on an intermittent schedule (IS) in patients with relapsed/refractory follicular lymphoma (FL) with progression of disease within 24 months of first-line chemoimmunotherapy (POD24).

7550 Background: FL patients (pts) with POD24 have poorer survival and may benefit from novel therapies at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study for FL demonstrating a high objective response rate (ORR) and well tolerated when given on IS (J Clin Oncol 2020;38:#8016). We report here results based on POD24 status (NCT02914938). Methods: Eligible pts had ≥1 prior therapy, adequate bone marrow and organ function, ECOG performance status ≤2, and no prior PI3K therapy. Zandelisib was administered at 60 mg once daily for 8 weeks followed by IS on days 1-7 of each subsequent 28-day cycle, either as monotherapy or with rituximab at 375 mg/m2 for 8 doses in Cycles 1-6. Treatment was continued until disease progression, intolerance, or withdrawal of consent. Imaging scans were obtained after 2 and 6 cycles, and then every 6 cycles. Response was reported based on Lugano criteria. Results: 37 FL pts were enrolled and received zandelisib on IS as monotherapy (N = 18) or in combination with rituximab (N = 19). Median number of prior therapies = 2 (range, 1-5). The ORR was 86.5% (32/37) with 27% CR (complete response). In the monotherapy group the ORR and CR were 77.8 % (14/18) and 27.8% and with rituximab 94.7% (18/19) and 26.3% respectively. Median duration of response (DOR) among all pts was not reached with a median follow-up of 16.9 months (mos) (1.2-33.1+). 22 pts (59%) were POD24, of which 15 (68%) had ≥2 prior lines of therapy. Despite more refractory disease, ORR among the POD24 pts was 81.8% (Table). Zandelisib on IS was well tolerated. 3 pts (8%) discontinued therapy due to an adverse event (AE) for any cause. Grade (Gr) 3 AE of special interest (AESI) were 2 (5.4%) diarrhea, 2 (5.4%) colitis, 3 (8.1%) rash, 3 (8.1%) ALT elevation, 1 (2.7%) AST elevation and no pulmonary infection. Conclusions: Zandelisib administered on IS as monotherapy or with rituximab resulted in a high-rate of durable responses in FL, both in POD24 and non-POD24 groups and therapy was well-tolerated with low rate of Gr 3 class-related AESI and discontinuation rate due to AE’s. Zandelisib as monotherapy is being evaluated in a global Phase 2 study in FL and MZL after failure of 2 prior therapies (NCT03768505). A Phase 3 study of zandelisib plus rituximab in FL and MZL after failure of prior immunochemotherapy will begin enrollment in 2021. Clinical trial information: NCT02914938. [Table: see text]

Duvelisib (Copiktra) in relapsed or refractory chronic lymphocytic leukemia: safety and efficacy

ABSTRACT Introduction: The treatment landscape of chronic lymphocytic leukemia (CLL) has changed dramatically with the introduction of novel targeted therapies. Phosphoinotiside-3 kinase (PI3K) is a B-cell receptor-associated kinase that is essential for growth, survival and migration of neoplastic B cells and is implicated in disease progression and drug resistance. Area covered: PI3K inhibitors idelalisib and duvelisib are approved in therapy of relapsed/refractory (R/R) CLL. In this drug profile review, we focus on duvelisib, an oral inhibitor of PI3Kδ and PI3Kγ isoforms, in treatment of patients with R/R CLL. Expert opinion: Duvelisib, a selective dual PI3Kδ/γ inhibitor, achieves meaningful efficacy in CLL, including in patients with high-risk features. Duvelisib therapy may be particularly appropriate for patients who are suboptimal candidates for Bruton tyrosine kinase inhibitors (BTK), such as those with cardiac conditions, poorly controlled hypertension, or requiring full-dose anticoagulation. Tumor lysis monitoring is not necessary with duvelisib, rendering advantage over the BCL2 inhibitor venetoclax. Patients who progress on both BTK inhibitors and venetoclax may be particularly good candidates for duvelisib therapy. With close monitoring and management of adverse events, duvelisib will continue to have a role in therapy of R/R CLL.

Safety Profile of Idelalisib in Patients with Refractory Follicular Lymphoma: Interim Analysis of a Noninterventional Study

Introduction: Idelalisib, a selective oral inhibitor of PI3Kδ, was approved by the FDA and EMA as monotherapy for patients with advanced follicular lymphoma (FL) based on positive efficacy and safety results from the registration phase 2 trial in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to 2 prior regimens (NCT01282424; 101-09). Phase 3 studies of idelalisib in earlier lines of treatment for iNHL were terminated prematurely due to an increased risk of death and higher incidence of serious adverse events (AEs) associated with idelalisib. Herein, we present the preplanned interim results as of June 8, 2020, of the safety of idelalisib monotherapy in patients with refractory FL treated in the EU from one of the largest noninterventional trials of idelalisib. Methods: This was a noninterventional, partially retrospective cohort study conducted in 10 European countries (EUPAS19618; NCT03568929). Eligible patients were adults aged ≥18 years treated with idelalisib for refractory FL, per the Summary of Product Characteristics and treatment guidelines, in routine clinical practice. Data was collected from patients' medical records and anonymized. Safety events were evaluated and included treatment-emergent AEs (TEAEs), health outcomes of interest (HOIs) requested by the EMA (bowel perforations, Grade ≥3 diarrhea/colitis, progressive multifocal leukoencephalopathy, pneumonitis, Grade ≥3 rash, infections, Stevens-Johnson syndrome, transaminase elevations, and hepatocellular injury), and deaths. TEAEs were defined as AEs that occurred between first dose and 30 days after last dose. Data were summarized using descriptive statistics. Rates per person-year were calculated as the number of patients experiencing an AE divided by the person-time at risk. Results: For the 158 patients included in this analysis, median age was 67 years and 84 (53%) were male. A summary of patient and disease characteristics at baseline are presented in Table 1. At treatment initiation, 47 (30%) patients had grade 2 FL and 105 (66%) had Ann Arbor stage III/IV disease, though these characteristics were not captured for 42% and 20% of patients, respectively; 149 (94%) had ≥2 prior therapies. The median duration of idelalisib exposure was 165 (range 11-1321) days, and patients were observed for a median of 323 (range 12-1676) days. In total, 144 (91%) patients experienced a TEAE, with a rate of 3.36 per person-year. The proportion of patients experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Table 2. Diarrhea of any grade was the most common TEAE, and infections were the most common treatment-emergent HOI. During the TEAE period, 19 (12%) patients died (Table 2). The proportion of common TEAEs reported in this analysis were lower compared with a subgroup analysis of patients with FL from the registration trial (Salles Haematologica 2017; DOI: 10.3324/haematol.2016.151738), including diarrhea 27% vs 51%, cough 9% vs 32%, fever/pyrexia 10% vs 29%, pneumonia 5% vs 11%; treatment-emergent Grade 3/4 diarrhea/colitis and transaminase elevations were also lower in this analysis: 8% vs 17% and 4% vs 14%. This comparison is limited due to differences in study populations, namely that patients in the registration trial had more advanced disease (stage III/IV, 66% vs 83%) and had a higher median number of prior therapies (3 vs 4). Conclusions: This interim analysis of the safety of idelalisib in patients with refractory FL in this large noninterventional safety study provides an estimate of potential final study findings. The AE profile from this study appears to corroborate the known safety profile of idelalisib. No new safety signals were detected. Disclosures Salles: Bristol Myers Squibb: Consultancy, Other; Genmab: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other. Pettengell:Celgene: Honoraria; MEI Pharma: Honoraria; Roche Ltd: Honoraria; Takeda: Honoraria. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Abbvie: Other: travel grants, Research Funding; Gilead: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Corradini:Kiowakirin: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other; BMS: Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other. De Belder:Gilead Sciences Europe, Ltd.: Current Employment. Shah Gupta:Gilead Sciences, Ltd.: Current Employment. van Troostenburg:Gilead Sciences GmbH: Current Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Current Employment. Ramroth:Gilead Sciences, Ltd.: Current Employment.

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia

PI3Kδ (phosphatidylinositol 3-kinase-δ), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL.

Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies.

8016 Background: ME-401, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study, and previously demonstrated a high objective response rate (ORR) in FL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) when given on a continuous (CS) or an intermittent schedule (IS). IS appeared to significantly reduce the incidence of immune-mediated adverse events of special interest (AESI) associated with PI3kδ inhibitors (diarrhea, rash, transaminase elevation, pneumonitis). We report maturing data from patients treated on the IS in this study. Methods: Eligible patients (pts) had FL, CLL/SLL, marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL), at least 1 prior therapy, adequate bone marrow and organs function, ECOG status ≤2, and no prior PI3K therapy. IS dosing: ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m2 for 8 doses in Cycles 1-6. Results: Total of 57 pts treated with IS: 35 FL, 10 CLL/SLL, 4 MZL, and 8 DLBCL with 38 (67%) currently still ongoing. Median age: 66 years (range 38-94) and median prior therapies: 2 (range 1-8). As of January 2020, median follow-up = 9.7 mo (range 0.6-25.4+). Grade 3 AESI reported in 7 pts: 2 diarrhea (3.5%), 2 colitis (3.5%), 1 rash (2%), 1 ALT increased (2%), and 1 pneumonitis (2%). No Grade 3 AESI reported beyond Cycle 3. Discontinuation for AE in 3 pts (5%). There were no discernable safety differences between the monotherapy and rituximab combination groups. ORR was 83% in FL (76% in monotherapy group, 88% in combination group) and 89 % in CLL/SLL (100%, 83%), with median duration of response not reached. Median PFS was not reached in all patients with FL and CLL (combined analysis of both single agent and with rituximab). ORR was 100% (4/4) in MZL and 25 % (2/8) in DLBCL (in combination group only). Conclusions: ME-401 administered on an IS was well-tolerated, with a low-rate of Grade 3 class-related AESI and achieved a high-rate of durable objective responses in R/R indolent B-cell malignancies. These results may differentiate ME-401 and support further evaluation as a single-agent and in combination regimens. An ongoing global trial is evaluating ME-401 by IS in pts with FL after failure of ≥2 prior therapies (NCT03768505). Clinical trial information: NCT02914938 .