PI3Kδ Inhibitor Research Articles

Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition

Targeting aberrantly expressed kinases in malignant pleural mesothelioma (MPM) is a promising therapeutic strategy. We here investigated the effect of the novel and highly selective Phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib (IOA-244) on MPM cells and on the immune cells in MPM microenvironment.To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). In a co-culture model of patient-derived MPM cells, autologous peripheral blood mononuclear cells and fibroblasts, the tumor cell viability and changes in immune cell composition were investigated after treatment of roginolisib with nivolumab and cisplatin. PI3K-δ was detected in 66/89 (74%) MPM tumors and was associated with reduced overall survival (12 vs. 25 months, P=0.0452). Roginolisib induced apoptosis in MPM cells and enhanced the anti-tumor efficacy of AKT and mTOR kinase inhibitors by suppressing PI3K-δ/AKT/mTOR and ERK1/2 signaling. Furthermore, the combination of roginolisib with chemotherapy and immunotherapy re-balanced the immune cell composition, increasing effector T-cells and reducing immune suppressive cells. Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin.These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen.

Evaluation of the cardiac safety of parsaclisib, a selective PI3Kδ inhibitor, in patients with previously treated B-cell malignancies: Results from the CITADEL-101 study.

Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B-cell malignancies and studied in patients with autoimmune diseases and myelofibrosis. The CITADEL-101 study (NCT02018861) assessed safety, tolerability, and preliminary efficacy of parsaclisib in patients with relapsed or refractory non-Hodgkin lymphoma. This study evaluated the cardiac safety of parsaclisib as monotherapy based on data from 72 patients enrolled in the CITADEL-101 study. Time-matched pharmacokinetic and ECG measurements were collected at specified times for 69 patients receiving monotherapy in doses of 5, 10, 15, 20, 30, and 45 mg once daily. Based on the categorical outlier analysis, no dose-dependent effect was observed on the incidence of outliers in QT interval corrected for heart rate (HR) by Fridericia's method (QTcF), HR, or cardiac conduction. Based on central tendency analysis, the least square means (LSMs) (90% confidence interval [CI]) of ΔQTcF from the central tendency analysis ranged from -6.83 (-18.8 to 5.19) to 4.75 ms (0.410-9.09) across dose groups (below 20 ms, the threshold of large QT effects) and was not considered dose dependent. Moreover, the LSMs of ΔHR, ΔPR interval, and ΔQRS interval were minor. From the concentration-ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (-1.75 to 2.48) and 7.87 ms (0.921-14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration-dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction.

Integrating cfDNA liquid biopsy and organoid-based drug screening reveals PI3K signaling as a promising therapeutic target in colorectal cancer

BackgroundThe current precision medicine relies on biomarkers, which are mainly obtained through next-generation sequencing (NGS). However, this model failed to find effective drugs for most cancer patients. This study tried to combine liquid biopsy with functional drug tests using organoid models to find potential drugs for cancer patients.MethodsColorectal cancer (CRC) patients were prospectively enrolled and blood samples were collected from patients before the start of treatment. Targeted deep sequencing of cfDNA samples was performed using a 14-gene panel. Gastrointestinal (GI) cancer organoids were established and PI3K and mTOR inhibitors were evaluated on organoid models.ResultsA total of 195 mutations were detected across 58 cfDNA samples. The most frequently mutated genes were KRAS, TP53, PIK3CA, and BRAF, all of which exhibited higher mutation rates than tissue biopsy. Although 81% of variants had an allele frequency of less than 1%, certain mutations in KRAS, TP53, and SMAD4 had high allele frequencies exceeding 10%. Notably, among the seven patients with high allele frequency mutations, six had metastatic tumors, indicating that a high allele frequency of ctDNA could potentially serve as a biomarker of later-stage cancer. A high rate of PIK3CA mutation (31 out of 67, or 46.3%) was discovered in CRC patients, suggesting possible tumor progression mechanisms and targeted therapy opportunities. To evaluate the value of anti PI3K strategy in GI cancer, different lines of GI cancer organoids were established. The organoids recapitulated the morphologies of the original tumors. Organoids were generally insensitive to PI3K inhibitors. However, CRC-3 and GC-4 showed response to mTOR inhibitor Everolimus, and GC-3 was sensitive to PI3Kδ inhibitor Idelalisib. The CRC organoid with a PIK3CA mutation showed greater sensitivity to the PI3K inhibitor Alpelisib than wildtype organoids, suggesting potential treatment options for the corresponding patients.ConclusionLiquid biopsy holds significant promise for improving precision treatment and tumor prognosis in colorectal cancer patients. The combination of biomarker-based drug prediction with organoid-based functional drug sensitivity assay may lead to more effective cancer treatment.

Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results

AbstractRuxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

Optimization of virtual screening against phosphoinositide 3-kinase delta: Integration of common feature pharmacophore and multicomplex-based molecular docking

Extensive research has accumulated which suggests that phosphatidylinositol 3-kinase delta (PI3Kδ) is closely related to the occurrence and development of various human diseases, making PI3Kδ a highly promising drug target. However, PI3Kδ exhibits high homology with other members of the PI3K family, which poses significant challenges to the development of PI3Kδ inhibitors. Therefore, in the present study, a hybrid virtual screening (VS) approach based on a ligand-based pharmacophore model and multicomplex-based molecular docking was developed to find novel PI3Kδ inhibitors. 13 crystal structures of the human PI3Kδ-inhibitor complex were collected to establish models. The inhibitors were extracted from the crystal structures to generate the common feature pharmacophore. The crystallographic protein structures were used to construct a naïve Bayesian classification model that integrates molecular docking based on multiple PI3Kδ conformations. Subsequently, three VS protocols involving sequential or parallel molecular docking and pharmacophore approaches were employed. External predictions demonstrated that the protocol combining molecular docking and pharmacophore resulted in a significant improvement in the enrichment of active PI3Kδ inhibitors. Finally, the optimal VS method was utilized for virtual screening against a large chemical database, and some potential hit compounds were identified. We hope that the developed VS strategy will provide valuable guidance for the discovery of novel PI3Kδ inhibitors.

Preclinical pharmacokinetic characterization of amdizalisib, a novel PI3Kδ inhibitor for the treatment of hematological malignancies.

Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.

PI3Kδ Inhibition Potentiates Glucocorticoids in B-lymphoblastic Leukemia by Decreasing Receptor Phosphorylation and Enhancing Gene Regulation.

Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.

A phase 2 study of the PI3Kδ inhibitor parsaclisib in relapsed and refractory marginal zone lymphoma (CITADEL-204)

AbstractParsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell lymphomas. The phase 2 CITADEL-204 study (NCT03144674, EudraCT 2017-000970-12) assessed efficacy and safety of parsaclisib in Bruton tyrosine kinase (BTK) inhibitor–experienced (cohort 1) or BTK inhibitor–naive (cohort 2) patients with R/R marginal zone lymphoma (MZL). Patients aged ≥18 years with histologically confirmed R/R MZL, treated with ≥1 prior systemic therapy (including ≥1 anti-CD20 antibody) received parsaclisib 20 mg once daily for 8 weeks then 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg once daily for 8 weeks then 2.5 mg once daily (daily dosing group [DG]); DG was selected for further assessment. Primary end point of the study was objective response rate (ORR). Owing to slower than expected recruitment, cohort 1 was closed with 10 patients (WG, n = 4; DG, n = 6) enrolled. Based on a planned interim analysis in cohort 2, the futility boundary was not crossed, and enrollment continued to study completion. At data cutoff (15 January 2021), 100 patients were enrolled and treated in cohort 2 (WG, n = 28; DG, n = 72). In the DG, the ORR was 58.3% (95% confidence interval [CI], 46.1-69.8), with a complete response rate of 4.2% (95% CI, 0.9-11.7); the lower bound of the ORR 95% CI exceeded the protocol-defined threshold of 40%. The median duration of response was 12.2 months (95% CI, 8.1-17.5) and progression-free survival was 16.5 months (95% CI, 11.5-20.6); median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) among all patients were diarrhea (47.0%), cough (23.0%), and rash (18.0%); the most common grade ≥3 TEAEs included diarrhea (12.0%), neutropenia, and pneumonia (9.0% each). TEAEs led to dose interruptions, reductions, and discontinuations in 56.0%, 16.0%, and 29.0% of all patients, respectively. Durable responses and an overall manageable safety profile were demonstrated in patients with R/R MZL treated with parsaclisib monotherapy.

Abstract B165: A pharmacologic screen identifies drugs to be combined with the non-ATP competitive PI3Kδ inhibitor roginolisib (IOA-244) for an improved anti-tumor activity in lymphoma models

Abstract Background. Despite a strong clinical activity against lymphomas, PI3Kδ inhibitors are now less used due to the risk of toxicities. Roginolisib is a non-ATP competitive PI3Kδ inhibitor (i) (Di Conza, SITC 2022; Johnson, Cancer Res Com 2023). Via a unique allosteric binding, it causes PI3Kδ inactive form stabilization without off-target effects typically seen with other PI3K inhibitors. Indeed, early clinical data show a very good safety profile (Di Giacomo, ASCO 2022; Carlo-Stella, ICML 2023). Here, we present an extensive combination study with roginolisib in lymphoma models. Methods. Cells were exposed (72h) to DMSO, 474 library compounds (5µM), single or with roginolisib (5µM), or roginolisib, followed by MTT assay. Library included 247 drugs of the Cambridge Cancer Compound Library, plus lymphoma treatment drugs or biologically relevant molecules. Hits were first validated in experiments with extended concentrations of both compounds in the same cell used in the screen. Combinations giving synergism/additivity according to Chou-Talalay algorithm were considered as beneficial. Results. A screen to identify active roginolisib-based combinations was done in two cell lines, SP-53 (mantle cell lymphoma, MCL), and HH (cutaneous T-cell lymphoma, CTCL). Combination partners identified and validated in both models included ruxolitinib (JAK1/2i), vorinostat (class I/II HDACi), venetoclax (BCL2i) BI-3802 (BCL6i), emavusertib (IRAK4i), safimaltib (MALT1i), tretinoin (all-trans-retinoic acid), and telaglenastat (glutaminase-i). Combinations with romidepsin (class I HDACi), valemetostat (EZH1/2i), diABZI (STING agonist), DNA methyltransferase i 5-azacytidine, and bromopyruvic acid (antimetabolite) were active only in the HH model. Multiple BTKi (ibrutinib, acalabrutinib, zanubrutinib, orelabrutinib, nemtabrutinib) showed increased activity when combined with roginolisib: validation was done using a 3rd generation BTK inhibitor, pirtobrutinib, observing a benefit in both cell lines. Selinexor (XPO1i) and pixantrone (chemo), with an already strong activity as single agents, showed benefit in both models. The combination of roginolisib with venetoclax or vorinostat was extended to eight more models of diffuse large B cell lymphoma (Farage, TMD8), MCL (Granta519, JVM2, SP49), chronic lymphocytic leukemia (MEC1), CTCL (MJ), NK cell lymphoma (YT), and to compounds with similar mechanism of action (class I/II HDAC i belinostat; BCL2 i S55746), and 2 MCL1i (S64315, S63845). Synergism or additivity were achieved with vorinostat, venetoclax and S63845 in 7/8 models, with belinostat and S55746 in 6/8 and with S64315 in 7/7. Roginolisib plus 5-azacytidine also achieved synergism/additivity in 5/8 cell lines. Finally, the addition of the JAK1/2i ruxolitinib to roginolisib was beneficial also in two Sezary syndrome cell lines (Hut78, H9). Conclusions. The study identified drugs that could be explored in combination with roginolisib for lymphoma patients taking advantage of the safe profile as single agent reported in clinical trials. Citation Format: Chiara Tarantelli, Elisa Civanelli, Eleonora Cannas, Filippo Spriano, Afua A. Mensah, Luciano Cascione, Alberto J Arribas, Anastasios Stathis, Karolina Niewola-Staszkowska, Giusy Di Conza, Michael Lahn, Francesco Bertoni. A pharmacologic screen identifies drugs to be combined with the non-ATP competitive PI3Kδ inhibitor roginolisib (IOA-244) for an improved anti-tumor activity in lymphoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B165.

Establishment and application of a microglial phagocytosis/cell health high content assay for Alzheimer’s disease drug discovery targeting microglia

AbstractBackgroundTargeting microglial phagocytosis has been proposed as a therapeutic strategy for Alzheimer’s disease drug discovery. A reliable cellular assay capable of measuring drug‐regulated phagocytosis activity while simultaneously measuring treatment‐caused cell stress and toxicity is needed for drug discovery research targeting microglia. This need motivated us to develop and establish a high content microglial phagocytosis/cell health assay to meet the challenge.MethodThe assay uses 384‐well cellular imaging plates, microglial cell lines (HMC3 and BV2) and mouse primary microglia, pHrodo‐myelin/membrane debris as ligand, and a high content imaging system for imaging and analysis. Assay procedures include 1) plate cells on day 1 and incubate cell plates overnight in 37oC; 2) treat cells with compounds on day 2; 3) add pHrodo‐myelin/membrane debris to cell plates on day 3 and incubate in 37oC for 20 hours; 4) stain cell nuclei with Hoechst‐33342 for 30 min before performing high content imaging and analysis on day 4. Three selected parameters are measured from cell images: 1) mean total fluorescence intensity per cell of pHrodo‐myelin/membrane debris in phagocytosis vesicles to quantify phagocytosis; 2) cell counts per well (assessing effects on proliferation and cell death); and 3) average nuclear intensity (detecting induced apoptosis).ResultVarious treatments targeting different mechanisms regulating microglial phagocytosis were tested; we observed that Cytochalasin D inhibited phagocytosis, LPS stimulated phagocytosis in BV2 cells but not HMC3 cells, Idelalisib (PI3Kd inhibitor) inhibited HMC3 cell phagocytosis, and Saracatinib (Src/abl family of kinases inhibitor) stimulated HMC3 phagocytosis. These results validated the assay for use in drug discovery targeting microglial phagocytosis. With the assay, we identified some INPP5D inhibitors and some PLCG2 activators stimulated phagocytosis in a concentration range without significant cell stress/toxicity with all three cell types tested.ConclusionA microglial phagocytosis/cell health assay was established. The simultaneous measurement of phagocytosis and cell health allows for the distinction of drug effects on regulation of phagocytosis from cellular stress/toxicity‐related changes, a distinguishing feature of the assay, which helped compound selection of drug discovery projects targeting INPP5D and PLCG2 respectively.

Novel Pi3kδ Inhibitor Roginolisib Synergizes with the Bcl-2 Inhibitor Venetoclax in Hematological Malignancies

Roginolisib (IOA-244) is a first in class allosteric modulator and non-ATP competitive, selective PI3Kδ inhibitor currently in a Phase 1 clinical study in lymphoma and solid tumors. Initial structural and biochemical studies identified unique chemical structure, excellent selectivity, and excellent PK properties for roginolisib as compared to earlier PI3Kδ inhibitors, while the clinical trial has demonstrated a favorable safety profile. Consistent with prior PI3Kδ inhibitors, roginolisib inhibits the in vitro growth of lymphoma cells. In contrast to other PI3Kδ inhibitors, roginolisib activity is correlated with the expression levels of PIK3CD, suggesting specific and on target cancer cell-intrinsic effects (PMID: 37066023). To identify rational combination strategies, initial pharmacological screening of 474 compounds in combination with roginolisib was carried out using a MTT assay in the lymphoma cell lines HH (cutaneous T cell lymphoma, CTCL) and SP-53 (mantle cell lymphoma, MCL). Initial screening identified that roginolisib synergized with the bcl-2 inhibitor venetoclax in the HH cell line with a combination index value (CI) of 0.003 by the Chou-Talalay method. To further validate this finding, the combination of roginolisib with venetoclax or with another bcl-2 inhibitor S55746 was tested in a broad range of lymphoma cell lines including GRANTA519, JVM2, SP49 (MCL); FARAGE, TMD8 (diffuse large B cell lymphoma); MEC1 (chronic lymphocytic leukemia); MJ (cutaneous T cell lymphoma); and YT (NK lymphoma). The combination showed synergism in all the cell lines (CI 0.81 - 0.05) except SP49 (CI- 1.3). Similarly, the combination of roginolisib with S55746 showed synergism in most of the cell lines (CI- 0.46 - 0.089), additive effect in SP49 (CI- 1) and antagonistic effect in GRANTA519 (CI- 1.3) and FARAGE (CI- 2.17). To assess the tumor-intrinsic effect of roginolisib in patient derived CLL cells, PBMCs isolated from CLL patients responding to prior BTK inhibitor (i) (n=4) or progressed on BTKi (n=6) were tested to check the effect of roginolisib on BCR signalling. Cells were treated with increasing doses of roginolisib from 0.625 μM to 5 μM in the presence of anti-IgM. Other BCRi such as idelalisib, duvelisib and acalabrutinib were used at 5 μM concentrations as positive controls. Roginolisib showed a dose dependent suppression of the activity of BCR downstream kinases such as AKT and ERK. The suppression of phosphorylation of AKT and ERK were comparable with other BCRi tested. Additionally, the apoptosis analysis by annexin/7AAD showed comparable activity of roginolisib with idelalisib, duvelisib or acalabrutinib at 5 μM concentration. To investigate the possible synergy of roginolisib with venetoclax in CLL patient samples who are BTKi responders (n=6) or BTKi progressors (n=8), apoptosis analysis was carried out in patient PBMCs. Viability of CLL cells following 48h of ex vivo treatment with increasing concentrations of roginolisib (0.625 to 5 μM) and venetoclax (1 to 8 nM) alone or in combination was tested. Both the BTKi responders and progressors showed strong synergy with the combination, with slightly better cell killing activity in BTKi progressors ( p=0.007) than responders ( p=0.019). To understand the mechanism by which roginolisib increases the sensitivity to venetoclax, changes in the expression levels of various Bcl-2 family proteins that have been implicated in venetoclax resistance such as Mcl-1, Bcl-xL, Bcl-2, A1 and BIM were measured by immunoblotting. Changes in expression were evaluated in PBMCs from both the BTKi responders (n=8) and progressors (n=7) after 24h treatment with 0.625 and 5 μM concentrations of roginolisib. A significant dose dependent downregulation of Mcl-1 was observed compared to DMSO treated cells in both BTKi responders ( p=0.0033) and progressors ( p= 0.0025). In addition, a significant increase in proapoptotic BIM EL was also observed at both the 0.625 μM ( p=0.0054) and 5 μM ( p=0.0194) concentrations compared to DMSO. In summary, the novel PI3Kδ selective inhibitor roginolisib shows tumor cell killing on various hematologic malignancies including CLL cells from patients with disease progression on BTK inhibitors. In addition, roginolisib synergized with venetoclax in lymphoma cell lines and CLL patient samples. Our data support extending this combination strategy to clinical trials in hematological malignancies.

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.

Selective PI3Kδ Inhibitor Parsaclisib Combined with HDAC Inhibitor Chidamide in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma: Preliminary Results of a Phase Ib/Ⅱ Study

Background: Peripheral T-cell lymphoma (PTCL) is a highly heterogenous non-Hodgkin lymphoma with poor survival. Pts with relapsed/refractory PTCL (r/r PTCL) have extremely poor prognosis and limited treatment options. Conventional salvage treatments have a median progression-free survival (PFS) of only 3-4 months. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor has shown encouraging efficacy and favorable safety profile in B-cell malignancies. We developed a phase Ib/II study to evaluate the safety and efficacy of parsaclisib with HDAC inhibitor (HDACi) chidamide in r/r PTCL (NCT05083208). Here, we report the preliminary results of this study. Method: Eligible pts were ≤ 75 years old adults with histologically confirmed PTCL who received ≥ prior line of systemic therapy. Phase Ib dose-escalation study determined the maximum tolerated dose (MTD) of parsaclisib with chidamide using a 3 + 3 design. Parsaclisib was administered once daily at 3 dose levels (dose-level (DL) 1: 10 mg; DL2: 15 mg; DL3: 20mg) in the first 8 weeks followed by 2.5 mg QD in the subsequent treatment. Chidamide was administered at a fixed dose of 20 mg twice a week throughout the study. Once the MTD was established, pts were enrolled into phase 2 study to further characterize safety and efficacy. MTD of parsaclisib and objective response rate (ORR) were the primary endpoints; complete response rate (CRR), PFS, overall survival (OS) and tolerability were secondary endpoints. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection in the first 8 weeks were required. Results: From March 2022 to July 27, 2023 (date cut-off), 11 pts were recruited with a median age of 52 (39-74) years old. The median number of prior systemic therapies was 2 (1-5). Of 6 pts treated at DL1, 1 had dose-limiting toxicity (DLT) (grade 3 elevation of ALT/AST). No DLT was observed in 3 pts at DL2 and 2 at DL3. The DLT was resolved subsequently but the patient died from lymphoma progression. Treatment-emergent adverse events (TEAEs) were observed in all pts. The TEAEs were mainly hematologic toxicities and gastrointestinal reactions, most of which were grade 1/2. Grade 3/4 TEAEs were neutropenia (n=4), leukopenia (n=1), elevation of ALT/AST (n=1), and diarrhea (n=1) (Table 1). TEAE led to dose interruption in one patient. In 9 pts evaluable for responses (1 withdrew from this study and 1 was unevaluable), 5 (55.6%) pts achieved complete response (CR) and one (11.1%) partial response at the first efficacy assessment. In 7 pts previously exposed to chidamide, 4 pts achieved CR and 2 of them had a PFS > 16 months (Table 2 and Figure 1). Conclusion: Preliminary data demonstrated that selective PI3Kδ Inhibitor parsaclisib with HDACi chidamide was tolerable and produced promising responses in r/r PTCL, including patients previously exposed to chidamide. This trial is currently ongoing.

Roginolisib a Highly Selective Allosteric Modulator of the Phosphoinositide 3-Kinase Delta (PI3Kδ) in Patients with Refractory/Relapsed Follicular Lymphoma

Introduction PI3Kδ inhibitors are active in patients (pts) with lymphomas, but their clinical development has been hampered by toxicity (Brown et al, Lancet Oncol 2022). Roginolisib (IOA-244) exerts an allosteric modulation of the PI3Kδ C-terminus and functions as a non-ATP competitive PI3Kδ inhibitor, delivering a selective inhibition without off-target effects typically seen with other PI3K inhibitors (Johnson et al, Cancer Res Commun 2023). Using the recommended phase 2 dose (RP2D) of 80 mg QD established in solid tumors patients, patients with refractory/relapsed (r/r) follicular lymphoma (FL) were treated to investigate its safety profile in pts with hematologic malignancies (NCT04328844). Methods In Part A of the FiH dose escalation study, roginolisib was investigated at 20 and 80 mg QD in pts with r/r FL. Primary objective: safety of the RP2D established in solid tumor pts. Secondary objectives: PK; PD (e.g., changes in immune cell subsets in peripheral blood); Lugano-based responses; PFS and OS. Results In Part A for pts with r/r FL, there were two cohorts: (a) Cohort 1: 20 mg QD daily (4/4; 2 female, 2 male); (b) Cohort 2: 80 mg QD (4/4; 3 female, 1 male). There were no DLT observed and no dose modifications were needed. The mean time on treatment was 1.9 months (20 mg QD) and 4.3 months (80 mg QD), with one patient at the 80 mg receiving Roginolisib for 9 mo. More than 4 prior lines of treatment were in 3/8 pts. Transient (lasting less than 48 hrs) platelet reduction (G3) and AST/ALT elevation (G3) were observed in 2/8 pts, which improved while pts continued without a treatment intervention, such as dose modification or medical treatment with steroids. Lugano-based PRs were observed in 2/4 pts at the 80 mg QD dose and none at the 20 mg QD. At the 80 mg QD dose a third pt had a clinical response manifested by improvement in night sweats and fever, reduction in cervical palpable lymph nodes and relief from chronic pleural effusion. This clinical improvement lasted less than 5 weeks. While Overall Survival (OS) is still ongoing, the median has not been reached in this study and is currently at 14.3 mo. Subsequent to ending Roginolisib treatment, patients received at least one additional therapy (6/8), one patient was able to undergo autologous transplant with a complete metabolic response (CMR). Biomarker evaluation using flow cytometry showed low counts of T regulatory cells (Treg) in peripheral blood in all 8 r/r FL patients compared to solid tumor patients at baseline and throughout the treatment. Myeloid derived suppressor cells in peripheral blood remained unchanged during the course of treatment with Roginolisib. Conclusions The safety profile of roginolisib in pts with r/r FL appears to match that in pts with solid malignancies. In contrast to other PI3Kδ inhibitors, roginolisib is highly selective for binding to PI3Kδ, favoring an inactive confirmation of PI3Kd and functions as a non-ATP competitive inhibitor.

PI3Kδ Inhibitor Linperlisib As a ≥ 3-Line Treatment for Relapsed or Refractory Follicular Lymphoma: A Subgroup Analysis of a Phase II, Single-Arm, Open-Label Trial

Introduction Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL), originating in follicular central B cells, and accounts for approximately 22% of all newly diagnosed cases of NHL. Chemo-immunotherapy is the standard treatment option for FL. Unfortunately, the progression of the disease to relapsed or refractory FL (r/r FL) is still inevitable, which raised concern about subsequent effective treatments. Several δ isoform of phosphatidylinositol 3-kinase (PI3K-δ) inhibitors have ever been approved for r/r FL after ≥2 lines of prior therapies. However, most of their indications for r/r FL were withdrawal for increased risk of death and serious side effects. The latest data from the Chinese phase II clinical trial of linperlisib (Trial registration ID: NCT04370405), a novel oral PI3Kδ-selective inhibitor, in patients with r/r FL who had received at least two systemic therapies were presented. In this trial, linperlisib demonstrated compelling efficacy and was generally well-tolerated in the treatment of r/r FL patients after ≥2 prior systemic therapies. Linperlisib was approved by China National Medical Products Administration (NMPA) for adult r/r FL previously treated with at least two system therapies in November 2022. The ≥3 lines of treatment options are still unmet for the r/r FL. In this setting, this subgroup analysis of the linperlisib phase II trial aimed to evaluate outcomes of linperlisib in later-line treatment of r/r FL. Methods This study included all the patients with r/r FL who had received at least two systemic therapies previously enrolled in the open-label, single-arm, phase II trial (linperlisib, 80mg, po, q.d., in a 28-day cycle), with overall response rate (ORR) as the primary endpoint. In this subgroup analysis, the patients were divided into two groups according to the treatment lines they received: >3 prior lines of treatment and ≤3 prior lines of treatment. All of the statistical analyses were descriptive. Results A total of 84 r/r FL patients from 25 sites in China from April 2019 to September 2020 were enrolled in this trial, with a cutoff date of September 30, 2021. The ORR was 79.8%, with statistical significance in a heavily pretreated FL patient population with a median of 4 prior therapies, with a well-tolerated safety profile. A total of 43 patients received >3 prior lines of treatment, while 41 patients received ≤3 prior lines of treatment. The median age between the two groups was similar (range: 29.0 - 78.0, 52.0 years for >3 prior lines vs. 48.0 years for ≤3 prior lines). The majority of patients had Ann Arbor staging III-IV (40 for >3 prior lines vs. 34 for ≤3 prior lines). The median number of prior regimens was 4 for >3 prior lines and 3 for ≤3 prior lines. Overall, there were 67 patients achieved responses, with ORR of 83.7% (36, 95%CI:69.3, 93.2) for >3 prior lines vs. 75.6% (31, 95% CI: 59.7, 87.6) for ≤3 prior lines based on independent review committee assessment. Compared with patients who received ≤3 prior lines, patients received ≤3 prior lines achieved higher disease control rate (41[95.3] vs. 37 [90.2%]). The median DOR was 12 months (95% CI: 7.3, 15.9) for >3 prior lines vs. 13 months (95% CI: 9.2, NE). The median PFS was 11.9 months (95% CI: 9.1,19.4) for >3 prior lines vs. 13.3 months (95% CI: 8.2, NE) for ≤3 prior lines. The OS of both groups was not reached. The most common treatment-related adverse events (≥20%, TRAEs) were neutropenia (21 [48.8%] for >3 prior lines vs. 18 [43.9%] for ≤3 prior lines), leukocyte count decreased (15 [34.9%] vs. 15 [36.6%]), alanine aminotransferase increased (10 [23.3%] vs. 9 [22.0%]), lymphocyte count decreased (9 [20.9%] vs. 5 [12.2%]), hypertriglyceridemia (9 [20.9%] vs. 11 [26.8%]), and hypercholesteremia (6 [24.0%] vs. 7 [11.9%]). The most common grade ≥3 TRAEs (≥10%) were neutropenia (9 [20.9%] vs. 4 [9.8%]), pulmonary inflammation (3 [7.0%] vs. 6 [14.6%]), infectious pneumonia (2 [4.7%] vs. 5 [12.2%]). Conclusions This subgroup analysis revealed that linperlisib could achieve benefit in r/r FL patients who received at least 2 prior system therapies regardless of treatment lines. The AEs were well-tolerated. Further trials with large-scale samples were warranted.

A Phase Ib Study of Linperlisib Monotherapy in Patients with Relapsed or Refractory B-Cell Malignancies

Background: B-cell malignancies, a diverse and complex spectrum of lymphoproliferative disorders, are marked by a gradient of severity, ranging from indolent non-Hodgkin lymphomas (NHLs) such as follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), to more aggressive variants of NHL like diffuse large B-cell lymphoma (DLBCL). This wide array of disorders brings unique challenges in treatment, particularly for relapsed or refractory (r/r) cases where there is a significant dearth of effective therapeutic options. The PI3K pathway, a vital regulator of cellular functions such as cell growth, survival, and differentiation, has increasingly been recognized as a promising therapeutic target in the context of B-cell lymphomas. Accumulating evidence points towards its role in the pathogenesis of these disorders, underlining the potential of PI3K inhibitors in their treatment. Linperlisib, an orally administered PI3Kδ inhibitor, has emerged as a potential candidate for the management of r/r B-cell malignancies, with a previous phase I study demonstrating its safety and suggesting preliminary clinical activity. In this light, our phase Ib study aimed to further assess the safety and efficacy of linperlisib in a broader cohort of patients with r/r B-cell malignancies. Methods: Patients with histologically or cytologically confirmed B-cell malignancies, relapsed, refractory, or lacking standard-of-care systemic therapies, were enrolled. The study encompassed several subtypes of the disease, including DLBCL, mantle cell lymphoma (MCL), FL, marginal zone lymphomas (MZL), and CLL/small-cell lymphocytic leukemia (SLL). Linperlisib was administered orally at a dose of 80 mg daily in a 28-day cycle until disease progression, onset of unacceptable toxicity, or patient withdrawal. The primary endpoint of the study was the objective response rate (ORR), as per the 2007 International Working Group Criteria for lymphomas. Secondary endpoints included safety, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: A total of 43 patients with r/r B-cell malignancies were enrolled between Jun 15, 2020, and Apr 02, 2021, and subsequently received linperlisib. At the data cutoff point of Jan 10, 2023, the median follow-up was 24.7 (range: 0.8, 30.6) months. The ORR was recorded at 46.5% (95%CI, 31.2% to 62.3%), and the DCR at 72.1% (95%CI, 56.3% to 84.7%) across all patients. More specifically, the ORR for individual diseases were as follows: 30.8% (4/13) for GCB DLBCL, 27.3% (3/11) for non-GCB DLBCL, 55.6% (5/9) for MCL, 100.0% (4/4) for FL, 66.7% (2/3) for CLL/SLL, and 66.7% (2/3) for MZL. The median DOR for the entire patient cohort was 9.3 months (95% CI: 5.4 to not reached), and the median PFS was 8.3 months (95% CI: 3.7 to not reached). The median OS was not reached, with 1-year and 2-year OS rates of 79.1% (95% CI: 63.6% to 88.5%) and 76.7% (95% CI: 61.1% to 86.8%), respectively. In terms of safety, the most common adverse events of grade 3 or higher were decreased neutrophil count, infectious pneumonia, and decreased white blood cell count (Table 1). Conclusion: In summary, our study underscores the significant potential of linperlisib in providing broad anti-tumor activity across a range of r/r B-cell malignancies, including DLBCL, MCL, MZL, FL, and SLL/CLL. These encouraging results justify further investigation of linperlisib, both as a monotherapy and in combination with other therapeutic agents. It is hoped that these findings will help evolve and enhance our treatment strategies for B-cell malignancies and ultimately improve patient outcomes.

Immunomodulatory Effects of Chemo-Immunotherapy ± Idelalisib in Chronic Lymphocytic Leukaemia (CLL)

Introduction: Chronic lymphocytic leukaemia (CLL) is characterised by a dysfunctional immune profile. However, the precise impact of therapy on this altered immune state, both short and long term, remains unclear. The collection of pre-treatment and longitudinal blood samples in the NCRI phase III RIAltO trial (NCT01678430) offered a unique opportunity to address this question in the context of frontline chemo-immunotherapy (CIT) containing bendamustine or chlorambucil. The factorial randomisation to idelalisib versus placebo also provided a framework for investigating the immunomodulatory effects of PI3Kδ inhibition in this setting. Methods: We conducted mass cytometry analysis on samples obtained from CLL patients enrolled in the RIAltO trial. Patients were randomly assigned to receive ofatumumab plus either bendamustine or chlorambucil, with or without idelalisib. Samples were collected before treatment and at early (median 5.9 [IQR 5.7 - 6.4] months) and late (18.5 [16.1 - 22.6] months) post-treatment timepoints. Three healthy controls (HC) were included for comparison. CD3 + T cells were analysed using a customised CyTOF panel comprising 36 markers. Uniform manifold approximation and projection (UMAP) and manual gating analysis were utilised to evaluate global and specific T-cell changes. Results: In all, 177 samples from 79 CLL patients, obtained before or after CIT, were analysed. Baseline characteristics were similar between the different treatment arms. Compared to HC, treatment-naïve CLL patients exhibited a distinct T-cell profile with increased regulatory T cells, decreased naïve and central memory (CM) cells, elevated effector memory (EM) cells, reduced non-senescent cells, and increased expression of HLA-DR, PD-1, TOX, T-bet, and Eomes. Following CIT, the T-cell profile was significantly altered but remained distinct from that of HCs. CIT-induced changes persisted at the late post-treatment timepoint, indicating a sustained effect. Analysis of specific T-cell populations showed that, although some CLL-associated features became less prominent following CIT (expression of PD-1, TOX and TIGIT), most were enhanced (shift from naïve and CM cells towards a terminal effector phenotype; shift from a non-senescent to a terminally senescent phenotype; increased HLA-DR and T-bet expression). The post-treatment immune profiles were similar in patients receiving bendamustine or chlorambucil. Despite its immunomodulatory effects when used as a single agent, idelalisib also induced minimal additional changes. Furthermore, the post-treatment immune profile was similar in patients achieving minimal residual disease (MRD) negativity versus those who remained MRD positive, suggesting a direct pharmacodynamic effect. Finally, non-metric multidimensional scaling (NMDS) analysis demonstrated that CIT shifted the overall CLL-associated immune profile further away from that of HC, and that the shift was independent of chemotherapy allocation, idelalisib, or the level of CLL cytoreduction achieved. Conclusion: CIT results in profound immune changes that persists up to 18.5 [16.1 - 22.6] months following treatment. Furthermore, the overall effect of these changes further differentiates the CLL-associated immune profile from that of HC, deepening the existing T-cell dysfunction irrespective of chemotherapy choice, or the addition of idelalisib. Our study has important potential implications for patients receiving CIT in a range of clinical settings and supports the move towards more targeted agents that are less likely to cause indiscriminate immune perturbation.

A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Background Targeting the B-cell receptor (BCR) signaling pathway is highly effective for the treatment of CLL. However, attainment of undetectable minimal residual disease (uMRD) is infrequent with current BCR targeting strategies. Here, we report results of a phase 2 study testing time-limited dual BCR inhibitor therapy with a BTK inhibitor acalabrutinib and a PI3Kδ inhibitor umbralisib. With the goal of enhancing depth of remission, a glycoengineered anti-CD20 antibody ublituximab was initiated during Cycle (C) 7. Methods In this investigator-sponsored trial, eligible patients with treatment-naïve (TN) or relapsed or refractory (RR) CLL received up to 24 cycles of AU2 (NCT04624633). Each cycle was 28 days. Daily oral doses of acalabrutinib (100mg BID) and umbralisib (800mg QD) began on C1 Day (D) 1. Ublituximab IV began on C7 for 6 cycles (D1, 2, 8, and 15 of C7, D1 of C8-12). Treatment was stopped after C12 if patients achieved complete response (CR) by IWCLL criteria, while all others continued acalabrutinib and umbralisib until C24. In March 2023, umbralisib was withdrawn from drug development, and those who were receiving study therapy at the time continued acalabrutinib alone until C24. The primary endpoint was the CR rate after C24. MRD was assessed in peripheral blood (PB) and bone marrow (BM) using multi-color flow cytometry at 10 -4. Results The study enrolled 29 patients from December 2020 to January 2022. The median age at enrollment was 63 years (range 40-77). Most patients were male (62%), had TN CLL (72%), and had unmutated IGHV (79%). RR CLL patients had a median of 1 prior line of therapy, most frequently (88%) with chemoimmunotherapy. Genetic alterations were commonly observed at study enrollment, including deletion 17p or TP53 mutation (21%), deletion 11q or ATM mutation (38%), trisomy 12 (24%), and mutations of NOTCH1(45%), SF3B1 (24%), and RAS/RAF pathway (21%). 7% had complex karyotype defined as ≥3 abnormalities. At a median follow-up of 23 months (range 2-29), with 7 patients still receiving therapy prior to reaching C24, there were no deaths, Richter's transformations, or CLL progression events on the study. The rates of CR, BM uMRD, and PB uMRD at best response were 30%, 44%, and 67%, respectively (Table 1). There were no statistically significant differences in CR and uMRD rates between TN and RR groups at best response. CR and BM uMRD rates improved during the second year of therapy (CR rate: 11% after C12, 28% after C24; BM uMRD rate: 22% after C12, 39% after C24). PB uMRD occurred earlier than BM uMRD, and the rate (44%) remained unchanged between C12 and C24. After completion of study therapy, PB MRD was monitored every 3 months. Five patients had MRD conversion at the end of therapy or shortly after treatment cessation. Median time from the last uMRD to detectable MRD (dMRD) in PB was 3 months (range 3-6). Most (80%, n=4/5) patients with MRD conversion had partial response or dMRD in BM at best response. Two patients stopped treatment early (due to the diagnosis of second cancer and G4 transaminitis, in 1 patient each). In addition, 7 (24%) patients stopped umbralisib between C15-19 due to discontinuation of drug supply; these patients remained on acalabrutinib monotherapy until C24. All others completed up to 24 cycles of treatment including 3 (10%) patients who stopped therapy per protocol after C12 once CR was achieved. Dose reduction of umbralisib (38%) was more common than acalabrutinib (7%) and was most frequently due to diarrhea (21%) and transaminitis (14%). Only 2 (7%) patients required temporary dose reduction of acalabrutinib to avoid drug-drug interaction. Notable adverse events included diarrhea or colitis (76%, 10% Grade 3 or higher [G≥3]), bruising (69%, 0% G≥3), transaminitis (62%, 17% G≥3), COVID-19 infection (55%, 7% G≥3), hypertension (52%, 10% G≥3), rash (24%, 0% G≥3), and pneumonitis (7%, 3% G≥3). One (3%) patient had Pneumocystis jirovecii pneumonia while being off of mandatory prophylaxis due to non-compliance. None had atrial fibrillation. Conclusions Dual inhibition of the BCR signaling pathway with up to 2 years of AU2 provided a time-limited treatment option for TN and RR CLL patients. Immune-related adverse events were frequently observed and required dose reduction of umbralisib in 38% of the patients but most were then able to stay on therapy. Longer follow-up is required to determine durability of remission off therapy.

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.