Zydelig (idelalisib)

Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.

P3, N=250, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P3, N=0, Withdrawn, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | N=200 --> 0 | Not yet recruiting --> Withdrawn

Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca2+ channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy.

HL-60 cells were treated with Idelalisib, MK-2206, and Everolimus, which respectively are selective inhibitors of phosphatidylinositol-3-kinase (PI3K), AKT, and the mammalian target of rapamycin (mTOR), either individually or in combination. A combination of PI3K/AKT/mTOR pathway inhibitors regulates the expression of genes involved in glycolysis, pyruvate dehydrogenase complex (PDH), and the tricarboxylic acid (TCA) cycle and interferes with metabolic reprogramming and immune evasion mechanisms of AML leukemic cells. Combinational therapy approaches to block these pathways might be a promising and novel therapeutic strategy for targeting the metabolic requirements of AML cells.

P1, N=2, Terminated, OHSU Knight Cancer Institute | Active, not recruiting --> Terminated; Low accrual

P1/2, N=4, Terminated, Asha Nayak | N=40 --> 4 | Unknown status --> Terminated; The study was terminated due to poor accrual.

CAL-101 suppressed the TNF-α-induced TRPV2 expression in OGD/R-treated PCs, thus inhibiting the Ca2+ uptake and PC contraction. Collectively, this study suggests that PI3Kδ is a critical regulator of PC function during ischemic stroke.

This study investigated the potential anticancer activity of some novel quinazolinone derivatives that were designed on the structural framework of two approved anticancer drugs, Ispinesib (KSP inhibitor) and Idelalisib (PI3Kδ inhibitor), to find out solutions for TNBC. The relative gene expression of pro-apoptotic and anti-apoptotic genes revealed an overexpression of the P53 and BAX genes and a downregulation of the BCL-2 gene by real-time PCR. So, this work proved that compounds 3a, 3b, and 3e could be developed as anticancer candidates, via their P53-dependent apoptotic activity.

Liquid 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.

Here, we investigated the radiochemosensitizing potential and adaptation mechanisms of four PI3K inhibitors, Alpelisib, Copanlisib, AZD8186, and Idelalisib in eight HNSCC models grown under physiological, three-dimensional matrix conditions. Finally, we demonstrate that targeting of the cell adhesion molecule β1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel β1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.

P3, N=200, Not yet recruiting, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company

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.

P1, N=203, Active, not recruiting, Gilead Sciences | Phase classification: P1b --> P1

We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug...Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors...Resistance factors were also shown to be expressed in clinical specimens. In conclusion, we showed that the overexpression of ERBB4 and its ligands represents a novel mechanism of resistance for lymphoma cells to bypass the antitumor activity of BTK and PI3K inhibitors and that targeted pharmacologic interventions can restore sensitivity to the small molecules.

PI3K inhibitors such as idelalisib and duvelisib have shown promising efficacy in CLL patients, but severe toxicities remain a significant hurdle to their implementation in the clinic (PMID: 24615777). In the non-toxicity group, more diversity of Tregs was identified with depletion of some clusters but also an increase in a cluster. At present, we are integrating the scRNA & scTCR-seq data to characterize the cellular diversity and heterogeneous phenotypic states of the T-cell populations and updated results unraveling molecular mechanisms that drive early severe toxicity in CLL patients with idelalisib treatment will be presented at the meeting.

Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

The mainstay of MCL therapies remains the chemo-immunotherapy followed by autologous transplantation but recently several novel therapies have been developed such as BTK inhibitors, Venetoclax, CDK4/6 inhibitors and more recently CAR-T therapies...Finally, the expression of PIK3CD which encodes for a therapeutic target in MCL (such as PI3KDelta inhibitor Idelalisib) was also significantly repressed in UPN-1 as compared to nine other MCL cell lines...This cell line exhibited a major upregulation of E2F1 expression and a down regulation of the cell cycle inhibitor CDKN1A(p21). The potential effects of the direct inhibition of E2F1 using the targeted inhibitor MTA demonstrated a reduction in cell proliferation and induction of apoptosis, suggesting the possibility of associating clinically acceptable E2F1 inhibition strategies to other current therapies.

In addition, patients initiating therapy after receiving idelalisib in the pivotal DELTA trial were included. These results demonstrate that axi-cel continues to show superior efficacy for R/R FL compared to other available therapies. The response to axi-cel is durable, and offers a clinically meaningful and significant benefit in PFS, TTNT, and OS. These longer follow-up results are particularly important in this indolent disease, where survival outcomes take time to reach maturity.

The discovery cohort comprised pre-treatment samples from 79 CLL patients enrolled in the NCRI RIAltO trial (NCT01678430) who underwent factorial randomisation to ofatumumab and either bendamustine or chlorambucil, with or without idelalisib. The present study has identified three previously undescribed T-cell subpopulations that appear to influence the risk of infection, SPM, and death in patients with CLL receiving frontline chemo-immunotherapy. Further studies are warranted to validate these findings in the setting of targeted agents and in patients receiving CIT for other haematological malignancies.

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)...Other BCRi such as idelalisib, duvelisib and acalabrutinib were used at 5 μM concentrations as positive controls...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.

The combination of CDK4/6 inhibitor palbociclib and PI3K inhibitor idelalisib synergistically induced anti-tumor activity in B-cell lymphoma through downregulation of PLK1 expression, suggested a new combination direction for the treatment of B-NHL and even BTK inhibitor-resistant patients.

Patients were randomly assigned to receive bendamustine or chlorambucil plus ofatumumab, with or without idelalisib. To our knowledge, this is the first study to identify correlations between the re-emergence of non-malignant B-cells following anti-CLL therapy and specific clinical endpoints such as haematopoietic recovery, serum Ig levels, TTP and OS. Although further validation is required in the context of targeted agents, our findings suggest that therapy-induced re-emergence of non-malignancy B-cells may have important biological and clinical implications in CLL.

Patients were randomly assigned to receive ofatumumab plus either bendamustine or chlorambucil, with or without idelalisib. 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.

In order to improve outcomes in patients with relapsed CD22 (+) NHL, or chronic lymphocytic leukemia (CLL) who failed targeted therapies and were candidates for allo-SCT, we prospectively studied the addition of InO to our standard chemo-conditioning of BFR (bendamustine, fludarabine and rituximab-Khouri Blood 2014)...Tacrolimus and mini-methotrexate were used for graft versus host disease (GVHD) prophylaxis...Patients with CLL/MCL were previously treated with ibritunib (n=10), venetoclax (n=5), idelalisib (n=2), nivolumab (n=1) and CAR T (n=1)... Our results show that InO is safe when combined with an allo-SCT conditioning regimen and may improve survival outcomes in patients with CD22 (+) NHL. This needs to be validated in a larger number of patients. An ongoing trial at our center involves fractionating InO dose pre-and post-allo-SCT in patients with lymphoma or acute lymphoblastic leukemia receiving a reduced-intensity conditioning, and adding post-transplant cyclophosphamide to decrease the risk of GVHD.

LOX, COL5A2, and CTGF were identified as the targets of swertiamarin on IPF.

Herein, we investigated the potential anti-inflammatory activities of several pharmacological PI3K inhibitors, including marketed drugs idelalisib (PI3Kδ), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K with preferential α/δ) and the clinical drug eganelisib (PI3Kγ), for treating acute lung injury (ALI). Collectively, all four representative PI3K inhibitors exerted prominent anti-inflammatory properties, indicating that PI3K δ and/or γ inhibition could be ideal targets to treat respiratory inflammatory diseases by reducing the inflammatory response. The findings of the current study provide a new basis for utilizing PI3K inhibitors to treat acute respiratory inflammatory diseases.

The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3Kδ in CLL.

Based on the fact that PI3K hyperactivation is one of the main properties of ALL cells, the effects of PI3K inhibition using CAL-101 on pioglitazone-induced cytotoxicity were evaluated by combinatorial experiments. Additionally, our result showed that inhibition of proteasome and autophagy system, two main cellular processes, increased the antileukemic effects of the agents. Taken together, we suggest a novel therapeutic application for PPARγ stimulators as a single agent or in combination with PI3K inhibitors that should be clinically evaluated in ALL patients.

Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.

P2, N=50, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Aug 2023 --> Jan 2024

Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC  = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC  = 0.035 μM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.

Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies...Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.

These results demonstrate that CAR4-DNTs can effectively target T-ALL and PTCL and support allogeneic CAR4-DNTs as adoptive cell therapy for T-cell malignancies.

In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells. In summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.

Treatment of relapsed and refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) has changed dramatically over the past decade due to the development of oral targeted agents in several therapeutic classes, including BTK inhibitors (such as ibrutinib, acalabrutinib, zanubrutinib, and the non-covalent BTK inhibitor pirtobrutinib), the first in class BCL2 inhibitor venetoclax, PI3K inhibitors (idelalisib and duvelisib), and monoclonal antibodies in monotherapy and in combination. In absence of a clinical trial, these patients can be challenged with PI3K inhibitors, though responses are usually not durable, and toxicity is high. Combination cytotoxic chemotherapy with novel agents, allogeneic hematopoietic stem cell transplant, and cellular therapy may be considered for very high-risk populations, such as patients with Richter's transformation, though novel approaches are urgently needed and clinical trial enrollment is highly encouraged.

The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.

Total number of patients 81 age at CLL diagnosis, median (range) 62 (37–79) age at tixagevimab/cilgavimab administration, median (range) 71 (42–90) males, n (%) 44 (54) prognostic markers unmutated iGhV, n (%)* 57 (73) Del(17p) and/or mutation TP53, n (%) 20 (25) Del(11q), n (%) 32 (40) Trisomy 12, n (%) 13 (16) Del13q as a sole abnormality, n (%) 15 (19) Complex karyotype, n (%) 11 (14) hypogammaglobulinemia, n (%)† 38 (52) obesity, n (%) ‡ 28 (35) CiRS score, median (range) 6 (2–14) major comorbidities, n (%) 49 (60) SaRS-CoV-2 vaccine in history, n (%) 73 (90) Type of treatment for CLL at administration of tixagevimab/cilgavimab idelalisib, n (%) 3 (4) Chemoimmunotherapy, n (%) 6 (7) Venetoclax, n (%) 32 (40) anti-CD20 monoclonal antibody, n (%) 35 (43) BTk inhibitor, n (%) 41 (51) *iGhV available in 78 pts; †data available in 73 pts; ‡defined as body mass index (Bmi) ≥ 30...Only 1 (1%) patient on ibrutinib reported red skin nodules five days post T/C prophylaxis... Our data show that T/C 150/150 mg failed to prevent COVID-19 in about a third of patients during CLL treatment. However, most CLL patients who developed COVID-19 after prophylactic T/C had a mild infection with a low hospitalization rate. We will present updated results, including a comparison with CLL patients who did not receive prophylaxis with T/C.

With regard to treatment, 56% received Brutone tyrosine kinase (BTK) inhibitors, others received Bcl-2 inhibitor venetoclax (31%) or PI3K inhibitor idelalisib (13%). This interim analysis points to the dynamic and complex nature of genomic alterations in CLL, with implications for disease progression and therapeutic responses. Our findings highlight the importance of longitudinal genomic monitoring to uncover evolving mutational profiles and their clinical implications.

I.st line, 6 × FCR (fludarabine, cyclophosphamide, rituximab) was given from November 2013 to April 2013 with achieved complete remission (CR)...1st line treatment (1 × RCD, 3 × R- bendamustine) patient received from August 2021 to November 2021 due to generalized lymphadenomegalia (LAM) with maximum in retroperitoneal space up to 42 mm, fluidothorax and B symptoms), immunochemotherapy (ICT) had to be stopped due to infectious complications and patient achieved PR... We present two patients where fluidothorax was observed at the time of diagnosis and two patients who developed fluidothorax after prior therapies. Fluidithoraxes were in two patients sensitive to ibrutinib and in two patients to venetoclax (refractory to idelalisib). Only one patient progressed during FU to Richter transformation.