P3, N=15, Recruiting, Pharming Technologies B.V. | Trial completion date: Nov 2025 --> Feb 2026

P1, N=24, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P1/2 --> P1 | Trial completion date: Mar 2025 --> Jul 2025

Over the last 20 years, both rapamycin and mycophenolate mofetil have been successfully used as steroid-sparing long-term measures in ALPS. Current therapeutic options for APDS/PASLI (phosphoinositide 3-kinase [PI3K]-associated senescent T lymphocytes, lymphadenopathy, and immunodeficiency) include the orally bioavailable PI3Kδ inhibitor, leniolisib, which was licensed by the US Food and Drug Administration (FDA) in 2023 for use in individuals older than 12 years as a targeted treatment. Paradigms learned from patients with rare genetic disorders like ALPS and APDS may help in exploring and streamlining molecular therapy strategies in the wider group of IEIs presenting with refractory cytopenias and lymphoproliferation.

These include single-agent brentuximab vedotin, histone deacetylase inhibitors, duvelisib, ruxolitinib, EZH2 inhibitors, and azacitidine, among others. Follicular helper T-cell lymphomas, given frequent mutations in epigenetic regulator genes, may preferentially respond to agents such as histone deacetylase inhibitors, EZH2 inhibitors, and hypomethylating agents. As these therapies evolve in their use for both relapsed/refractory disease and then into frontline treatment, subtype-specific therapy will likely help personalize care for patients with PTCL.

P2, N=85, Not yet recruiting, iOnctura

We report a favorable response rate when combining a selective PI3K pathway inhibitor and taxane in patients with anti-PD-1 refractory HNSCC.

These findings demonstrate that amdizalisib is rapidly absorbed, extensively metabolized, and primarily excreted via feces and urine, supporting its continued development as a potential therapeutic for Hodgkin's lymphoma. https://www.chinadrugtrials.org.cn/, identifier CTR20212448.

P1, N=33, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P3, N=124, Not yet recruiting, SecuraBio | Initiation date: Dec 2024 --> Mar 2025

P1/2, N=54, Completed, Incyte Corporation | Active, not recruiting --> Completed

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.

P2, N=12, Recruiting, Pharming Technologies B.V. | Not yet recruiting --> Recruiting | Trial primary completion date: Jan 2025 --> Oct 2025

Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.

P1/2, N=32, Active, not recruiting, Dana-Farber Cancer Institute | Phase classification: P1b/2 --> P1/2

We present the 6-year update of a phase 2 study evaluating the combination of obinutuzumab and idelalisib in relapse/refractory Waldenstrom macroglobulinemia. Moreover, ibrutinib remains an effective treatment after this combination. This study was registered on the clinicaltrial.gov web (NCT02962401, November 9, 2016).

P1/2, N=40, Completed, Nanjing Zenshine Pharmaceuticals | Recruiting --> Completed | N=70 --> 40

P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 --> Dec 2026

We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT)...Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin...In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers.

P2, N=112, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=200 --> 112

P1/2, N=0, Withdrawn, Memorial Sloan Kettering Cancer Center | N=37 --> 0 | Active, not recruiting --> Withdrawn

P=N/A, N=6, Completed, Bayer | Active, not recruiting --> Completed | N=50 --> 6

Targeting this pathway has been approved as a therapeutic option for breast cancer and lymphoma (e.g. alpelisib, idelalisib), and there are several clinical trials underway in additional types of cancer...We report the case of a 53-year-old female with metastatic breast cancer who developed acute grade 3 hyperglycemia from a novel PI3K inhibitor, inavolisib...All patients treated with PI3K inhibitors should receive pre-treatment screening for hyperglycemia, lifestyle advice, and a glucometer to measure fasting BGL and 2-h post-dinner BGL levels twice per week for at least the first 30 days of treatment. Insulin or insulin secretagogues (e.g. sulfonylurea) may inhibit the anti-tumor activity of PI3K inhibitors, and thus treatment of PI3K inhibitor-associated hyperglycemia should prefer alternative approaches such as a low carbohydrate diet, metformin, SGLT2i, or dose reduction of the PI3K inhibitor.

P2, N=200, Recruiting, Incyte Corporation | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027

P1, N=121, Active, not recruiting, Incyte Corporation | Trial completion date: Aug 2024 --> Jan 2025 | Trial primary completion date: Aug 2024 --> Jan 2025

P2, N=27, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | N=50 --> 27

P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Jan 2025 --> Dec 2023

P1/2, N=37, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

P3, N=252, Active, not recruiting, Incyte Corporation | Trial completion date: Jul 2024 --> Nov 2024

P1, N=6, Terminated, University of Michigan Rogel Cancer Center | N=35 --> 6 | Trial completion date: Jun 2026 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2025 --> Nov 2023; Loss of study funding

Linperlisib treatment for these patients with r/r PTCL, consisting of the major PTCL subtypes, was observed to have a 60.5% overall response rate with 35% complete responses and led to a median duration of response of 11.1 months, median progression-free survival of 11.8 months, and a median overall survival of >38 months (not reached). With the very promising clinical activity against r/r PTCL, the results of this study support the further investigation of linperlisib for the treatment of r/r PTCL.

P2, N=17, Active, not recruiting, University of Maryland, Baltimore | N=34 --> 17

P1/2, N=131, Not yet recruiting, The First Affiliated Hospital,Zhejiang University School of Medicine; The First Affiliated Hospital,Zhejiang University School of Medicine

P1/2, N=35, Recruiting, The First Hospital of Jilin University

P1/2, N=97, Completed, BeiGene | Active, not recruiting --> Completed

Then, an in silico docking with these lichen-derived metabolites against the PI3Kα receptor predicted these compounds has a binding affinity close to a standard PI3Kα inhibitor copanlisib. The study concludes that the extract restricts lung cancer possibly through the PI3Kα/FOXO1 axis and thus Parmelinella wallichiana represents a potential resource for anti-lung cancer drug development in future.

BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.

P3, N=177, Terminated, Incyte Corporation | Active, not recruiting --> Terminated; The study was terminated due to futility.

P2, N=37, Active, not recruiting, Fondazione Italiana Linfomi - ETS | Trial completion date: Aug 2024 --> Dec 2024 | Trial primary completion date: Aug 2024 --> Dec 2024

Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.

P2/3, N=606, Not yet recruiting, Shanghai YingLi Pharmaceutical Co. Ltd.

P2, N=12, Not yet recruiting, Pharming Technologies B.V.

P1/2, N=13, Active, not recruiting, John Kirkwood | Recruiting --> Active, not recruiting | N=42 --> 13 | Trial completion date: Oct 2029 --> Dec 2028 | Trial primary completion date: Apr 2028 --> Feb 2024