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phosphoinositide 3-kinase inhibitor

Image:PI3K inhibitors overview Mishra2021.jpg. There are pan-class I PI3K inhibitors such as copanlisib, isoform-specific PI3K inhibitors such as idelalisib, and dual PI3K/mTOR inhibitors such as dactolisib. Note that fimepinostat and rigosertib inhibit the PI3K/AKT/mTOR pathway, but not PI3K itself.{{cite journal | vauthors = Mishra R, Patel H, Alanazi S, Kilroy MK, Garrett JT | title = PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects | journal = International Journal of Molecular Sciences | volume = 22 | issue = 7 | pages = 3464 | date = March 2021 | pmid = 33801659 | pmc = 8037248 | doi = 10.3390/ijms22073464 | doi-access = free }}]]

Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth.{{cite journal | vauthors = Hoxhaj G, Manning BD | title = The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism | journal = Nature Reviews. Cancer | volume = 20 | issue = 2 | pages = 74–88 | date = February 2020 | pmid = 31686003 | pmc = 7314312 | doi = 10.1038/s41568-019-0216-7 }}{{cite journal | vauthors = Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA | title = Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020) | journal = Expert Opinion on Therapeutic Patents | volume = 31 | issue = 10 | pages = 877–892 | date = October 2021 | pmid = 33970742 | doi = 10.1080/13543776.2021.1924150 | s2cid = 234360275 }} They are examples of a targeted therapy.{{cite journal|doi=10.1038/s41392-021-00572-w|title=Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives |year=2021 |last1=Zhong |first1=Lei |last2=Li |first2=Yueshan |last3=Xiong |first3=Liang |last4=Wang |first4=Wenjing |last5=Wu |first5=Ming |last6=Yuan |first6=Ting |last7=Yang |first7=Wei |last8=Tian |first8=Chenyu |last9=Miao |first9=Zhuang |last10=Wang |first10=Tianqi |last11=Yang |first11=Shengyong |journal=Signal Transduction and Targeted Therapy |volume=6 |issue=1 |page=201 |pmid=34054126 |pmc=8165101 }} While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.{{cite journal | vauthors = Curigliano G, Shah RR | title = Safety and Tolerability of Phosphatidylinositol-3-Kinase (PI3K) Inhibitors in Oncology | journal = Drug Safety | volume = 42 | issue = 2 | pages = 247–262 | date = February 2019 | pmid = 30649751 | doi = 10.1007/s40264-018-0778-4 | s2cid = 58657824 }}{{cite journal | vauthors = Hanlon A, Brander DM | title = Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors | journal = Hematology. American Society of Hematology. Education Program | volume = 2020 | issue = 1 | pages = 346–356 | date = December 2020 | pmid = 33275709 | pmc = 7727518 | doi = 10.1182/hematology.2020000119 }}

After PI3K inhibitors had been under investigation as anti-cancer drugs for several years,{{cite web |url=http://www.genengnews.com/articles/chitem.aspx?aid=2695&chid=1 |archive-url=https://archive.today/20130124041737/http://www.genengnews.com/articles/chitem.aspx?aid=2695&chid=1 |url-status=dead |archive-date=2013-01-24 |title=Zeroing in on PI3K Pathway |date=Dec 2008 |author=Flanagan}}{{cite journal | vauthors = Wu P, Liu T, Hu Y | title = PI3K inhibitors for cancer therapy: what has been achieved so far? | journal = Current Medicinal Chemistry | volume = 16 | issue = 8 | pages = 916–930 | year = 2009 | pmid = 19275602 | doi = 10.2174/092986709787581905 }}{{cite journal | vauthors = Maira SM, Stauffer F, Schnell C, García-Echeverría C | title = PI3K inhibitors for cancer treatment: where do we stand? | journal = Biochemical Society Transactions | volume = 37 | issue = Pt 1 | pages = 265–272 | date = February 2009 | pmid = 19143644 | doi = 10.1042/BST0370265 }}{{cite journal | vauthors = Heavey S, O'Byrne KJ, Gately K | title = Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC | journal = Cancer Treatment Reviews | volume = 40 | issue = 3 | pages = 445–456 | date = April 2014 | pmid = 24055012 | doi = 10.1016/j.ctrv.2013.08.006 }} the first one to be approved for treatment in clinical practice was idelalisib in 2014.{{cite web | url = https://wayback.archive-it.org/7993/20170112023830/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm | title = FDA approves Zydelig for three types of blood cancers | date = July 23, 2014 | publisher = US Food and Drug Administration}} Several others followed, and even more are still under development (see below).{{cite journal | vauthors = Vanhaesebroeck B, Perry MW, Brown JR, André F, Okkenhaug K | title = PI3K inhibitors are finally coming of age | journal = Nature Reviews. Drug Discovery | volume = 20 | issue = 10 | pages = 741–769 | date = October 2021 | pmid = 34127844 | doi = 10.1038/s41573-021-00209-1 | pmc = 9297732 | s2cid = 235437841 }}

There are different classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) and p110 delta (PIK3CD).[http://www.news-medical.net/news/20100810/Study-results-provide-rationale-for-use-of-PI3K-inhibitors-in-therapeutic-settings.aspx Study results provide rationale for use of PI3K inhibitors in therapeutic settings]. News-medical.net. Retrieved on 2010-11-05. All PI3K inhibitors that are currently approved inhibit one or more p110 isoforms of the class I PI3Ks. Inhibiting different p110 isoforms can have different effects,{{cite journal | vauthors = Edgar KA, Wallin JJ, Berry M, Lee LB, Prior WW, Sampath D, Friedman LS, Belvin M | display-authors = 6 | title = Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors | journal = Cancer Research | volume = 70 | issue = 3 | pages = 1164–1172 | date = February 2010 | pmid = 20103642 | doi = 10.1158/0008-5472.CAN-09-2525 }} e.g. PTEN-negative tumors may be more sensitive to PIK3CB inhibitors.

PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease,{{cite journal | vauthors = Ito K, Caramori G, Adcock IM | title = Therapeutic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 321 | issue = 1 | pages = 1–8 | date = April 2007 | pmid = 17021257 | doi = 10.1124/jpet.106.111674 | s2cid = 1906947 }}{{cite journal | vauthors = Crabbe T | title = Exploring the potential of PI3K inhibitors for inflammation and cancer | journal = Biochemical Society Transactions | volume = 35 | issue = Pt 2 | pages = 253–256 | date = April 2007 | pmid = 17371252 | doi = 10.1042/BST0350253 }} and are used to investigate the role of the PI3K pathway in aging.Blagosklonny MV. Anti-aging: senolytics or gerostatics (unconventional view). Oncotarget. 2021 Aug 31;12(18):1821-1835. {{doi|10.18632/oncotarget.28049}} {{PMID|34504654}}

Approved for treatment

  • Idelalisib (trade name Zydelig; codenamed CAL-101, GS-1101; PIK3CD inhibitor): FDA-approved in July 2014 for treatment of three types of blood cancers: treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) in combination with rituximab, treatment of relapsed small lymphocytic lymphoma after at least two prior systemic therapies, and treatment of follicular lymphoma (FL) after at least two prior systemic therapies.
  • Copanlisib (trade name Aliqopa; codenamed BAY 80-6946; predominantly a PIK3CA and PIK3CD inhibitor): FDA-approved in September 2017 for treatment of relapsed follicular lymphoma after at least two prior systemic therapies.{{cite web | url = https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576129.htm | title = FDA approves new treatment for adults with relapsed follicular lymphoma | date = September 14, 2017 | publisher = US Food and Drug Administration}}
  • Duvelisib (trade name Copiktra; codenamed INK1197, IPI-145; PIK3CD and PIK3CG inhibitor): FDA-approved on 24 September 2018 for treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, and treatment of relapsed or refractory follicular lymphoma after at least two prior systemic therapies.{{cite web | url = https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621503.htm | title = FDA Approval for duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) | date = September 24, 2018 | publisher = US Food and Drug Administration}}
  • Alpelisib (trade names Piqray and Pivikto; codenamed BYL719; PIK3CA inhibitor): FDA-approved in May 2019 for treatment of HR-positive and HER2/neu-negative breast cancer in combination with the endocrine therapy fulvestrant.{{Cite web | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer | title=FDA approves first PI3K inhibitor for breast cancer| website=Food and Drug Administration| date=2019-05-24}}
  • Umbralisib (trade name Ukoniq; codenamed TGR-1202, Rp-5264; PIK3CD and casein kinase CSNK1E inhibitor): FDA-approved in February 2021 for treatment of relapsed or refractory marginal zone lymphoma (MZL) after at least one prior anti-CD20-based regimen, and treatment of relapsed or refractory follicular lymphoma after at least three prior lines of systemic therapy.{{cite web | title=Ukoniq (umbralisib) tablets, for oral use | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213176s000lbl.pdf | publisher=TG Therapeutics }}{{cite web | title=FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma | website=U.S. Food and Drug Administration (FDA) | date=5 February 2021 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-umbralisib-marginal-zone-lymphoma-and-follicular-lymphoma | access-date=5 February 2021}} {{PD-notice}} As of May 31, 2022, umbralisib was withdrawn from the US market due to the decrement in overall survival and increased serious adverse events when using umbralisib.{{Cite web |title=Federal Register :: Request Access |url=https://unblock.federalregister.gov/ |access-date=2022-10-06 |website=unblock.federalregister.gov}}
  • Leniolisib (codenamed CDZ173; PIK3CD inhibitor, trade name [https://joenja.com/ Joenja]) was tested as a potential treatment for activated PI3K delta syndrome (APDS) / PASLI disease in a placebo-controlled phase II/III trial (NCT02435173).{{ClinicalTrialsGov|NCT02435173|Study of Efficacy of CDZ173 in Patients With APDS/PASLI}}{{cite journal |author3=Dalm VASH |display-authors=6 |vauthors=Rao VK, Webster S, Dalm VA, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C |date=November 2017 |title=Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib |journal=Blood |volume=130 |issue=21 |pages=2307–2316 |doi=10.1182/blood-2017-08-801191 |pmc=5701526 |pmid=28972011}} The trial was completed in August 2021 and results have become available in March 2022. Another phase II/III trial for APDS/PASLI that serves as an extension study (NCT02859727) is still ongoing and results are expected for October 2026.{{ClinicalTrialsGov|NCT02859727|Extension to the Study of Efficacy of CDZ173 in Patients With APDS/PASLI}} The FDA has [https://www.pharming.com/news/pharming-announces-us-fda-approval-joenja-leniolisib-first-and-only-treatment-indicated-apds approved] leniolisib on March 24, 2023.

Under clinical development

=Late stage=

In phase III clinical trials:

  • Buparlisib (codenamed BKM120, NVP-BKM120; pan-class I PI3K inhibitor):
  • The phase III trial BURAN compares buparlisib + paclitaxel to paclitaxel alone in patients with head and neck squamous cell carcinoma (HNSCC). Results are expected for December 2022.{{ClinicalTrialsGov|NCT04338399|The BURAN Study of Buparlisib in Patients With Recurrent or Metastatic HNSCC (BURAN)}}
  • The phase III trials BELLE-2{{cite journal | vauthors = Baselga J, Im SA, Iwata H, Cortés J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M | display-authors = 6 | title = Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial | journal = The Lancet. Oncology | volume = 18 | issue = 7 | pages = 904–916 | date = July 2017 | pmid = 28576675 | pmc = 5549667 | doi = 10.1016/S1470-2045(17)30376-5 }}{{ClinicalTrialsGov|NCT01610284|Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor (BELLE-2)}} and BELLE-3{{cite journal | vauthors = Di Leo A, Johnston S, Lee KS, Ciruelos E, Lønning PE, Janni W, O'Regan R, Mouret-Reynier MA, Kalev D, Egle D, Csőszi T, Bordonaro R, Decker T, Tjan-Heijnen VC, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T | display-authors = 6 | title = Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial | journal = The Lancet. Oncology | volume = 19 | issue = 1 | pages = 87–100 | date = January 2018 | pmid = 29223745 | doi = 10.1016/S1470-2045(17)30688-5 }}{{ClinicalTrialsGov|NCT01633060|A Phase III Study of BKM120 With Fulvestrant in Patients With HR+,HER2-, AI Treated, Locally Advanced or Metastatic Breast Cancer Who Progressed on or After mTORi (BELLE-3)}} comparing buparlisib + fulvestrant with fulvestrant alone in patients with breast cancer both showed excessive side effects. The phase II/III trial BELLE-4 comparing buparlisib + paclitaxel with paclitaxel alone in patients with breast cancer did not improve progression-free survival and was stopped for futility at the end of phase II.{{cite journal | vauthors = Martín M, Chan A, Dirix L, O'Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista López N, Campone M, Ruiz Borrego M, Khan QJ, Beck JT, Ramos Vázquez M, Urban P, Goteti S, Di Tomaso E, Massacesi C, Delaloge S | display-authors = 6 | title = A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4) | journal = Annals of Oncology | volume = 28 | issue = 2 | pages = 313–320 | date = February 2017 | pmid = 27803006 | doi = 10.1093/annonc/mdw562 | doi-access = free }}{{ClinicalTrialsGov|NCT01572727|A Study of the Experimental Drug BKM120 With Paclitaxel in Patients With HER2 Negative, Locally Advanced or Metastatic Breast Cancer, With or Without PI3K Activation (BELLE-4)}} These results led the sponsor, Novartis, to cancel their breast cancer study program with buparlisib.
  • Copanlisib (codenamed BAY 80-6946; predominantly a PIK3CA and PIK3CD inhibitor) ist currently undergoing three phase III trials, all of which are testing it in patients with indolent non-Hodgkin lymphoma (iNHL):
  • The trial CHRONOS-2 was planned as a placebo-controlled randomized phase III trial with about 190 patients. However, recruitment was stopped after 25 patients were included and the trial continues as a non-randomized single-arm trial. Results are expected for November 2022.{{ClinicalTrialsGov|NCT02369016|Phase III Copanlisib in Rituximab-refractory iNHL (CHRONOS-2)}}
  • The phase III trial CHRONOS-3 compares copanlisib + rituximab with placebo + rituximab in patients with relapsed iNHL. Study completion is expected for January 2023.{{ClinicalTrialsGov|NCT02367040|Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin's Lymphoma (iNHL) (CHRONOS-3)}} Preliminary results show a strong and significant improvement of progression-free survival under copanlisib treatment, but also considerably more severe and serious side effects.{{cite journal | vauthors = Matasar MJ, Capra M, Özcan M, Lv F, Li W, Yañez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor Á, Bouabdallah K, Galiulin R, Uchida T, Soler LM, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL | display-authors = 6 | title = Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial | journal = The Lancet. Oncology | volume = 22 | issue = 5 | pages = 678–689 | date = May 2021 | pmid = 33848462 | doi = 10.1016/S1470-2045(21)00145-5 | s2cid = 233234876 }}
  • The phase III trial CHRONOS-4 compares copanlisib + immunochemotherapy (R-CHOP regimen) with placebo + immunochemotherapy in patients with relapsed iNHL who have received 1–3 previous lines of therapy. Results are expected for February 2023.{{ClinicalTrialsGov|NCT02626455|Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL) (CHRONOS-4)}}
  • Dactolisib (codenamed BEZ235, NVP-BEZ235; dual pan-class I PI3K and mTOR inhibitor){{cite journal | vauthors = Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, Garcia-Echevrria C, Yung WK | display-authors = 6 | title = NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas | journal = Molecular Cancer Therapeutics | volume = 8 | issue = 8 | pages = 2204–2210 | date = August 2009 | pmid = 19671762 | pmc = 2752877 | doi = 10.1158/1535-7163.MCT-09-0160 }} was tested in the placebo-controlled phase III trial PROTECTOR 1 (RTB-101-204) to prevent clinically symptomatic respiratory illness in generally healthy elderly people.{{ClinicalTrialsGov|NCT04668352|A Phase 3 Study to Determine if RTB101 Prevents Clinically Symptomatic Respiratory Illness in the Elderly}} However, the trial did not meet this endpoint.{{cite journal | vauthors = Kaeberlein M |doi=10.1016/j.tma.2020.01.002 |title=RTB101 and immune function in the elderly: Interpreting an unsuccessful clinical trial|year=2020 |journal=Translational Medicine of Aging |volume=4 |pages=32–34 |s2cid=213379077|doi-access=free }} Consequently, the related phase III trial PROTECTOR 2 (RTB-101-205) was terminated by the sponsor.{{ClinicalTrialsGov|NCT04139915|Effect of RTB101 on Illness Associated With Respiratory Tract Infections in the Elderly}} Dactolisib has also undergone several phase II trials as a potential treatment for solid tumours as well as for respiratory diseases, most of which have been terminated {{as of|2022|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=Dactolisib&phase=1|access-date=2022-03-04|title=Search for phase 2 clinical trials with Dactolisib on clinicaltrials.gov}}
  • Duvelisib (codenamed INK1197, IPI-145; PIK3CD and PIK3CG inhibitor):
  • The results of the completed pivotal phase III trial DUO comparing duvelisib monotherapy with ofatumumab led to its approval for CLL/SLL{{ClinicalTrialsGov|NCT02004522|A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL (DUO)}} An extension trial to DUO was completed in 2020, but its results have not yet been published.{{ClinicalTrialsGov|NCT02049515|A Phase 3 Extension Study of Duvelisib and Ofatumumab in Patients With CLL/SLL Previously Enrolled in Study IPI-145-07}}
  • The phase III trial BRAVURA comparing duvelisib + rituximab + bendamustine with rituximab + bendamustine in patients with non-Hodgkin lymphoma was withdrawn by the sponsor when it was no longer expected to lead to approval.{{ClinicalTrialsGov|NCT02576275|A Study of Duvelisib in Combination With Rituximab and Bendamustine vs Placebo in Combination With Rituximab and Bendamustine in Subjects With Previously-Treated Indolent Non-Hodgkin Lymphoma (BRAVURA)}}
  • Similarly, the phase III trial DYNAMO + R comparing duvelisib + rituximab with rituximab alone in patients with follicular lymphoma was terminated by the sponsor when it was no longer expected to lead to approval.{{ClinicalTrialsGov|NCT02204982|Study of Duvelisib in Combination With Rituximab vs Rituximab in Subjects With Previously Treated Follicular Lymphoma (DYNAMO + R)}}
  • Idelalisib has undergone eleven phase III clinical trials {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=CAL-101&phase=2|accessdate=2022-03-21|title=Search for phase 3 clinical trials with CAL-101 on clinicaltrials.gov}} These include the pivotal trial GS-US-312-0116 that lead to approval of idelalisib by FDA and EMA for treatment of patients with CLL. All other phase III trials testing idelalisib-based therapy as an experimental treatment, e.g. in first-line CLL and second-line NHL, had been terminated by end of 2016, mainly due to increased toxicity and mortality.{{cite journal|url=https://www.ema.europa.eu/documents/scientific-conclusion/zydelig-epar-scientific-conclusions_en.pdf|title=Zydelig : EPAR - Scientific conclusions|date=2016-11-21}} Two trials comparing new experimental treatments to idelalisib as a comparator and a dose optimization study in FL are still ongoing.{{ClinicalTrialsGov|NCT02970318|A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL}}{{ClinicalTrialsGov|NCT04666038|Study of LOXO-305 Versus Investigator's Choice (IdelaR or BR) in Patients With Previously Treated Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) (BRUIN CLL-321)}}{{ClinicalTrialsGov|NCT02536300|Dose Optimization Study of Idelalisib in Follicular Lymphoma}}
  • Parsaclisib (codenamed INCB050465, INCB 50465; PIK3CD inhibitor) will be tested as a potential treatment for different diseases in five phase III trials:
  • Follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase III trial CITADEL-302{{ClinicalTrialsGov|NCT04796922|To Evaluate Efficacy and Safety of Parsaclisib Plus Either Rituximab or Obinutuzumab in R/R Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL) (CITADEL-302)}}
  • Mantle cell lymphoma (MCL) in the phase III trial CITADEL-310{{ClinicalTrialsGov|NCT04849715|A Study of Parsaclisib, a PI3Kδ Inhibitor, in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma (CITADEL-310)}}
  • Myelofibrosis in the phase III trials LIMBER-304{{ClinicalTrialsGov|NCT04551053|To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304)}} and LIMBER-313{{ClinicalTrialsGov|NCT04551066|To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313)}}
  • Warm antibody autoimmune hemolytic anemia (WAIHA) in the phase III trial PATHWAY{{ClinicalTrialsGov|NCT05073458|Study of the Efficacy and Safety of Parsaclisib in Participants With Primary Warm Autoimmune Hemolytic Anemia (PATHWAY)}}
  • Paxalisib (codenamed GDC-0084; pan-class I PI3K and mTOR inhibitor) was tested as a potential treatment for newly diagnosed, unmethylated as well as recurrent glioblastoma in the phase II/III trial GBM AGILE. Kazia reported positive study results for the newly diagnosed, unmethylated population in the concurrent analysis which compares patients treated with paxalisib between January 2021 and March 2022 with those treated with temozolomide during the same time. The results showed a clinically meaningful increase in medium overall survival of 3.8 months, representing an increase of 33% vs. the temozolomide arm which is currently the standard of care.{{ClinicalTrialsGov|NCT03970447|A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (GBM AGILE)}} [https://www.kaziatherapeutics.com/site/pdf/be0e3a1c-e12c-44f4-bf3f-2d79f8829cf8/Kazia-Therapeutics-Announces-Phase-IIIII-Clinical-Trial-Results-for-Paxalisib-in-Glioblastoma.pdf Kazia PR July 2024]
  • Taselisib (codenamed GDC-0032, RG7604; PIK3CA inhibitor): Development was discontinued due to strong side effects and only a minor survival benefit in the phase III trial SANDPIPER in patients with breast cancer.{{Cite web|url=https://endpts.com/roche-dumps-its-phiii-pi3k-effort-on-taselisib-after-researchers-track-poor-survival-edge-harsh-side-effects-for-breast-cancer/|title = Roche dumps its PhIII PI3K effort on taselisib after researchers track poor survival edge, harsh side effects for breast cancer}}{{ClinicalTrialsGov|NCT02340221|A Study of Taselisib + Fulvestrant Versus Placebo + Fulvestrant in Participants With Advanced or Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After Aromatase Inhibitor Therapy (SANDPIPER)}}
  • Zandelisib (codenamed ME-401; PIK3CD inhibitor) will be tested as a potential treatment for iNHL in the phase III trial COASTAL. The trial is currently recruiting patients {{as of|2022|03|lc=y}} and will compare zandelisib + rituximab to chemotherapy (CHOP regimen) + rituximab. Results are expected for April 2026.{{ClinicalTrialsGov|NCT04745832|Phase 3 Study of Zandelisib (ME-401) in Combination With Rituximab in Patients With iNHL - (COASTAL)}}
  • Inavolisib (codenamed GDC-0077; PIK3CA inhibitor) will be tested as a potential treatment for PIK3CA-mutant breast cancer in a phase II/III trial (NCT04191499). The trial is currently recruiting patients {{as of|2022|03|lc=y}} and will compare inavolisib + palbociclib + fulvestrant with placebo + palbociclib + fulvestrant. Results are expected for September 2025.{{ClinicalTrialsGov|NCT04191499|A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer}}

In phase II clinical trials:

  • Apitolisib (codenamed GDC-0980, GNE 390, RG7422; pan-class I PI3K and mTOR inhibitor) has undergone four phase II trials as a potential treatment for different solid tumours, three of which have been completed or terminated {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=GDC-0980&phase=1|access-date=2022-03-17|title=Search for phase 2 clinical trials with GDC-0980 on clinicaltrials.gov}}
  • Bimiralisib (codenamed PQR309; brain-permeant dual PI3K/mTOR inhibitor) has undergone several phase II trials as a potential treatment for different solid tumours, all of which have been completed or terminated {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=PQR309&phase=1|access-date=2022-03-17|title=Search for phase 2 clinical trials with PQR309 on clinicaltrials.gov}}
  • Eganelisib (codenamed IPI-549; PIK3CD inhibitor) is currently undergoing three phase II trials as a potential treatment for different solid tumours, with no published results {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=IPI-549&phase=1|access-date=2022-03-07|title=Search for phase 2 clinical trials with IPI-549 on clinicaltrials.gov}}
  • Fimepinostat (codenamed CUDC-907; PI3K p110 and HDAC inhibitor): A phase II trial in patients with diffuse large B-cell lymphoma (DLBCL) was completed in 2019 but its results have not yet been published.{{ClinicalTrialsGov|NCT02674750|Study to Evaluate the Efficacy and Safety of CUDC-907 in Patients With RR DLBCL, Including Patients With MYC Alterations}} Other phase II trials with fimepinostat have been terminated.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=CUDC-907&phase=1|access-date=2022-03-04|title=Search for phase 2 clinical trials with CUDC-907 on clinicaltrials.gov}}
  • Gedatolisib (codenamed PF-05212384, PKI-587; PIK3CA, PIK3CG and mTOR inhibitor) has undergone several phase II trials as a potential treatment for different cancers, most of which have been terminated for different reasons. {{As of|2022|03}}, two phase II trials on breast cancer are still recruiting patients.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=PKI-587&phase=1|access-date=2022-03-17|title=Search for phase 2 clinical trials with PKI-587 on clinicaltrials.gov}}
  • Linperlisib (codenamed YY-20394; PIK3CD inhibitor) will be tested as a potential treatment for different types of lymphoma in several phase II trials that are currently recruiting or scheduled to recruit patients {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=YY-20394&phase=1|access-date=2022-03-18|title=Search for phase 2 clinical trials with YY-20394 on clinicaltrials.gov}}
  • Nemiralisib (codenamed GSK2269557; PIK3CD inhibitor) has undergone several phase II trials as a potential treatment for different respiratory diseases (asthma and COPD) as well as for APDS/PASLI, all of which have been completed or terminated {{as of|2022|03|lc=y}}. Results are available for all of these trials.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=GSK2269557&phase=1|access-date=2022-03-17|title=Search for phase 2 clinical trials with GSK2269557 on clinicaltrials.gov}}
  • Pictilisib (codenamed GDC-0941; pan-class I PI3K inhibitor){{cite journal | vauthors = Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V, Clarke PA, Raynaud FI, Levy G, Ware JA, Mazina K, Lin R, Wu J, Fredrickson J, Spoerke JM, Lackner MR, Yan Y, Friedman LS, Kaye SB, Derynck MK, Workman P, de Bono JS | display-authors = 6 | title = First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors | journal = Clinical Cancer Research | volume = 21 | issue = 1 | pages = 77–86 | date = January 2015 | pmid = 25370471 | pmc = 4287394 | doi = 10.1158/1078-0432.CCR-14-0947 }} has undergone five phase II trials as a potential treatment for different solid tumours, with no results published {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=GDC-0941&phase=1|access-date=2022-03-07|title=Search for phase 2 clinical trials with IPI-549 on clinicaltrials.gov}}
  • Pilaralisib (codenamed SAR245408 and XL147; inhibitor of PIK3CA, PIK3CD, and PIK3CG) has undergone several phase II trials as a potential treatment for different solid tumours, all of which have been completed {{as of|2022|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=SAR245408&phase=1|access-date=2022-03-09|title=Search for phase 2 clinical trials with SAR245408 on clinicaltrials.gov}}
  • Samotolisib (codenamed GTPL8918, LY3023414; triple pan-class I PI3K, mTOR, and DNA-PK inhibitor) has undergone several phase II trials as a potential treatment for different cancers, three of which have been completed or terminated and have results {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=LY3023414&phase=1|access-date=2022-03-17|title=Search for phase 2 clinical trials with LY3023414 on clinicaltrials.gov}}
  • Seletalisib (codenamed UCB-5857; PIK3CD inhibitor) has undergone one phase II trial as a potential treatment for Sjögren syndrome. The trial has been terminated due to enrolment challenges.{{ClinicalTrialsGov|NCT02610543|UCB Proof of Concept Study in Patients With Primary Sjögren's Syndrome}}
  • Serabelisib (codenamed MLN1117 and TAK-117; PIK3CA inhibitor) is undergoing several phase II trials as a potential treatment for different cancers. {{As of|2022|03}}, results have been reported for renal cell carcinoma and endometrial cancer.{{ClinicalTrialsGov|NCT02724020|MLN0128 and MLN0128 + MLN1117 Compared With Everolimus in the Treatment of Adults With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma}}{{ClinicalTrialsGov|NCT02725268|A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer}}
  • Sonolisib (codenamed PX-866; a wortmannin derivative){{cite journal | vauthors = Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT | title = The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 9 | pages = 2505–2514 | date = September 2007 | pmid = 17766839 | doi = 10.1158/1535-7163.MCT-06-0698 | doi-access = free }} has undergone several phase II trials as a potential treatment for different solid tumours, all of which have been completed or terminated {{as of|2022|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=PX-866&phase=1|access-date=2022-03-04|title=Search for phase 2 clinical trials with PX-866 on clinicaltrials.gov}}
  • Tenalisib (codenamed RP6530; dual PIK3CD and PIK3CG inhibitor) is undergoing several phase II trials as a potential treatment for different cancers. Two single-arm trials (in CLL and iNHL) have reported results.{{ClinicalTrialsGov|NCT04204057|Efficacy and Safety of Tenalisib (RP6530) in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)}}{{ClinicalTrialsGov|NCT03711578|Efficacy and Safety Study of Tenalisib (RP6530), a Novel PI3K δ/γ Dual Inhibitor in Patients With Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma (iNHL)}}
  • Voxtalisib (codenamed SAR245409, XL765; pan-class I PI3K inhibitor and weaker inhibitor of mTOR), in trial for B-cell lymphomas, e.g. CLL and follicular lymphoma.{{Cite web|url=https://www.cancertherapyadvisor.com/home/cancer-topics/chronic-lymphocytic-leukemia/in-focus-voxtalisib-for-cll-and-b-cell-lymphomas/|title=In Focus: Voxtalisib for CLL and B-Cell Lymphomas|date=March 27, 2018|website=Cancer Therapy Advisor}}{{ClinicalTrialsGov|NCT01403636|A Study of Investigational SAR245409 in Patients With Certain Lymphoma or Leukemia}}
  • AMG 319 (PIK3CD inhibitor) has undergone a phase II trial as a potential treatment for HNSCC. The trial was terminated in 2018 due to safety reasons.{{ClinicalTrialsGov|NCT02540928|AMG 319 in HPV Positive and Negative HNSCC}}
  • AZD8186 (PIK3CB and PIK3CD inhibitor) will be tested as a potential treatment for gastric cancer in a phase II trial that is currently recruiting patients {{as of|2022|03|lc=y}}.{{ClinicalTrialsGov|NCT04001569|AZD8186 and Paclitaxel in Advanced Gastric Cancer}}
  • GSK2636771 (PIK3CB inhibitor) has undergone several phase II trials as a potential treatment for different cancers, one of which have been completed, with no results published {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?term=GSK2636771&phase=1|access-date=2022-03-17|title=Search for phase 2 clinical trials with GSK2636771 on clinicaltrials.gov}}
  • SF1126 is a peptidic prodrug targeting integrin receptors that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors.{{cite journal | doi = 10.1182/blood.V116.21.1783.1783 | title = Phase I Study of Novel Prodrug Dual PI3K/MTOR Inhibitor SF1126 in B-Cell Malignancies | year = 2010 | vauthors = Garlich JR, Becker MD, Shelton CF, Qi W, Liu X, Cooke L, Mahadevan D | journal = Blood | volume = 116 | issue = 21 | page = 1783 }} A phase II trial with SF1126 has been terminated due to slow enrolment.{{ClinicalTrialsGov|NCT02644122|SF1126 in Recurrent or Progressive SCCHN and Mutations in PIK3CA Gene and/or PI-3 Kinase Pathway Genes}}

=Early stage=

In early stage clinical trials

  • Acalisib (codenamed CAL-120, GS-9820) has completed one phase I trial in 2016. No data have been published for this trial and no further trials have been conducted since then {{as of|2022|03|lc=y}}.{{ClinicalTrialsGov|NCT01705847|A Phase 1b Study Evaluating GS-9820 in Subjects With Lymphoid Malignancies}}
  • Omipalisib (codenamed GSK2126458, GSK458) has completed two phase I trials in 2015 and 2016, respectively. No data have been published for these trials and no further trials have been conducted since then {{as of|2022|03|lc=y}}.{{cite web|url=https://clinicaltrials.gov/ct2/results?cond=&term=GSK2126458|access-date=2022-03-17|title=Search for clinical trials with GSK2126458 on clinicaltrials.gov}}
  • AZD8835 (PIK3CA and PIK3CD inhibitor) has completed one phase I trial in 2016. No data have been published for this trial and no further trials have been conducted since then {{as of|2022|03|lc=y}}.{{ClinicalTrialsGov|NCT02260661|Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours}}
  • CAL263 (PIK3CD inhibitor){{ClinicalTrialsGov|NCT01066611|Study to Investigate Effects of CAL-263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber}}
  • GSK1059615 (dual pan-class I PI3K and mTOR inhibitor): The phase I trial of this drug was terminated due to lack of sufficient exposure following single- and repeat-dosing.{{ClinicalTrialsGov|NCT00695448|Phase I Open-Label, Dose-Escalation Study of GSK1059615 in Patients With Solid Tumors or Lymphoma}}
  • MEN1611 (CH5132799, PA799; mainly a PIK3CA inhibitor) will be tested in a phase I/II trial with PIK3CA-mutated colorectal cancer patients that is currently recruiting patients {{as of|2022|03|lc=y}}.{{ClinicalTrialsGov|NCT04495621|MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01)}}
  • PWT33597 (dual PIK3CA and mTOR inhibitor){{cite web|url=https://clinicaltrials.gov/ct2/results?term=PWT33597&phase=0|access-date=2022-03-09|title=Search for phase 1 clinical trials with PWT33597 on clinicaltrials.gov}}
  • TG100-115 (mainly a PIK3CD and PIK3CG inhibitor){{cite web|url=https://clinicaltrials.gov/ct2/results?term=TG100-115&phase=0|access-date=2022-03-09|title=Search for phase 1 clinical trials with TG100-115 on clinicaltrials.gov}}
  • ZSTK474 (mainly a PIK3CD inhibitor){{cite web|url=https://clinicaltrials.gov/ct2/results?term=ZSTK474&phase=0|access-date=2022-03-09|title=Search for phase 1 clinical trials with ZSTK474 on clinicaltrials.gov}}

Not in clinical trials

  • AEZS-136 (dual PI3K and ERK inhibitor){{cite journal|doi=10.1182/blood.V122.21.3067.3067|title=The PI3K/ERK Dual Inhibitor AEZS-136 Induces ROS-Dependent Necroptotic Cell Death and Exerts Potent Antitumor Effects in NOD/SCID Mice with Hodgkin Lymphoma Cell Line Xenografts|year=2013| vauthors = Locatelli SL, Stirparo GG, Tartari S, Saba E, Rubino L, Brusamolino E, Castagna L, Santoro A, Carlo-Stella C |journal=Blood|volume=122|issue=21|page=3067}}
  • B591 (pan-class I PI3K inhibitor){{cite journal | vauthors = Zhou H, Yu C, Kong L, Xu X, Yan J, Li Y, An T, Gong L, Gong Y, Zhu H, Zhang H, Yang X, Li Y | display-authors = 6 | title = B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells | journal = Oncogene | volume = 38 | issue = 18 | pages = 3371–3386 | date = May 2019 | pmid = 30635656 | pmc = 6756013 | doi = 10.1038/s41388-018-0674-5 }}
  • GNE-477 (dual PIK3CA and mTOR inhibitor with IC50 values of 4 nM and 21 nM){{cite journal | vauthors = Heffron TP, Berry M, Castanedo G, Chang C, Chuckowree I, Dotson J, Folkes A, Gunzner J, Lesnick JD, Lewis C, Mathieu S, Nonomiya J, Olivero A, Pang J, Peterson D, Salphati L, Sampath D, Sideris S, Sutherlin DP, Tsui V, Wan NC, Wang S, Wong S, Zhu BY | display-authors = 6 | title = Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 8 | pages = 2408–2411 | date = April 2010 | pmid = 20346656 | doi = 10.1016/j.bmcl.2010.03.046 }}
  • Hibiscone C (irreversible PI3K inhibitor)
  • IC87114 (mainly a PIK3CD inhibitor)
  • LY294002 (reversible PI3K inhibitor), mainly used as a research tool
  • PI-103 (triple pan-class I PI3K, mTOR, and DNA-PK inhibitor){{cite journal | vauthors = Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I, Folkes A, Gowan S, De Haven Brandon A, Di Stefano F, Hayes A, Henley AT, Lensun L, Pergl-Wilson G, Robson A, Saghir N, Zhyvoloup A, McDonald E, Sheldrake P, Shuttleworth S, Valenti M, Wan NC, Clarke PA, Workman P | display-authors = 6 | title = Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941 | journal = Molecular Cancer Therapeutics | volume = 8 | issue = 7 | pages = 1725–1738 | date = July 2009 | pmid = 19584227 | pmc = 2718129 | doi = 10.1158/1535-7163.MCT-08-1200 }}
  • Wortmannin (irreversible PI3K inhibitor), mainly used as a research tool

See also

References

{{Reflist|30em}}

Further reading

  • {{cite journal | vauthors = Williams R, Berndt A, Miller S, Hon WC, Zhang X | title = Form and flexibility in phosphoinositide 3-kinases | journal = Biochemical Society Transactions | volume = 37 | issue = Pt 4 | pages = 615–626 | date = August 2009 | pmid = 19614567 | doi = 10.1042/BST0370615 }}

External links

  • [https://web.archive.org/web/20110714202938/http://www.novartisoncology.com/research-innovation/pipeline/bez235.jsp?usertrack.filter_applied=true&NovaId=4029461991482045523 Novartis on BEZ235 and BKM120 PI3K inhibitors]

{{Intracellular chemotherapeutic agents}}

Category:Experimental cancer drugs

Category:Targeted therapy