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Phosphoinositide 3-kinase inhibitor

January 28, 2023

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.[2][3] They are examples of a targeted therapy.[4] 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.[5][6]

Overview of phosphoinositide 3-kinase (PI3K) inhibitors and their interaction with the PI3K/AKT/mTOR pathway. 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.[1]

After PI3K inhibitors had been under investigation as anti-cancer drugs for several years,[7][8][9][10] the first one to be approved for treatment in clinical practice was idelalisib in 2014.[11] Several others followed, and even more are still under development (see below).[3][12]

There are different classes and isoforms of PI3Ks.[13] 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).[14] 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,[15] e.g. PTEN-negative tumors may be more sensitive to PIK3CB inhibitors.[15]

PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease,[13][16] and are used to investigate the role of the PI3K pathway in aging.[17]

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.[11]
  • 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.[18]
  • 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.[19]
  • 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.[20]
  • 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.[21][22] 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.[23]

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.[24]
    • The phase III trials BELLE-2[25][26] and BELLE-3[27][28] 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.[29][30] 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.[31]
    • The phase III trial CHRONOS-3 compares copanlisib + rituximab with placebo + rituximab in patients with relapsed iNHL. Study completion is expected for January 2023.[32] Preliminary results show a strong and significant improvement of progression-free survival under copanlisib treatment, but also considerably more severe and serious side effects.[33]
    • 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.[34]
  • Dactolisib (codenamed BEZ235, NVP-BEZ235; dual pan-class I PI3K and mTOR inhibitor)[35] 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.[36] However, the trial did not meet this endpoint.[37] Consequently, the related phase III trial PROTECTOR 2 (RTB-101-205) was terminated by the sponsor.[38] 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.[39]
  • 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[40] An extension trial to DUO was completed in 2020, but its results have not yet been published.[41]
    • 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.[42]
    • 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.[43]
  • Idelalisib has undergone eleven phase III clinical trials as of March 2022.[44] These include the pivotal trial GS-US-312-0116 that lead to approval of idelalisib by FDA and EMA for tratment 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.[45] Two trials comparing new experimental treatments to idelalisib as a comparator and a dose optimization study in FL are still ongoing.[46][47][48]
  • Leniolisib (codenamed CDZ173; PIK3CD inhibitor) was tested as a potential treatment for activated PI3K delta syndrome (APDS) / PASLI disease in a placebo-controlled phase II/III trial (NCT02435173).[49][50] The trial was completed in August 2021 and results have become available in March 2022.[49] 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.[51]
  • Parsaclisib (codenamed INCB050465, INCB 50465; PIK3CD inhibitor) will be tested as a potential treatment for different diseases in five phase III trials:
  • Paxalisib (codenamed GDC-0084; pan-class I PI3K and mTOR inhibitor) will be tested as a potential treatment for glioblastoma in the phase II/III trial GBM AGILE. The trial is currently recruiting patients as of March 2022 and will compare multiple experimental treatments including paxalisib with temozolomide + radiotherapy (+ lomustine).[57]
  • 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.[58][59]
  • 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 March 2022 and will compare zandelisib + rituximab to chemotherapy (CHOP regimen) + rituximab. Results are expected for April 2026.[60]
  • 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 March 2022 and will compare inavolisib + palbociclib + fulvestrant with placebo + palbociclib + fulvestrant. Results are expected for September 2025.[61]

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 March 2022.[62]
  • 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 March 2022.[63]
  • 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 March 2022.[64]
  • 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.[65] Other phase II trials with fimepinostat have been terminated.[66]
  • 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 March 2022, two phase II trials on breast cancer are still recruiting patients.[67]
  • 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 March 2022.[68]
  • 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 March 2022. Results are available for all of these trials.[69]
  • Pictilisib (codenamed GDC-0941; pan-class I PI3K inhibitor)[70] has undergone five phase II trials as a potential treatment for different solid tumours, with no results published as of March 2022.[71]
  • 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.[72]
  • 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 March 2022.[73]
  • 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.[74]
  • Serabelisib (codenamed MLN1117 and TAK-117; PIK3CA inhibitor) is undergoing several phase II trials as a potential treatment for different cancers. As of March 2022, results have been reported for renal cell carcinoma and endometrial cancer.[75][76]
  • Sonolisib (codenamed PX-866; a wortmannin derivative)[77] 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.[78]
  • 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.[79][80]
  • 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.[81][82]
  • 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.[83]
  • 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 March 2022.[84]
  • 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 March 2022.[85]
  • SF1126 is a peptidic prodrug targeting integrin receptors that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors.[86] A phase II trial with SF1126 has been terminated due to slow enrolment.[87]

Early stage

In early stage clinical trials[9]

  • 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 March 2022.[88]
  • 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 March 2022.[89]
  • 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 March 2022.[90]
  • CAL263 (PIK3CD inhibitor)[91]
  • 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.[92]
  • 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 March 2022.[93]
  • PWT33597 (dual PIK3CA and mTOR inhibitor)[94]
  • TG100-115 (mainly a PIK3CD and PIK3CG inhibitor)[95]
  • ZSTK474 (mainly a PIK3CD inhibitor)[96]

Not in clinical trials

  • AEZS-136 (dual PI3K and ERK inhibitor)[97]
  • B591 (pan-class I PI3K inhibitor)[98]
  • GNE-477 (dual PIK3CA and mTOR inhibitor with IC50 values of 4 nM and 21 nM)[99]
  • Hibiscone C (irreversible PI3K inhibitor)
  • IC87114 (mainly a PIK3CD inhibitor)[16]
  • LY294002 (reversible PI3K inhibitor),[16] mainly used as a research tool
  • PI-103 (triple pan-class I PI3K, mTOR, and DNA-PK inhibitor)[100]
  • Wortmannin (irreversible PI3K inhibitor), mainly used as a research tool

See also

References

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Further reading

  • Williams R, Berndt A, Miller S, Hon WC, Zhang X (August 2009). "Form and flexibility in phosphoinositide 3-kinases". Biochemical Society Transactions. 37 (Pt 4): 615–626. doi:10.1042/BST0370615. PMID 19614567.

External links

    January 28, 2023
    phosphoinositide, kinase, inhibitor, pi3k, inhibitors, class, medical, drugs, that, mainly, used, treat, advanced, cancers, they, function, inhibiting, more, phosphoinositide, kinase, pi3k, enzymes, which, part, pi3k, mtor, pathway, this, signal, pathway, regu. 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 2 3 They are examples of a targeted therapy 4 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 5 6 Overview of phosphoinositide 3 kinase PI3K inhibitors and their interaction with the PI3K AKT mTOR pathway 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 1 After PI3K inhibitors had been under investigation as anti cancer drugs for several years 7 8 9 10 the first one to be approved for treatment in clinical practice was idelalisib in 2014 11 Several others followed and even more are still under development see below 3 12 There are different classes and isoforms of PI3Ks 13 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 14 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 15 e g PTEN negative tumors may be more sensitive to PIK3CB inhibitors 15 PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease 13 16 and are used to investigate the role of the PI3K pathway in aging 17 Contents 1 Approved for treatment 2 Under clinical development 2 1 Late stage 2 2 Early stage 3 Not in clinical trials 4 See also 5 References 6 Further reading 7 External linksApproved for treatment EditIdelalisib 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 11 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 18 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 19 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 20 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 21 22 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 23 Under clinical development EditLate stage Edit 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 24 The phase III trials BELLE 2 25 26 and BELLE 3 27 28 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 29 30 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 31 The phase III trial CHRONOS 3 compares copanlisib rituximab with placebo rituximab in patients with relapsed iNHL Study completion is expected for January 2023 32 Preliminary results show a strong and significant improvement of progression free survival under copanlisib treatment but also considerably more severe and serious side effects 33 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 34 Dactolisib codenamed BEZ235 NVP BEZ235 dual pan class I PI3K and mTOR inhibitor 35 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 36 However the trial did not meet this endpoint 37 Consequently the related phase III trial PROTECTOR 2 RTB 101 205 was terminated by the sponsor 38 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 update 39 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 40 An extension trial to DUO was completed in 2020 but its results have not yet been published 41 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 42 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 43 Idelalisib has undergone eleven phase III clinical trials as of March 2022 update 44 These include the pivotal trial GS US 312 0116 that lead to approval of idelalisib by FDA and EMA for tratment 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 45 Two trials comparing new experimental treatments to idelalisib as a comparator and a dose optimization study in FL are still ongoing 46 47 48 Leniolisib codenamed CDZ173 PIK3CD inhibitor was tested as a potential treatment for activated PI3K delta syndrome APDS PASLI disease in a placebo controlled phase II III trial NCT02435173 49 50 The trial was completed in August 2021 and results have become available in March 2022 49 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 51 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 52 Mantle cell lymphoma MCL in the phase III trial CITADEL 310 53 Myelofibrosis in the phase III trials LIMBER 304 54 and LIMBER 313 55 Warm antibody autoimmune hemolytic anemia WAIHA in the phase III trial PATHWAY 56 Paxalisib codenamed GDC 0084 pan class I PI3K and mTOR inhibitor will be tested as a potential treatment for glioblastoma in the phase II III trial GBM AGILE The trial is currently recruiting patients as of March 2022 update and will compare multiple experimental treatments including paxalisib with temozolomide radiotherapy lomustine 57 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 58 59 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 March 2022 update and will compare zandelisib rituximab to chemotherapy CHOP regimen rituximab Results are expected for April 2026 60 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 March 2022 update and will compare inavolisib palbociclib fulvestrant with placebo palbociclib fulvestrant Results are expected for September 2025 61 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 March 2022 update 62 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 March 2022 update 63 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 March 2022 update 64 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 65 Other phase II trials with fimepinostat have been terminated 66 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 March 2022 update two phase II trials on breast cancer are still recruiting patients 67 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 March 2022 update 68 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 March 2022 update Results are available for all of these trials 69 Pictilisib codenamed GDC 0941 pan class I PI3K inhibitor 70 has undergone five phase II trials as a potential treatment for different solid tumours with no results published as of March 2022 update 71 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 update 72 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 March 2022 update 73 Seletalisib codenamed UCB 5857 PIK3CD inhibitor has undergone one phase II trial as a potential treatment for Sjogren syndrome The trial has been terminated due to enrolment challenges 74 Serabelisib codenamed MLN1117 and TAK 117 PIK3CA inhibitor is undergoing several phase II trials as a potential treatment for different cancers As of March 2022 update results have been reported for renal cell carcinoma and endometrial cancer 75 76 Sonolisib codenamed PX 866 a wortmannin derivative 77 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 update 78 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 79 80 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 81 82 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 83 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 March 2022 update 84 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 March 2022 update 85 SF1126 is a peptidic prodrug targeting integrin receptors that converts to LY294002 one of the most widely studied dual PI3K mTOR inhibitors 86 A phase II trial with SF1126 has been terminated due to slow enrolment 87 Early stage Edit In early stage clinical trials 9 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 March 2022 update 88 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 March 2022 update 89 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 March 2022 update 90 CAL263 PIK3CD inhibitor 91 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 92 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 March 2022 update 93 PWT33597 dual PIK3CA and mTOR inhibitor 94 TG100 115 mainly a PIK3CD and PIK3CG inhibitor 95 ZSTK474 mainly a PIK3CD inhibitor 96 Not in clinical trials EditAEZS 136 dual PI3K and ERK inhibitor 97 B591 pan class I PI3K inhibitor 98 GNE 477 dual PIK3CA and mTOR inhibitor with IC50 values of 4 nM and 21 nM 99 Hibiscone C irreversible PI3K inhibitor IC87114 mainly a PIK3CD inhibitor 16 LY294002 reversible PI3K inhibitor 16 mainly used as a research tool PI 103 triple pan class I PI3K mTOR and DNA PK inhibitor 100 Wortmannin irreversible PI3K inhibitor mainly used as a research toolSee also EditPI3K AKT mTOR pathway for inhibitors of AKT and mTOR downstream from PI3K P110d Pharmacology P110d PI3K delta as a drug targetReferences Edit Mishra R Patel 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effects in solid tumors Cancer Research 70 3 1164 1172 doi 10 1158 0008 5472 CAN 09 2525 PMID 20103642 a b c Crabbe T April 2007 Exploring the potential of PI3K inhibitors for inflammation and cancer Biochemical Society Transactions 35 Pt 2 253 256 doi 10 1042 BST0350253 PMID 17371252 Blagosklonny MV Anti aging senolytics or gerostatics unconventional view Oncotarget 2021 Aug 31 12 18 1821 1835 doi 10 18632 oncotarget 28049 PMID 34504654 FDA approves new treatment for adults with relapsed follicular lymphoma US Food and Drug Administration September 14 2017 FDA Approval for duvelisib COPIKTRA Verastem Inc for adult patients with relapsed or refractory chronic lymphocytic leukemia CLL or small lymphocytic lymphoma SLL US Food and Drug Administration September 24 2018 FDA approves first PI3K inhibitor for breast cancer Food and Drug Administration 2019 05 24 Ukoniq umbralisib tablets for oral use PDF TG Therapeutics FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma U S Food and Drug Administration FDA 5 February 2021 Retrieved 5 February 2021 This article incorporates text from this source which is in the public domain Federal Register Request Access unblock federalregister gov Retrieved 2022 10 06 Clinical trial number NCT04338399 for The BURAN Study of Buparlisib in Patients With Recurrent or Metastatic HNSCC BURAN at ClinicalTrials gov Baselga J Im SA Iwata H Cortes J De Laurentiis M Jiang Z et al July 2017 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 The Lancet Oncology 18 7 904 916 doi 10 1016 S1470 2045 17 30376 5 PMC 5549667 PMID 28576675 Clinical trial number NCT01610284 for 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 at ClinicalTrials gov Di Leo A Johnston S Lee KS Ciruelos E Lonning PE Janni W et al January 2018 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 The Lancet Oncology 19 1 87 100 doi 10 1016 S1470 2045 17 30688 5 PMID 29223745 Clinical trial number NCT01633060 for 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 at ClinicalTrials gov Martin M Chan A Dirix L O Shaughnessy J Hegg R Manikhas A et al February 2017 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 Annals of Oncology 28 2 313 320 doi 10 1093 annonc mdw562 PMID 27803006 Clinical trial number NCT01572727 for 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 at ClinicalTrials gov Clinical trial number NCT02369016 for Phase III Copanlisib in Rituximab refractory iNHL CHRONOS 2 at ClinicalTrials gov Clinical trial number NCT02367040 for Copanlisib and Rituximab in Relapsed Indolent B cell Non Hodgkin s Lymphoma iNHL CHRONOS 3 at ClinicalTrials gov Matasar MJ Capra M Ozcan M Lv F Li W Yanez E et al May 2021 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 The Lancet Oncology 22 5 678 689 doi 10 1016 S1470 2045 21 00145 5 PMID 33848462 S2CID 233234876 Clinical trial number NCT02626455 for Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non Hodgkin s Lymphoma iNHL CHRONOS 4 at ClinicalTrials gov Liu TJ Koul D LaFortune T Tiao N Shen RJ Maira SM et al August 2009 NVP BEZ235 a novel dual phosphatidylinositol 3 kinase mammalian target of rapamycin inhibitor elicits multifaceted antitumor activities in human gliomas Molecular Cancer Therapeutics 8 8 2204 2210 doi 10 1158 1535 7163 MCT 09 0160 PMC 2752877 PMID 19671762 Clinical trial number NCT04668352 for A Phase 3 Study to Determine if RTB101 Prevents Clinically Symptomatic Respiratory Illness in the Elderly at ClinicalTrials gov Kaeberlein M 2020 RTB101 and immune function in the elderly Interpreting an unsuccessful clinical trial Translational Medicine of Aging 4 32 34 doi 10 1016 j tma 2020 01 002 S2CID 213379077 Clinical trial number NCT04139915 for Effect of RTB101 on Illness Associated With Respiratory Tract Infections in the Elderly at ClinicalTrials gov Search for phase 2 clinical trials with Dactolisib on clinicaltrials gov Retrieved 2022 03 04 Clinical trial number NCT02004522 for A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL SLL DUO at ClinicalTrials gov Clinical trial number NCT02049515 for A Phase 3 Extension Study of Duvelisib and Ofatumumab in Patients With CLL SLL Previously Enrolled in Study IPI 145 07 at ClinicalTrials gov Clinical trial number NCT02576275 for 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 at ClinicalTrials gov Clinical trial number NCT02204982 for Study of Duvelisib in Combination With Rituximab vs Rituximab in Subjects With Previously Treated Follicular Lymphoma DYNAMO R at ClinicalTrials gov Search for phase 3 clinical trials with CAL 101 on clinicaltrials gov Retrieved 2022 03 21 Zydelig EPAR Scientific conclusions PDF 2016 11 21 a href Template Cite journal html title Template Cite journal cite journal a Cite journal requires journal help Clinical trial number NCT02970318 for A Study of Acalabrutinib vs Investigator s Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R R CLL at ClinicalTrials gov Clinical trial number NCT04666038 for 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 at ClinicalTrials gov Clinical trial number NCT02536300 for Dose Optimization Study of Idelalisib in Follicular Lymphoma at ClinicalTrials gov a b Clinical trial number NCT02435173 for Study of Efficacy of CDZ173 in Patients With APDS PASLI at ClinicalTrials gov Rao VK Webster S Dalm VA Sediva A van Hagen PM Holland S et al November 2017 Effective activated PI3Kd syndrome targeted therapy with the PI3Kd inhibitor leniolisib Blood 130 21 2307 2316 doi 10 1182 blood 2017 08 801191 PMC 5701526 PMID 28972011 Clinical trial number NCT02859727 for Extension to the Study of Efficacy of CDZ173 in Patients With APDS PASLI at ClinicalTrials gov Clinical trial number NCT04796922 for 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 at ClinicalTrials gov Clinical trial number NCT04849715 for A Study of Parsaclisib a PI3Kd Inhibitor in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma CITADEL 310 at ClinicalTrials gov Clinical trial number NCT04551053 for To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib LIMBER 304 at ClinicalTrials gov Clinical trial number NCT04551066 for To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis LIMBER 313 at ClinicalTrials gov Clinical trial number NCT05073458 for Study of the Efficacy and Safety of Parsaclisib in Participants With Primary Warm Autoimmune Hemolytic Anemia PATHWAY at ClinicalTrials gov Clinical trial number NCT03970447 for A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma GBM AGILE at ClinicalTrials gov Roche dumps its PhIII PI3K effort on taselisib after researchers track poor survival edge harsh side effects for breast cancer Clinical trial number NCT02340221 for 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 at ClinicalTrials gov Clinical trial number NCT04745832 for Phase 3 Study of Zandelisib ME 401 in Combination With Rituximab in Patients With iNHL COASTAL at ClinicalTrials gov Clinical trial number NCT04191499 for 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 at ClinicalTrials gov Search for phase 2 clinical trials with GDC 0980 on clinicaltrials gov Retrieved 2022 03 17 Search for phase 2 clinical trials with PQR309 on clinicaltrials gov Retrieved 2022 03 17 Search for phase 2 clinical trials with IPI 549 on clinicaltrials gov Retrieved 2022 03 07 Clinical trial number NCT02674750 for Study to Evaluate the Efficacy and Safety of CUDC 907 in Patients With RR DLBCL Including Patients With MYC Alterations at ClinicalTrials gov Search for phase 2 clinical trials with CUDC 907 on clinicaltrials gov Retrieved 2022 03 04 Search for phase 2 clinical trials with PKI 587 on clinicaltrials gov Retrieved 2022 03 17 Search for phase 2 clinical trials with YY 20394 on clinicaltrials gov Retrieved 2022 03 18 Search for phase 2 clinical trials with GSK2269557 on clinicaltrials gov Retrieved 2022 03 17 Sarker D Ang JE Baird R Kristeleit R Shah K Moreno V et al January 2015 First in human phase I study of pictilisib GDC 0941 a potent pan class I 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gov Howes AL Chiang GG Lang ES Ho CB Powis G Vuori K Abraham RT September 2007 The phosphatidylinositol 3 kinase inhibitor PX 866 is a potent inhibitor of cancer cell motility and growth in three dimensional cultures Molecular Cancer Therapeutics 6 9 2505 2514 doi 10 1158 1535 7163 MCT 06 0698 PMID 17766839 Search for phase 2 clinical trials with PX 866 on clinicaltrials gov Retrieved 2022 03 04 Clinical trial number NCT04204057 for Efficacy and Safety of Tenalisib RP6530 in Patients With Relapsed Refractory Chronic Lymphocytic Leukemia CLL at ClinicalTrials gov Clinical trial number NCT03711578 for Efficacy and Safety Study of Tenalisib RP6530 a Novel PI3K d g Dual Inhibitor in Patients With Relapsed Refractory Indolent Non Hodgkin s Lymphoma iNHL at ClinicalTrials gov In Focus Voxtalisib for CLL and B Cell Lymphomas Cancer Therapy Advisor March 27 2018 Clinical trial number NCT01403636 for A Study of Investigational SAR245409 in Patients With Certain Lymphoma or Leukemia at ClinicalTrials gov Clinical trial number NCT02540928 for AMG 319 in HPV Positive and Negative HNSCC at ClinicalTrials gov Clinical trial number NCT04001569 for AZD8186 and Paclitaxel in Advanced Gastric Cancer at ClinicalTrials gov Search for phase 2 clinical trials with GSK2636771 on clinicaltrials gov Retrieved 2022 03 17 Garlich JR Becker MD Shelton CF Qi W Liu X Cooke L Mahadevan D 2010 Phase I Study of Novel Prodrug Dual PI3K MTOR Inhibitor SF1126 in B Cell Malignancies Blood 116 21 1783 doi 10 1182 blood V116 21 1783 1783 Clinical trial number NCT02644122 for SF1126 in Recurrent or Progressive SCCHN and Mutations in PIK3CA Gene and or PI 3 Kinase Pathway Genes at ClinicalTrials gov Clinical trial number NCT01705847 for A Phase 1b Study Evaluating GS 9820 in Subjects With Lymphoid Malignancies at ClinicalTrials gov Search for clinical trials with GSK2126458 on clinicaltrials gov Retrieved 2022 03 17 Clinical trial number NCT02260661 for Phase I Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours at ClinicalTrials gov Clinical trial number NCT01066611 for Study to Investigate Effects of CAL 263 in Subjects With Allergic Rhinitis Exposed to Allergen in an Environmental Chamber at ClinicalTrials gov Clinical trial number NCT00695448 for Phase I Open Label Dose Escalation Study of GSK1059615 in Patients With Solid Tumors or Lymphoma at ClinicalTrials gov Clinical trial number NCT04495621 for MEN1611 With Cetuximab in Metastatic Colorectal Cancer C PRECISE 01 at ClinicalTrials gov Search for phase 1 clinical trials with PWT33597 on clinicaltrials gov Retrieved 2022 03 09 Search for phase 1 clinical trials with TG100 115 on clinicaltrials gov Retrieved 2022 03 09 Search for phase 1 clinical trials with ZSTK474 on clinicaltrials gov Retrieved 2022 03 09 Locatelli SL Stirparo GG Tartari S Saba E Rubino L Brusamolino E Castagna L Santoro A Carlo Stella C 2013 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 Blood 122 21 3067 doi 10 1182 blood V122 21 3067 3067 Zhou H Yu C Kong L Xu X Yan J Li Y et al May 2019 B591 a novel specific pan PI3K inhibitor preferentially targets cancer stem cells Oncogene 38 18 3371 3386 doi 10 1038 s41388 018 0674 5 PMC 6756013 PMID 30635656 Heffron TP Berry M Castanedo G Chang C Chuckowree I Dotson J et al April 2010 Identification of GNE 477 a potent and efficacious dual PI3K mTOR inhibitor Bioorganic amp Medicinal Chemistry Letters 20 8 2408 2411 doi 10 1016 j bmcl 2010 03 046 PMID 20346656 Raynaud FI Eccles SA Patel S Alix S Box G Chuckowree I et al July 2009 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 Molecular Cancer Therapeutics 8 7 1725 1738 doi 10 1158 1535 7163 MCT 08 1200 PMC 2718129 PMID 19584227 Further reading EditWilliams R Berndt A Miller S Hon WC Zhang X August 2009 Form and flexibility in phosphoinositide 3 kinases Biochemical Society Transactions 37 Pt 4 615 626 doi 10 1042 BST0370615 PMID 19614567 External links EditNovartis on BEZ235 and BKM120 PI3K inhibitors Retrieved from https en wikipedia org w index php title Phosphoinositide 3 kinase inhibitor amp oldid 1135338337 Early stage, wikipedia, wiki, book, books, library,

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