Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies
Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210...
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| Veröffentlicht in: | Blood 2018-02, Vol.131 (8), p.877-887 |
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| creator | Flinn, Ian W. O'Brien, Susan Kahl, Brad Patel, Manish Oki, Yasuhiro Foss, Francine F. Porcu, Pierluigi Jones, Jeffrey Burger, Jan A. Jain, Nitin Kelly, Virginia M. Allen, Kerstin Douglas, Mark Sweeney, Jennifer Kelly, Patrick Horwitz, Steven |
| description | Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ∼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.
•Duvelisib, an oral dual inhibitor of PI3K-δ and γ, is clinically and pharmacodynamically active across a range of hematologic malignancies.•75 mg twice daily was determined to be the MTD, with 25 mg twice daily selected for further evaluation in phase 2 and 3 studies.
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| doi_str_mv | 10.1182/blood-2017-05-786566 |
| format | Article |
| fullrecord | <record><control><sourceid>elsevier_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6033052</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006497120324514</els_id><sourcerecordid>S0006497120324514</sourcerecordid><originalsourceid>FETCH-LOGICAL-c393t-fd0de5fef338f8c7eec899355ae229fafa1951b3d8b6751521c910cebf85afdb3</originalsourceid><addsrcrecordid>eNp9UduOFCEQJUbjjqt_YAwfMGgBQ19eTMx627iJPugzoaGYKcM0m6ank_0u_Y79JhlHV30xJEUoOKc45zD2VMJzKTv1Ykg5B6FAtgKMaLvGNM09tpJGdQJAwX22AoBGbPpWnrFHpXwFkButzEN2pnp5XM2K5deHBRMVGtbc8THXA8-TSzwcaqFxRwPNeeI58k-X-oO4_b6-_bbmVLhPNJJ3Kd1w52dasL7mLixu9Bj4DvduzilvyfO9S7Qda5-wPGYPoksFn_zaz9mXt28-X7wXVx_fXV68uhJe93oWMUBAEzFq3cXOt4i-63ttjEOl-uiik72Rgw7d0LSmapa-l-BxiJ1xMQz6nL088V4fhj0Gj-NcVdnrifZuurHZkf33ZqSd3ebFNqA1GFUJNicCP-VSJox3WAn2GID9GYA9BmDB2FMAFfbs77l3oN-O__kYVvUL4WRL9eXoGU3oZxsy_X_CDztrnFc</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><source>EZB Electronic Journals Library</source><creator>Flinn, Ian W. ; O'Brien, Susan ; Kahl, Brad ; Patel, Manish ; Oki, Yasuhiro ; Foss, Francine F. ; Porcu, Pierluigi ; Jones, Jeffrey ; Burger, Jan A. ; Jain, Nitin ; Kelly, Virginia M. ; Allen, Kerstin ; Douglas, Mark ; Sweeney, Jennifer ; Kelly, Patrick ; Horwitz, Steven</creator><creatorcontrib>Flinn, Ian W. ; O'Brien, Susan ; Kahl, Brad ; Patel, Manish ; Oki, Yasuhiro ; Foss, Francine F. ; Porcu, Pierluigi ; Jones, Jeffrey ; Burger, Jan A. ; Jain, Nitin ; Kelly, Virginia M. ; Allen, Kerstin ; Douglas, Mark ; Sweeney, Jennifer ; Kelly, Patrick ; Horwitz, Steven</creatorcontrib><description>Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ∼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.
•Duvelisib, an oral dual inhibitor of PI3K-δ and γ, is clinically and pharmacodynamically active across a range of hematologic malignancies.•75 mg twice daily was determined to be the MTD, with 25 mg twice daily selected for further evaluation in phase 2 and 3 studies.
[Display omitted]</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2017-05-786566</identifier><identifier>PMID: 29191916</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Class Ib Phosphatidylinositol 3-Kinase ; Female ; Hematologic Neoplasms - drug therapy ; Hematologic Neoplasms - enzymology ; Hematologic Neoplasms - pathology ; Humans ; Isoquinolines - administration & dosage ; Isoquinolines - pharmacokinetics ; Isoquinolines - pharmacology ; Lymphoid Neoplasia ; Male ; Maximum Tolerated Dose ; Middle Aged ; Phosphoinositide-3 Kinase Inhibitors ; Prognosis ; Purines - administration & dosage ; Purines - pharmacokinetics ; Purines - pharmacology ; Safety ; Tissue Distribution</subject><ispartof>Blood, 2018-02, Vol.131 (8), p.877-887</ispartof><rights>2018 American Society of Hematology</rights><rights>2018 by The American Society of Hematology.</rights><rights>2018 by The American Society of Hematology 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-fd0de5fef338f8c7eec899355ae229fafa1951b3d8b6751521c910cebf85afdb3</citedby><cites>FETCH-LOGICAL-c393t-fd0de5fef338f8c7eec899355ae229fafa1951b3d8b6751521c910cebf85afdb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29191916$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flinn, Ian W.</creatorcontrib><creatorcontrib>O'Brien, Susan</creatorcontrib><creatorcontrib>Kahl, Brad</creatorcontrib><creatorcontrib>Patel, Manish</creatorcontrib><creatorcontrib>Oki, Yasuhiro</creatorcontrib><creatorcontrib>Foss, Francine F.</creatorcontrib><creatorcontrib>Porcu, Pierluigi</creatorcontrib><creatorcontrib>Jones, Jeffrey</creatorcontrib><creatorcontrib>Burger, Jan A.</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Kelly, Virginia M.</creatorcontrib><creatorcontrib>Allen, Kerstin</creatorcontrib><creatorcontrib>Douglas, Mark</creatorcontrib><creatorcontrib>Sweeney, Jennifer</creatorcontrib><creatorcontrib>Kelly, Patrick</creatorcontrib><creatorcontrib>Horwitz, Steven</creatorcontrib><title>Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies</title><title>Blood</title><addtitle>Blood</addtitle><description>Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ∼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.
•Duvelisib, an oral dual inhibitor of PI3K-δ and γ, is clinically and pharmacodynamically active across a range of hematologic malignancies.•75 mg twice daily was determined to be the MTD, with 25 mg twice daily selected for further evaluation in phase 2 and 3 studies.
[Display omitted]</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Class Ib Phosphatidylinositol 3-Kinase</subject><subject>Female</subject><subject>Hematologic Neoplasms - drug therapy</subject><subject>Hematologic Neoplasms - enzymology</subject><subject>Hematologic Neoplasms - pathology</subject><subject>Humans</subject><subject>Isoquinolines - administration & dosage</subject><subject>Isoquinolines - pharmacokinetics</subject><subject>Isoquinolines - pharmacology</subject><subject>Lymphoid Neoplasia</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Middle Aged</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Prognosis</subject><subject>Purines - administration & dosage</subject><subject>Purines - pharmacokinetics</subject><subject>Purines - pharmacology</subject><subject>Safety</subject><subject>Tissue Distribution</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UduOFCEQJUbjjqt_YAwfMGgBQ19eTMx627iJPugzoaGYKcM0m6ank_0u_Y79JhlHV30xJEUoOKc45zD2VMJzKTv1Ykg5B6FAtgKMaLvGNM09tpJGdQJAwX22AoBGbPpWnrFHpXwFkButzEN2pnp5XM2K5deHBRMVGtbc8THXA8-TSzwcaqFxRwPNeeI58k-X-oO4_b6-_bbmVLhPNJJ3Kd1w52dasL7mLixu9Bj4DvduzilvyfO9S7Qda5-wPGYPoksFn_zaz9mXt28-X7wXVx_fXV68uhJe93oWMUBAEzFq3cXOt4i-63ttjEOl-uiik72Rgw7d0LSmapa-l-BxiJ1xMQz6nL088V4fhj0Gj-NcVdnrifZuurHZkf33ZqSd3ebFNqA1GFUJNicCP-VSJox3WAn2GID9GYA9BmDB2FMAFfbs77l3oN-O__kYVvUL4WRL9eXoGU3oZxsy_X_CDztrnFc</recordid><startdate>20180222</startdate><enddate>20180222</enddate><creator>Flinn, Ian W.</creator><creator>O'Brien, Susan</creator><creator>Kahl, Brad</creator><creator>Patel, Manish</creator><creator>Oki, Yasuhiro</creator><creator>Foss, Francine F.</creator><creator>Porcu, Pierluigi</creator><creator>Jones, Jeffrey</creator><creator>Burger, Jan A.</creator><creator>Jain, Nitin</creator><creator>Kelly, Virginia M.</creator><creator>Allen, Kerstin</creator><creator>Douglas, Mark</creator><creator>Sweeney, Jennifer</creator><creator>Kelly, Patrick</creator><creator>Horwitz, Steven</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20180222</creationdate><title>Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies</title><author>Flinn, Ian W. ; O'Brien, Susan ; Kahl, Brad ; Patel, Manish ; Oki, Yasuhiro ; Foss, Francine F. ; Porcu, Pierluigi ; Jones, Jeffrey ; Burger, Jan A. ; Jain, Nitin ; Kelly, Virginia M. ; Allen, Kerstin ; Douglas, Mark ; Sweeney, Jennifer ; Kelly, Patrick ; Horwitz, Steven</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-fd0de5fef338f8c7eec899355ae229fafa1951b3d8b6751521c910cebf85afdb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Class Ib Phosphatidylinositol 3-Kinase</topic><topic>Female</topic><topic>Hematologic Neoplasms - drug therapy</topic><topic>Hematologic Neoplasms - enzymology</topic><topic>Hematologic Neoplasms - pathology</topic><topic>Humans</topic><topic>Isoquinolines - administration & dosage</topic><topic>Isoquinolines - pharmacokinetics</topic><topic>Isoquinolines - pharmacology</topic><topic>Lymphoid Neoplasia</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Middle Aged</topic><topic>Phosphoinositide-3 Kinase Inhibitors</topic><topic>Prognosis</topic><topic>Purines - administration & dosage</topic><topic>Purines - pharmacokinetics</topic><topic>Purines - pharmacology</topic><topic>Safety</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flinn, Ian W.</creatorcontrib><creatorcontrib>O'Brien, Susan</creatorcontrib><creatorcontrib>Kahl, Brad</creatorcontrib><creatorcontrib>Patel, Manish</creatorcontrib><creatorcontrib>Oki, Yasuhiro</creatorcontrib><creatorcontrib>Foss, Francine F.</creatorcontrib><creatorcontrib>Porcu, Pierluigi</creatorcontrib><creatorcontrib>Jones, Jeffrey</creatorcontrib><creatorcontrib>Burger, Jan A.</creatorcontrib><creatorcontrib>Jain, Nitin</creatorcontrib><creatorcontrib>Kelly, Virginia M.</creatorcontrib><creatorcontrib>Allen, Kerstin</creatorcontrib><creatorcontrib>Douglas, Mark</creatorcontrib><creatorcontrib>Sweeney, Jennifer</creatorcontrib><creatorcontrib>Kelly, Patrick</creatorcontrib><creatorcontrib>Horwitz, Steven</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flinn, Ian W.</au><au>O'Brien, Susan</au><au>Kahl, Brad</au><au>Patel, Manish</au><au>Oki, Yasuhiro</au><au>Foss, Francine F.</au><au>Porcu, Pierluigi</au><au>Jones, Jeffrey</au><au>Burger, Jan A.</au><au>Jain, Nitin</au><au>Kelly, Virginia M.</au><au>Allen, Kerstin</au><au>Douglas, Mark</au><au>Sweeney, Jennifer</au><au>Kelly, Patrick</au><au>Horwitz, Steven</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2018-02-22</date><risdate>2018</risdate><volume>131</volume><issue>8</issue><spage>877</spage><epage>887</epage><pages>877-887</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Duvelisib is an oral dual inhibitor of phosphoinositide 3-kinase-δ (PI3K-δ) and PI3K-γ in late-stage clinical development for hematologic malignancy treatment. This phase 1 study evaluated maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the dose escalation phase (n = 31), duvelisib 8 to 100 mg twice daily was administered, with MTD determined as 75 mg twice daily. In the expansion phase (n = 179), patients with indolent non-Hodgkin lymphoma (iNHL), chronic lymphocytic leukemia (CLL), or T-cell lymphoma (TCL) were treated with 25 or 75 mg duvelisib twice daily continuously. Single-dose duvelisib was rapidly absorbed (time to maximum concentration, 1-2 hours), with a half-life of 5.2 to 10.9 hours. PD results showed inhibition of phospho-AKT (S473) in CLL tumor cells following a single dose and near-complete inhibition of CLL proliferation (Ki-67) by cycle 2. Clinical responses were seen across a range of doses and disease subtypes: iNHL overall response rate, 58% (n = 31) with 6 complete responses (CRs); relapsed/refractory CLL, 56% (n = 55) with 1 CR; peripheral TCL, 50% (n = 16) with 3 CR; and cutaneous TCL, 32% (n = 19). Median time to response was ∼1.8 months. Severe (grade ≥3) adverse events occurred in 84% of patients: neutropenia (32%), alanine transaminase increase (20%), aspartate transaminase increase (15%), anemia and thrombocytopenia (each 14%), diarrhea (11%), and pneumonia (10%). These data support further investigation of duvelisib in phase 2 and 3 studies. This trial was registered at clinicaltrials.gov as #NCT01476657.
•Duvelisib, an oral dual inhibitor of PI3K-δ and γ, is clinically and pharmacodynamically active across a range of hematologic malignancies.•75 mg twice daily was determined to be the MTD, with 25 mg twice daily selected for further evaluation in phase 2 and 3 studies.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29191916</pmid><doi>10.1182/blood-2017-05-786566</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Oral Adult Aged Aged, 80 and over Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors Class Ib Phosphatidylinositol 3-Kinase Female Hematologic Neoplasms - drug therapy Hematologic Neoplasms - enzymology Hematologic Neoplasms - pathology Humans Isoquinolines - administration & dosage Isoquinolines - pharmacokinetics Isoquinolines - pharmacology Lymphoid Neoplasia Male Maximum Tolerated Dose Middle Aged Phosphoinositide-3 Kinase Inhibitors Prognosis Purines - administration & dosage Purines - pharmacokinetics Purines - pharmacology Safety Tissue Distribution |
| title | Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies |
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