Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies
We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malign...
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| Veröffentlicht in: | Journal of clinical oncology 2009-06, Vol.27 (16), p.2705-2711 |
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| creator | KUMMAR, Shivaani KINDERS, Robert MURGO, Anthony J COLLINS, Jerry STEINBERG, Seth M ELIOPOULOS, Helen GIRANDA, Vincent L GORDON, Gary HELMAN, Lee WILTROUT, Robert TOMASZEWSKI, Joseph E DOROSHOW, James H GUTIERREZ, Martin E RUBINSTEIN, Larry PARCHMENT, Ralph E PHILLIPS, Lawrence R JIUPING JI MONKS, Anne LOW, Jennifer A CHEN, Alice |
| description | We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.
ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.
Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.
Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology. |
| doi_str_mv | 10.1200/JCO.2008.19.7681 |
| format | Article |
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ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.
Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.
Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.</description><identifier>ISSN: 0732-183X</identifier><identifier>EISSN: 1527-7755</identifier><identifier>DOI: 10.1200/JCO.2008.19.7681</identifier><identifier>PMID: 19364967</identifier><language>eng</language><publisher>Alexandria, VA: American Society of Clinical Oncology</publisher><subject>Administration, Oral ; Aged ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Benzimidazoles - administration & dosage ; Benzimidazoles - pharmacokinetics ; Benzimidazoles - therapeutic use ; Biological and medical sciences ; Biological Availability ; Biopsy ; Clinical Trials, Phase I as Topic ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - therapeutic use ; Feasibility Studies ; Female ; Humans ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - enzymology ; Male ; Medical sciences ; Middle Aged ; Neoplasms - drug therapy ; Neoplasms - enzymology ; Neoplasms - pathology ; Original Reports ; Poly(ADP-ribose) Polymerase Inhibitors ; Research Design ; Treatment Outcome ; Tumors</subject><ispartof>Journal of clinical oncology, 2009-06, Vol.27 (16), p.2705-2711</ispartof><rights>2009 INIST-CNRS</rights><rights>2009 by American Society of Clinical Oncology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c425t-b58d5b45c710cc6ce0d946c411f611eea93d24ab382252e43de13e6f68c13d3a3</citedby><cites>FETCH-LOGICAL-c425t-b58d5b45c710cc6ce0d946c411f611eea93d24ab382252e43de13e6f68c13d3a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3716,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21538398$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19364967$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KUMMAR, Shivaani</creatorcontrib><creatorcontrib>KINDERS, Robert</creatorcontrib><creatorcontrib>MURGO, Anthony J</creatorcontrib><creatorcontrib>COLLINS, Jerry</creatorcontrib><creatorcontrib>STEINBERG, Seth M</creatorcontrib><creatorcontrib>ELIOPOULOS, Helen</creatorcontrib><creatorcontrib>GIRANDA, Vincent L</creatorcontrib><creatorcontrib>GORDON, Gary</creatorcontrib><creatorcontrib>HELMAN, Lee</creatorcontrib><creatorcontrib>WILTROUT, Robert</creatorcontrib><creatorcontrib>TOMASZEWSKI, Joseph E</creatorcontrib><creatorcontrib>DOROSHOW, James H</creatorcontrib><creatorcontrib>GUTIERREZ, Martin E</creatorcontrib><creatorcontrib>RUBINSTEIN, Larry</creatorcontrib><creatorcontrib>PARCHMENT, Ralph E</creatorcontrib><creatorcontrib>PHILLIPS, Lawrence R</creatorcontrib><creatorcontrib>JIUPING JI</creatorcontrib><creatorcontrib>MONKS, Anne</creatorcontrib><creatorcontrib>LOW, Jennifer A</creatorcontrib><creatorcontrib>CHEN, Alice</creatorcontrib><title>Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies</title><title>Journal of clinical oncology</title><addtitle>J Clin Oncol</addtitle><description>We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.
ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.
Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.
Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.</description><subject>Administration, Oral</subject><subject>Aged</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Benzimidazoles - administration & dosage</subject><subject>Benzimidazoles - pharmacokinetics</subject><subject>Benzimidazoles - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Biopsy</subject><subject>Clinical Trials, Phase I as Topic</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Feasibility Studies</subject><subject>Female</subject><subject>Humans</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - enzymology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - pathology</subject><subject>Original Reports</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>Research Design</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>0732-183X</issn><issn>1527-7755</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1v1DAQtRCIbgt3TsgXRDlk8djxRy5Iy_JVVNQVWgQ3y3EmG1fZpLJDUf89DrsqcJkZ2e-9Gb1HyDNgS-CMvf68vlrmbpZQLbUy8IAsQHJdaC3lQ7JgWvACjPhxQk5TumYMSiPkY3IClVBlpfSCpE3nElJG130Ygnc93caQ69jSqUO6Gfs7er56tym-hnpM-OrPyx7jTLoYulCHaYx09XZbGGNoGOjGTQGHKdHvYeroqrl1g8eGfnF92A15DpiekEet6xM-PfYz8u3D--36U3F59fFivbosfMnlVNTSNLIupdfAvFceWVOVypcArQJAdJVoeOlqYTiXHEvRIAhUrTIeRCOcOCNvDro3P-s9Nj6fFV1vb2LYu3hnRxfs_z9D6OxuvLVci0oJmQXYQcDHMaWI7T0XmJ0DsDkAOwdgobJzAJny_N-dfwlHxzPgxRHgUra7jbMn6R7HQQojKpNxLw-4Luy6XyGiTXvX91mW22s_cm1B5UOZFL8BVUKbiQ</recordid><startdate>20090601</startdate><enddate>20090601</enddate><creator>KUMMAR, Shivaani</creator><creator>KINDERS, Robert</creator><creator>MURGO, Anthony J</creator><creator>COLLINS, Jerry</creator><creator>STEINBERG, Seth M</creator><creator>ELIOPOULOS, Helen</creator><creator>GIRANDA, Vincent L</creator><creator>GORDON, Gary</creator><creator>HELMAN, Lee</creator><creator>WILTROUT, Robert</creator><creator>TOMASZEWSKI, Joseph E</creator><creator>DOROSHOW, James H</creator><creator>GUTIERREZ, Martin E</creator><creator>RUBINSTEIN, Larry</creator><creator>PARCHMENT, Ralph E</creator><creator>PHILLIPS, Lawrence R</creator><creator>JIUPING JI</creator><creator>MONKS, Anne</creator><creator>LOW, Jennifer A</creator><creator>CHEN, Alice</creator><general>American Society of Clinical Oncology</general><scope>IQODW</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>20090601</creationdate><title>Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies</title><author>KUMMAR, Shivaani ; KINDERS, Robert ; MURGO, Anthony J ; COLLINS, Jerry ; STEINBERG, Seth M ; ELIOPOULOS, Helen ; GIRANDA, Vincent L ; GORDON, Gary ; HELMAN, Lee ; WILTROUT, Robert ; TOMASZEWSKI, Joseph E ; DOROSHOW, James H ; GUTIERREZ, Martin E ; RUBINSTEIN, Larry ; PARCHMENT, Ralph E ; PHILLIPS, Lawrence R ; JIUPING JI ; MONKS, Anne ; LOW, Jennifer A ; CHEN, Alice</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c425t-b58d5b45c710cc6ce0d946c411f611eea93d24ab382252e43de13e6f68c13d3a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Aged</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Benzimidazoles - administration & dosage</topic><topic>Benzimidazoles - pharmacokinetics</topic><topic>Benzimidazoles - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Biopsy</topic><topic>Clinical Trials, Phase I as Topic</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Feasibility Studies</topic><topic>Female</topic><topic>Humans</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - enzymology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - pathology</topic><topic>Original Reports</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>Research Design</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KUMMAR, Shivaani</creatorcontrib><creatorcontrib>KINDERS, Robert</creatorcontrib><creatorcontrib>MURGO, Anthony J</creatorcontrib><creatorcontrib>COLLINS, Jerry</creatorcontrib><creatorcontrib>STEINBERG, Seth M</creatorcontrib><creatorcontrib>ELIOPOULOS, Helen</creatorcontrib><creatorcontrib>GIRANDA, Vincent L</creatorcontrib><creatorcontrib>GORDON, Gary</creatorcontrib><creatorcontrib>HELMAN, Lee</creatorcontrib><creatorcontrib>WILTROUT, Robert</creatorcontrib><creatorcontrib>TOMASZEWSKI, Joseph E</creatorcontrib><creatorcontrib>DOROSHOW, James H</creatorcontrib><creatorcontrib>GUTIERREZ, Martin E</creatorcontrib><creatorcontrib>RUBINSTEIN, Larry</creatorcontrib><creatorcontrib>PARCHMENT, Ralph E</creatorcontrib><creatorcontrib>PHILLIPS, Lawrence R</creatorcontrib><creatorcontrib>JIUPING JI</creatorcontrib><creatorcontrib>MONKS, Anne</creatorcontrib><creatorcontrib>LOW, Jennifer A</creatorcontrib><creatorcontrib>CHEN, Alice</creatorcontrib><collection>Pascal-Francis</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>Journal of clinical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KUMMAR, Shivaani</au><au>KINDERS, Robert</au><au>MURGO, Anthony J</au><au>COLLINS, Jerry</au><au>STEINBERG, Seth M</au><au>ELIOPOULOS, Helen</au><au>GIRANDA, Vincent L</au><au>GORDON, Gary</au><au>HELMAN, Lee</au><au>WILTROUT, Robert</au><au>TOMASZEWSKI, Joseph E</au><au>DOROSHOW, James H</au><au>GUTIERREZ, Martin E</au><au>RUBINSTEIN, Larry</au><au>PARCHMENT, Ralph E</au><au>PHILLIPS, Lawrence R</au><au>JIUPING JI</au><au>MONKS, Anne</au><au>LOW, Jennifer A</au><au>CHEN, Alice</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies</atitle><jtitle>Journal of clinical oncology</jtitle><addtitle>J Clin Oncol</addtitle><date>2009-06-01</date><risdate>2009</risdate><volume>27</volume><issue>16</issue><spage>2705</spage><epage>2711</epage><pages>2705-2711</pages><issn>0732-183X</issn><eissn>1527-7755</eissn><abstract>We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.
ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.
Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.
Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.</abstract><cop>Alexandria, VA</cop><pub>American Society of Clinical Oncology</pub><pmid>19364967</pmid><doi>10.1200/JCO.2008.19.7681</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0732-183X |
| ispartof | Journal of clinical oncology, 2009-06, Vol.27 (16), p.2705-2711 |
| issn | 0732-183X 1527-7755 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2739635 |
| source | MEDLINE; American Society of Clinical Oncology Online Journals; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Administration, Oral Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Benzimidazoles - administration & dosage Benzimidazoles - pharmacokinetics Benzimidazoles - therapeutic use Biological and medical sciences Biological Availability Biopsy Clinical Trials, Phase I as Topic Dose-Response Relationship, Drug Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - therapeutic use Feasibility Studies Female Humans Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - enzymology Male Medical sciences Middle Aged Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - pathology Original Reports Poly(ADP-ribose) Polymerase Inhibitors Research Design Treatment Outcome Tumors |
| title | Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies |
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