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A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer
Summary Purpose , Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with an...
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| Published in: | Investigational new drugs 2015-08, Vol.33 (4), p.890-894 |
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| container_end_page | 894 |
| container_issue | 4 |
| container_start_page | 890 |
| container_title | Investigational new drugs |
| container_volume | 33 |
| creator | Mitri, Zahi Karakas, Cansu Wei, Caimiao Briones, Brian Simmons, Holly Ibrahim, Nuhad Alvarez, Ricardo Murray, James L. Keyomarsi, Khandan Moulder, Stacy |
| description | Summary
Purpose
, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC.
Methods
, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %.
Results
, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3,
n
= 2), syncope (grade 3,
n
= 2) and vomiting (grade 3,
n
= 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3–12 weeks). Thus, accrual was stopped rather than explore the −1 dose level.
Conclusion
, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC. |
| doi_str_mv | 10.1007/s10637-015-0244-4 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1693728383</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3735153171</sourcerecordid><originalsourceid>FETCH-LOGICAL-c442t-98999dd068f7de8423d16d21e4096254d3f21472620b3046278bc3dab799e0dc3</originalsourceid><addsrcrecordid>eNp1kc1u1DAUha0KRKeFB-gGWWJTFgH_xY6X1bRQRCUWLWsrtm86rmacYDuFPhJviYe0FRskS1e-3znnLg5CJ5R8oISoj5kSyVVDaNsQJkQjDtCKtoo3RAr5Aq0IlaqRWqtDdJTzHSGEayVeoUPWaqFa2a7Q7zM8bfoMmOJcZv-Af4aywX6sG_g19TGHMeJxwGUDeH3-FYe4CTaUMWEfYu-C2waLT6_Xl1gxpWX7viqwG3e20rL3_s2DKaTZBldZfVMlEEte2A5Kn0tdOVxSmLaAI9zW7z1gm6Ai7ProIL1GL4d-m-HN4zxG3z9d3Kwvm6tvn7-sz64aJwQrje601t4T2Q3KQycY91R6RkEQLVkrPB8YFYpJRiwnQjLVWcd9b5XWQLzjx-jdkjul8ccMuZi7cU6xnjRUaq5YxzteVXRRuTTmnGAwUwq7Pj0YSsy-HLOUY2o5Zl-OEdXz9jF5tjvwz46nNqqALYJcUbyF9M_p_6b-AQZHmfQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1693728383</pqid></control><display><type>article</type><title>A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer</title><source>ABI/INFORM Collection</source><source>Springer Link</source><creator>Mitri, Zahi ; Karakas, Cansu ; Wei, Caimiao ; Briones, Brian ; Simmons, Holly ; Ibrahim, Nuhad ; Alvarez, Ricardo ; Murray, James L. ; Keyomarsi, Khandan ; Moulder, Stacy</creator><creatorcontrib>Mitri, Zahi ; Karakas, Cansu ; Wei, Caimiao ; Briones, Brian ; Simmons, Holly ; Ibrahim, Nuhad ; Alvarez, Ricardo ; Murray, James L. ; Keyomarsi, Khandan ; Moulder, Stacy</creatorcontrib><description>Summary
Purpose
, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC.
Methods
, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %.
Results
, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3,
n
= 2), syncope (grade 3,
n
= 2) and vomiting (grade 3,
n
= 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3–12 weeks). Thus, accrual was stopped rather than explore the −1 dose level.
Conclusion
, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-015-0244-4</identifier><identifier>PMID: 25947565</identifier><identifier>CODEN: INNDDK</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adult ; Aged ; Antibiotics, Antineoplastic - adverse effects ; Antibiotics, Antineoplastic - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Apoptosis ; Binding sites ; Breast cancer ; Bridged Bicyclo Compounds, Heterocyclic - adverse effects ; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use ; Cancer therapies ; Cell death ; Chemotherapy ; Clinical trials ; Cyclin-Dependent Kinases - antagonists & inhibitors ; Drug dosages ; Epirubicin - adverse effects ; Epirubicin - therapeutic use ; Female ; Humans ; Inhibitor drugs ; Maximum Tolerated Dose ; Medical prognosis ; Medicine ; Medicine & Public Health ; Metastasis ; Middle Aged ; Molecular weight ; Neutropenia ; Oncology ; Patients ; Pharmacology/Toxicology ; Phase I Studies ; Phase transitions ; Polyclonal antibodies ; Protein Kinase Inhibitors - adverse effects ; Protein Kinase Inhibitors - therapeutic use ; Pyridinium Compounds - adverse effects ; Pyridinium Compounds - therapeutic use ; Studies ; Toxicity ; Treatment Outcome ; Triple Negative Breast Neoplasms - drug therapy ; Tumors ; Vomiting</subject><ispartof>Investigational new drugs, 2015-08, Vol.33 (4), p.890-894</ispartof><rights>Springer Science+Business Media New York 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-98999dd068f7de8423d16d21e4096254d3f21472620b3046278bc3dab799e0dc3</citedby><cites>FETCH-LOGICAL-c442t-98999dd068f7de8423d16d21e4096254d3f21472620b3046278bc3dab799e0dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1693728383/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1693728383?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,11686,27922,27923,36058,44361,74665</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25947565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mitri, Zahi</creatorcontrib><creatorcontrib>Karakas, Cansu</creatorcontrib><creatorcontrib>Wei, Caimiao</creatorcontrib><creatorcontrib>Briones, Brian</creatorcontrib><creatorcontrib>Simmons, Holly</creatorcontrib><creatorcontrib>Ibrahim, Nuhad</creatorcontrib><creatorcontrib>Alvarez, Ricardo</creatorcontrib><creatorcontrib>Murray, James L.</creatorcontrib><creatorcontrib>Keyomarsi, Khandan</creatorcontrib><creatorcontrib>Moulder, Stacy</creatorcontrib><title>A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Purpose
, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC.
Methods
, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %.
Results
, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3,
n
= 2), syncope (grade 3,
n
= 2) and vomiting (grade 3,
n
= 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3–12 weeks). Thus, accrual was stopped rather than explore the −1 dose level.
Conclusion
, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.</description><subject>Adult</subject><subject>Aged</subject><subject>Antibiotics, Antineoplastic - adverse effects</subject><subject>Antibiotics, Antineoplastic - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Breast cancer</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - adverse effects</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - therapeutic use</subject><subject>Cancer therapies</subject><subject>Cell death</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Cyclin-Dependent Kinases - antagonists & inhibitors</subject><subject>Drug dosages</subject><subject>Epirubicin - adverse effects</subject><subject>Epirubicin - therapeutic use</subject><subject>Female</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Maximum Tolerated Dose</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Molecular weight</subject><subject>Neutropenia</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmacology/Toxicology</subject><subject>Phase I Studies</subject><subject>Phase transitions</subject><subject>Polyclonal antibodies</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Pyridinium Compounds - adverse effects</subject><subject>Pyridinium Compounds - therapeutic use</subject><subject>Studies</subject><subject>Toxicity</subject><subject>Treatment Outcome</subject><subject>Triple Negative Breast Neoplasms - drug therapy</subject><subject>Tumors</subject><subject>Vomiting</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>M0C</sourceid><recordid>eNp1kc1u1DAUha0KRKeFB-gGWWJTFgH_xY6X1bRQRCUWLWsrtm86rmacYDuFPhJviYe0FRskS1e-3znnLg5CJ5R8oISoj5kSyVVDaNsQJkQjDtCKtoo3RAr5Aq0IlaqRWqtDdJTzHSGEayVeoUPWaqFa2a7Q7zM8bfoMmOJcZv-Af4aywX6sG_g19TGHMeJxwGUDeH3-FYe4CTaUMWEfYu-C2waLT6_Xl1gxpWX7viqwG3e20rL3_s2DKaTZBldZfVMlEEte2A5Kn0tdOVxSmLaAI9zW7z1gm6Ai7ProIL1GL4d-m-HN4zxG3z9d3Kwvm6tvn7-sz64aJwQrje601t4T2Q3KQycY91R6RkEQLVkrPB8YFYpJRiwnQjLVWcd9b5XWQLzjx-jdkjul8ccMuZi7cU6xnjRUaq5YxzteVXRRuTTmnGAwUwq7Pj0YSsy-HLOUY2o5Zl-OEdXz9jF5tjvwz46nNqqALYJcUbyF9M_p_6b-AQZHmfQ</recordid><startdate>20150801</startdate><enddate>20150801</enddate><creator>Mitri, Zahi</creator><creator>Karakas, Cansu</creator><creator>Wei, Caimiao</creator><creator>Briones, Brian</creator><creator>Simmons, Holly</creator><creator>Ibrahim, Nuhad</creator><creator>Alvarez, Ricardo</creator><creator>Murray, James L.</creator><creator>Keyomarsi, Khandan</creator><creator>Moulder, Stacy</creator><general>Springer US</general><general>Springer Nature B.V</general><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>3V.</scope><scope>7QO</scope><scope>7RV</scope><scope>7WY</scope><scope>7WZ</scope><scope>7X7</scope><scope>7XB</scope><scope>87Z</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8FL</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BEZIV</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FRNLG</scope><scope>FYUFA</scope><scope>F~G</scope><scope>GHDGH</scope><scope>K60</scope><scope>K6~</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>L.-</scope><scope>M0C</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQBIZ</scope><scope>PQBZA</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope></search><sort><creationdate>20150801</creationdate><title>A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer</title><author>Mitri, Zahi ; Karakas, Cansu ; Wei, Caimiao ; Briones, Brian ; Simmons, Holly ; Ibrahim, Nuhad ; Alvarez, Ricardo ; Murray, James L. ; Keyomarsi, Khandan ; Moulder, Stacy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-98999dd068f7de8423d16d21e4096254d3f21472620b3046278bc3dab799e0dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antibiotics, Antineoplastic - adverse effects</topic><topic>Antibiotics, Antineoplastic - therapeutic use</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Apoptosis</topic><topic>Binding sites</topic><topic>Breast cancer</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - adverse effects</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - therapeutic use</topic><topic>Cancer therapies</topic><topic>Cell death</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Cyclin-Dependent Kinases - antagonists & inhibitors</topic><topic>Drug dosages</topic><topic>Epirubicin - adverse effects</topic><topic>Epirubicin - therapeutic use</topic><topic>Female</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Maximum Tolerated Dose</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Molecular weight</topic><topic>Neutropenia</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmacology/Toxicology</topic><topic>Phase I Studies</topic><topic>Phase transitions</topic><topic>Polyclonal antibodies</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Pyridinium Compounds - adverse effects</topic><topic>Pyridinium Compounds - therapeutic use</topic><topic>Studies</topic><topic>Toxicity</topic><topic>Treatment Outcome</topic><topic>Triple Negative Breast Neoplasms - drug therapy</topic><topic>Tumors</topic><topic>Vomiting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mitri, Zahi</creatorcontrib><creatorcontrib>Karakas, Cansu</creatorcontrib><creatorcontrib>Wei, Caimiao</creatorcontrib><creatorcontrib>Briones, Brian</creatorcontrib><creatorcontrib>Simmons, Holly</creatorcontrib><creatorcontrib>Ibrahim, Nuhad</creatorcontrib><creatorcontrib>Alvarez, Ricardo</creatorcontrib><creatorcontrib>Murray, James L.</creatorcontrib><creatorcontrib>Keyomarsi, Khandan</creatorcontrib><creatorcontrib>Moulder, Stacy</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>ABI/INFORM Collection</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Databases</collection><collection>Business Premium Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Business Premium Collection (Alumni)</collection><collection>Health Research Premium Collection</collection><collection>ABI/INFORM Global (Corporate)</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Business Collection (Alumni Edition)</collection><collection>ProQuest Business Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>One Business</collection><collection>ProQuest One Business (Alumni)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mitri, Zahi</au><au>Karakas, Cansu</au><au>Wei, Caimiao</au><au>Briones, Brian</au><au>Simmons, Holly</au><au>Ibrahim, Nuhad</au><au>Alvarez, Ricardo</au><au>Murray, James L.</au><au>Keyomarsi, Khandan</au><au>Moulder, Stacy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2015-08-01</date><risdate>2015</risdate><volume>33</volume><issue>4</issue><spage>890</spage><epage>894</epage><pages>890-894</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><coden>INNDDK</coden><abstract>Summary
Purpose
, Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC.
Methods
, Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %.
Results
, Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3,
n
= 2), syncope (grade 3,
n
= 2) and vomiting (grade 3,
n
= 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3–12 weeks). Thus, accrual was stopped rather than explore the −1 dose level.
Conclusion
, The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>25947565</pmid><doi>10.1007/s10637-015-0244-4</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0167-6997 |
| ispartof | Investigational new drugs, 2015-08, Vol.33 (4), p.890-894 |
| issn | 0167-6997 1573-0646 |
| language | eng |
| recordid | cdi_proquest_journals_1693728383 |
| source | ABI/INFORM Collection; Springer Link |
| subjects | Adult Aged Antibiotics, Antineoplastic - adverse effects Antibiotics, Antineoplastic - therapeutic use Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis Binding sites Breast cancer Bridged Bicyclo Compounds, Heterocyclic - adverse effects Bridged Bicyclo Compounds, Heterocyclic - therapeutic use Cancer therapies Cell death Chemotherapy Clinical trials Cyclin-Dependent Kinases - antagonists & inhibitors Drug dosages Epirubicin - adverse effects Epirubicin - therapeutic use Female Humans Inhibitor drugs Maximum Tolerated Dose Medical prognosis Medicine Medicine & Public Health Metastasis Middle Aged Molecular weight Neutropenia Oncology Patients Pharmacology/Toxicology Phase I Studies Phase transitions Polyclonal antibodies Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - therapeutic use Pyridinium Compounds - adverse effects Pyridinium Compounds - therapeutic use Studies Toxicity Treatment Outcome Triple Negative Breast Neoplasms - drug therapy Tumors Vomiting |
| title | A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer |
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