A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours
Summary Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling. Method Two dose escalation schedules (Arm-A...
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| Veröffentlicht in: | Investigational new drugs 2018-12, Vol.36 (6), p.1026-1036 |
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| creator | Aung, Kyaw L. El-Khoueiry, Anthony B. Gelmon, Karen Tran, Ben Bajaj, Gaurav He, Bing Chen, Tian Zhu, Lili Poojary, Sharath Basak, Shashwati Qi, Zhenhao Spreafico, Anna Fischer, Bruce S. Desai, Jayesh |
| description | Summary
Background
Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling.
Method
Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115.
Results
Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months.
Conclusion
The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition. |
| doi_str_mv | 10.1007/s10637-018-0597-6 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7523345</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2023585620</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-2cb5dc14c3c0442fe3e1f36ebd2d3a7382af6b50d8df79e82f073372347ae2c83</originalsourceid><addsrcrecordid>eNp1UctuFDEQtBCILIEP4IIscTZpv2cuSCHiESmQA3C2PLZn19HMeLE9ifL3ONokwIFTS9VV1dUqhF5TeEcB9EmhoLgmQDsCstdEPUEbKjUnoIR6ijZAVQP7Xh-hF6VcAQDvtXiOjljfdELTDbo5xfM61UhsnvF-Z0vA59inNkJxdrI1Lltc6upvcRqxXXDKdsLfLn-cfcFx2cUh1pTxh6_fSd8pSmUD8b6pwlILvol1h62_tosLHpc0RY_rOqc1l5fo2WinEl7dz2P089PHZkouLj-fn51eECc0VMLcIL2jwnEHQrAx8EBHrsLgmedW847ZUQ0SfOdH3YeOjaA514wLbQNzHT9G7w---3WYg3ctV3vA7HOcbb41yUbz72aJO7NN10ZLxrmQzeDtvUFOv9ZQqrlq-ZeW2TBgXHZSMWgsemC5nErJYXy8QMHcdWUOXZnWlbnryqimefN3tEfFQzmNwA6E0lbLNuQ_p__v-hvpg5-X</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2023585620</pqid></control><display><type>article</type><title>A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Aung, Kyaw L. ; El-Khoueiry, Anthony B. ; Gelmon, Karen ; Tran, Ben ; Bajaj, Gaurav ; He, Bing ; Chen, Tian ; Zhu, Lili ; Poojary, Sharath ; Basak, Shashwati ; Qi, Zhenhao ; Spreafico, Anna ; Fischer, Bruce S. ; Desai, Jayesh</creator><creatorcontrib>Aung, Kyaw L. ; El-Khoueiry, Anthony B. ; Gelmon, Karen ; Tran, Ben ; Bajaj, Gaurav ; He, Bing ; Chen, Tian ; Zhu, Lili ; Poojary, Sharath ; Basak, Shashwati ; Qi, Zhenhao ; Spreafico, Anna ; Fischer, Bruce S. ; Desai, Jayesh</creatorcontrib><description>Summary
Background
Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling.
Method
Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115.
Results
Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months.
Conclusion
The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-018-0597-6</identifier><identifier>PMID: 29637471</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Angiogenesis ; Benzodiazepines - administration & dosage ; Benzodiazepines - adverse effects ; Benzodiazepines - pharmacokinetics ; Benzodiazepines - therapeutic use ; Biological activity ; Cancer ; Diarrhea ; Dose-Response Relationship, Drug ; Female ; Humans ; Hypophosphatemia ; Inhibition ; Inhibitors ; Male ; Maximum Tolerated Dose ; Medicine ; Medicine & Public Health ; Middle Aged ; Nausea ; Neoplasms - drug therapy ; Notch protein ; Oncology ; Patients ; Pharmacology/Toxicology ; Phase I Studies ; Pruritus ; Pyrazoles - administration & dosage ; Pyrazoles - adverse effects ; Pyrazoles - pharmacokinetics ; Pyrazoles - therapeutic use ; Receptors, Notch - antagonists & inhibitors ; Receptors, Notch - metabolism ; Schedules ; Secretase ; Signal transduction ; Signaling ; Solid tumors ; Stem cells ; Toxicity ; Treatment Outcome ; Tumors ; Urticaria ; Withholding Treatment ; Young Adult</subject><ispartof>Investigational new drugs, 2018-12, Vol.36 (6), p.1026-1036</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2018</rights><rights>Investigational New Drugs is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-2cb5dc14c3c0442fe3e1f36ebd2d3a7382af6b50d8df79e82f073372347ae2c83</citedby><cites>FETCH-LOGICAL-c470t-2cb5dc14c3c0442fe3e1f36ebd2d3a7382af6b50d8df79e82f073372347ae2c83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10637-018-0597-6$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-018-0597-6$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29637471$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aung, Kyaw L.</creatorcontrib><creatorcontrib>El-Khoueiry, Anthony B.</creatorcontrib><creatorcontrib>Gelmon, Karen</creatorcontrib><creatorcontrib>Tran, Ben</creatorcontrib><creatorcontrib>Bajaj, Gaurav</creatorcontrib><creatorcontrib>He, Bing</creatorcontrib><creatorcontrib>Chen, Tian</creatorcontrib><creatorcontrib>Zhu, Lili</creatorcontrib><creatorcontrib>Poojary, Sharath</creatorcontrib><creatorcontrib>Basak, Shashwati</creatorcontrib><creatorcontrib>Qi, Zhenhao</creatorcontrib><creatorcontrib>Spreafico, Anna</creatorcontrib><creatorcontrib>Fischer, Bruce S.</creatorcontrib><creatorcontrib>Desai, Jayesh</creatorcontrib><title>A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Background
Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling.
Method
Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115.
Results
Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months.
Conclusion
The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Angiogenesis</subject><subject>Benzodiazepines - administration & dosage</subject><subject>Benzodiazepines - adverse effects</subject><subject>Benzodiazepines - pharmacokinetics</subject><subject>Benzodiazepines - therapeutic use</subject><subject>Biological activity</subject><subject>Cancer</subject><subject>Diarrhea</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Humans</subject><subject>Hypophosphatemia</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Nausea</subject><subject>Neoplasms - drug therapy</subject><subject>Notch protein</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmacology/Toxicology</subject><subject>Phase I Studies</subject><subject>Pruritus</subject><subject>Pyrazoles - administration & dosage</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - therapeutic use</subject><subject>Receptors, Notch - antagonists & inhibitors</subject><subject>Receptors, Notch - metabolism</subject><subject>Schedules</subject><subject>Secretase</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Solid tumors</subject><subject>Stem cells</subject><subject>Toxicity</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Urticaria</subject><subject>Withholding Treatment</subject><subject>Young Adult</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp1UctuFDEQtBCILIEP4IIscTZpv2cuSCHiESmQA3C2PLZn19HMeLE9ifL3ONokwIFTS9VV1dUqhF5TeEcB9EmhoLgmQDsCstdEPUEbKjUnoIR6ijZAVQP7Xh-hF6VcAQDvtXiOjljfdELTDbo5xfM61UhsnvF-Z0vA59inNkJxdrI1Lltc6upvcRqxXXDKdsLfLn-cfcFx2cUh1pTxh6_fSd8pSmUD8b6pwlILvol1h62_tosLHpc0RY_rOqc1l5fo2WinEl7dz2P089PHZkouLj-fn51eECc0VMLcIL2jwnEHQrAx8EBHrsLgmedW847ZUQ0SfOdH3YeOjaA514wLbQNzHT9G7w---3WYg3ctV3vA7HOcbb41yUbz72aJO7NN10ZLxrmQzeDtvUFOv9ZQqrlq-ZeW2TBgXHZSMWgsemC5nErJYXy8QMHcdWUOXZnWlbnryqimefN3tEfFQzmNwA6E0lbLNuQ_p__v-hvpg5-X</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Aung, Kyaw L.</creator><creator>El-Khoueiry, Anthony B.</creator><creator>Gelmon, Karen</creator><creator>Tran, Ben</creator><creator>Bajaj, Gaurav</creator><creator>He, Bing</creator><creator>Chen, Tian</creator><creator>Zhu, Lili</creator><creator>Poojary, Sharath</creator><creator>Basak, Shashwati</creator><creator>Qi, Zhenhao</creator><creator>Spreafico, Anna</creator><creator>Fischer, Bruce S.</creator><creator>Desai, Jayesh</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><scope>5PM</scope></search><sort><creationdate>20181201</creationdate><title>A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours</title><author>Aung, Kyaw L. ; El-Khoueiry, Anthony B. ; Gelmon, Karen ; Tran, Ben ; Bajaj, Gaurav ; He, Bing ; Chen, Tian ; Zhu, Lili ; Poojary, Sharath ; Basak, Shashwati ; Qi, Zhenhao ; Spreafico, Anna ; Fischer, Bruce S. ; Desai, Jayesh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-2cb5dc14c3c0442fe3e1f36ebd2d3a7382af6b50d8df79e82f073372347ae2c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Angiogenesis</topic><topic>Benzodiazepines - administration & dosage</topic><topic>Benzodiazepines - adverse effects</topic><topic>Benzodiazepines - pharmacokinetics</topic><topic>Benzodiazepines - therapeutic use</topic><topic>Biological activity</topic><topic>Cancer</topic><topic>Diarrhea</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Humans</topic><topic>Hypophosphatemia</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Nausea</topic><topic>Neoplasms - drug therapy</topic><topic>Notch protein</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmacology/Toxicology</topic><topic>Phase I Studies</topic><topic>Pruritus</topic><topic>Pyrazoles - administration & dosage</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - therapeutic use</topic><topic>Receptors, Notch - antagonists & inhibitors</topic><topic>Receptors, Notch - metabolism</topic><topic>Schedules</topic><topic>Secretase</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Solid tumors</topic><topic>Stem cells</topic><topic>Toxicity</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><topic>Urticaria</topic><topic>Withholding Treatment</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aung, Kyaw L.</creatorcontrib><creatorcontrib>El-Khoueiry, Anthony B.</creatorcontrib><creatorcontrib>Gelmon, Karen</creatorcontrib><creatorcontrib>Tran, Ben</creatorcontrib><creatorcontrib>Bajaj, Gaurav</creatorcontrib><creatorcontrib>He, Bing</creatorcontrib><creatorcontrib>Chen, Tian</creatorcontrib><creatorcontrib>Zhu, Lili</creatorcontrib><creatorcontrib>Poojary, Sharath</creatorcontrib><creatorcontrib>Basak, Shashwati</creatorcontrib><creatorcontrib>Qi, Zhenhao</creatorcontrib><creatorcontrib>Spreafico, Anna</creatorcontrib><creatorcontrib>Fischer, Bruce S.</creatorcontrib><creatorcontrib>Desai, Jayesh</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 Global (Alumni Edition)</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 Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</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 Global</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>ProQuest 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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aung, Kyaw L.</au><au>El-Khoueiry, Anthony B.</au><au>Gelmon, Karen</au><au>Tran, Ben</au><au>Bajaj, Gaurav</au><au>He, Bing</au><au>Chen, Tian</au><au>Zhu, Lili</au><au>Poojary, Sharath</au><au>Basak, Shashwati</au><au>Qi, Zhenhao</au><au>Spreafico, Anna</au><au>Fischer, Bruce S.</au><au>Desai, Jayesh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>36</volume><issue>6</issue><spage>1026</spage><epage>1036</epage><pages>1026-1036</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
Background
Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling.
Method
Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115.
Results
Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months.
Conclusion
The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>29637471</pmid><doi>10.1007/s10637-018-0597-6</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Investigational new drugs, 2018-12, Vol.36 (6), p.1026-1036 |
| issn | 0167-6997 1573-0646 |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adult Aged Aged, 80 and over Angiogenesis Benzodiazepines - administration & dosage Benzodiazepines - adverse effects Benzodiazepines - pharmacokinetics Benzodiazepines - therapeutic use Biological activity Cancer Diarrhea Dose-Response Relationship, Drug Female Humans Hypophosphatemia Inhibition Inhibitors Male Maximum Tolerated Dose Medicine Medicine & Public Health Middle Aged Nausea Neoplasms - drug therapy Notch protein Oncology Patients Pharmacology/Toxicology Phase I Studies Pruritus Pyrazoles - administration & dosage Pyrazoles - adverse effects Pyrazoles - pharmacokinetics Pyrazoles - therapeutic use Receptors, Notch - antagonists & inhibitors Receptors, Notch - metabolism Schedules Secretase Signal transduction Signaling Solid tumors Stem cells Toxicity Treatment Outcome Tumors Urticaria Withholding Treatment Young Adult |
| title | A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T16%3A49%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20multi-arm%20phase%20I%20dose%20escalating%20study%20of%20an%20oral%20NOTCH%20inhibitor%20BMS-986115%20in%20patients%20with%20advanced%20solid%20tumours&rft.jtitle=Investigational%20new%20drugs&rft.au=Aung,%20Kyaw%20L.&rft.date=2018-12-01&rft.volume=36&rft.issue=6&rft.spage=1026&rft.epage=1036&rft.pages=1026-1036&rft.issn=0167-6997&rft.eissn=1573-0646&rft_id=info:doi/10.1007/s10637-018-0597-6&rft_dat=%3Cproquest_pubme%3E2023585620%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2023585620&rft_id=info:pmid/29637471&rfr_iscdi=true |