A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer
Summary Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid ca...
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| Veröffentlicht in: | Investigational new drugs 2021-10, Vol.39 (5), p.1335-1347 |
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| creator | Jeong, Hyehyun Hong, Yong Sang Kim, Jeong Eun Lim, Hyeong-Seok Ahn, Joong Bae Shin, Sang Joon Park, Young Suk Kim, Seung Tae Han, Sae-Won Kim, Tae-You Kim, Tae Won |
| description | Summary
Introduction
The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer.
Methods
This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m
2
) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used.
Results
In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m
2
. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively.
Conclusion
This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted.
Trial registration number
NCT03076957 (Registered at March 10, 2017). |
| doi_str_mv | 10.1007/s10637-021-01110-9 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2510252604</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2510252604</sourcerecordid><originalsourceid>FETCH-LOGICAL-c375t-237e0e2baf13adf6690b1a274a8d2bd77333f6bbbe10d1260308f3cba4b012bc3</originalsourceid><addsrcrecordid>eNp9ks2O1DAQhCMEYoeFF-CALHHhsAH_JPHkuBr-VqzEBc5R2-nMeJWxg9sZmOflRfBsBpA4cLLU9VV1S66ieC74a8G5fkOCN0qXXIqSCyF42T4oVqLWquRN1TwsVlw0umzaVl8UT4juOOeq1dXj4kKptWxVXa-Kn9ds2gEhE6wPhCWShRGSC56B78-zHxN4Oo0ozf2RpcCACIlY2iEjGDAd72kcBmfBHlkY2ObT27IWzRUD5sMBR3YAsvMIkfWO4jwl57cMtujTFXOe2bA3zi-Lv7u0YzfR-ZDQgj_JU1YySos2RTy4MNOYb4kICXu2xwSUMmVz1Bgi2gQjy26L8WnxaICR8Nn5vSy-vn_3ZfOxvP384WZzfVtapetUSqWRozQwCAX90DQtNwKkrmDdS9NrrZQaGmMMCt4L2XDF14OyBirDhTRWXRavltwphm8zUur2jiyOI3jM13ayFlzW2Vhl9OU_6F2Yo8_XZUqfkuVaZEoulI2BKOLQTdHtIR47wbtTBbqlAl2uQHdfga7Nphfn6Nnssf9j-f3nGVALQFnyW4x_d_8n9hcY78Bk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2570308281</pqid></control><display><type>article</type><title>A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Jeong, Hyehyun ; Hong, Yong Sang ; Kim, Jeong Eun ; Lim, Hyeong-Seok ; Ahn, Joong Bae ; Shin, Sang Joon ; Park, Young Suk ; Kim, Seung Tae ; Han, Sae-Won ; Kim, Tae-You ; Kim, Tae Won</creator><creatorcontrib>Jeong, Hyehyun ; Hong, Yong Sang ; Kim, Jeong Eun ; Lim, Hyeong-Seok ; Ahn, Joong Bae ; Shin, Sang Joon ; Park, Young Suk ; Kim, Seung Tae ; Han, Sae-Won ; Kim, Tae-You ; Kim, Tae Won</creatorcontrib><description>Summary
Introduction
The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer.
Methods
This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m
2
) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used.
Results
In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m
2
. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively.
Conclusion
This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted.
Trial registration number
NCT03076957 (Registered at March 10, 2017).</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-021-01110-9</identifier><identifier>PMID: 33829355</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adult ; Adverse events ; Aged ; Angiogenesis ; Antiangiogenic agents ; Antiangiogenics ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Area Under Curve ; Benzophenones - administration & dosage ; Benzophenones - adverse effects ; Benzophenones - pharmacokinetics ; Benzophenones - therapeutic use ; Cancer ; Chemotherapy ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - pathology ; Cytotoxicity ; Diarrhea ; Disruption ; Dose-Response Relationship, Drug ; Expansion ; Female ; Half-Life ; Humans ; Intravenous administration ; Irinotecan ; Irinotecan - therapeutic use ; Ischemia ; Kaplan-Meier Estimate ; Male ; Maximum Tolerated Dose ; Medicine ; Medicine & Public Health ; Metabolic Clearance Rate ; Metastases ; Metastasis ; Middle Aged ; Nausea ; Neoplasm Metastasis ; Neutropenia ; Oncology ; Patients ; Pharmacology/Toxicology ; Phase I Studies ; Progression-Free Survival ; Safety ; Survival ; Thromboembolism ; Toxicity ; Valine - administration & dosage ; Valine - adverse effects ; Valine - analogs & derivatives ; Valine - pharmacokinetics ; Valine - therapeutic use ; Vomiting</subject><ispartof>Investigational new drugs, 2021-10, Vol.39 (5), p.1335-1347</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-237e0e2baf13adf6690b1a274a8d2bd77333f6bbbe10d1260308f3cba4b012bc3</citedby><cites>FETCH-LOGICAL-c375t-237e0e2baf13adf6690b1a274a8d2bd77333f6bbbe10d1260308f3cba4b012bc3</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/s10637-021-01110-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10637-021-01110-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33829355$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jeong, Hyehyun</creatorcontrib><creatorcontrib>Hong, Yong Sang</creatorcontrib><creatorcontrib>Kim, Jeong Eun</creatorcontrib><creatorcontrib>Lim, Hyeong-Seok</creatorcontrib><creatorcontrib>Ahn, Joong Bae</creatorcontrib><creatorcontrib>Shin, Sang Joon</creatorcontrib><creatorcontrib>Park, Young Suk</creatorcontrib><creatorcontrib>Kim, Seung Tae</creatorcontrib><creatorcontrib>Han, Sae-Won</creatorcontrib><creatorcontrib>Kim, Tae-You</creatorcontrib><creatorcontrib>Kim, Tae Won</creatorcontrib><title>A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><addtitle>Invest New Drugs</addtitle><description>Summary
Introduction
The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer.
Methods
This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m
2
) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used.
Results
In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m
2
. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively.
Conclusion
This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted.
Trial registration number
NCT03076957 (Registered at March 10, 2017).</description><subject>Adult</subject><subject>Adverse events</subject><subject>Aged</subject><subject>Angiogenesis</subject><subject>Antiangiogenic agents</subject><subject>Antiangiogenics</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Area Under Curve</subject><subject>Benzophenones - administration & dosage</subject><subject>Benzophenones - adverse effects</subject><subject>Benzophenones - pharmacokinetics</subject><subject>Benzophenones - therapeutic use</subject><subject>Cancer</subject><subject>Chemotherapy</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Cytotoxicity</subject><subject>Diarrhea</subject><subject>Disruption</subject><subject>Dose-Response Relationship, Drug</subject><subject>Expansion</subject><subject>Female</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Intravenous administration</subject><subject>Irinotecan</subject><subject>Irinotecan - therapeutic use</subject><subject>Ischemia</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Clearance Rate</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Nausea</subject><subject>Neoplasm Metastasis</subject><subject>Neutropenia</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmacology/Toxicology</subject><subject>Phase I Studies</subject><subject>Progression-Free Survival</subject><subject>Safety</subject><subject>Survival</subject><subject>Thromboembolism</subject><subject>Toxicity</subject><subject>Valine - administration & dosage</subject><subject>Valine - adverse effects</subject><subject>Valine - analogs & derivatives</subject><subject>Valine - pharmacokinetics</subject><subject>Valine - therapeutic use</subject><subject>Vomiting</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9ks2O1DAQhCMEYoeFF-CALHHhsAH_JPHkuBr-VqzEBc5R2-nMeJWxg9sZmOflRfBsBpA4cLLU9VV1S66ieC74a8G5fkOCN0qXXIqSCyF42T4oVqLWquRN1TwsVlw0umzaVl8UT4juOOeq1dXj4kKptWxVXa-Kn9ds2gEhE6wPhCWShRGSC56B78-zHxN4Oo0ozf2RpcCACIlY2iEjGDAd72kcBmfBHlkY2ObT27IWzRUD5sMBR3YAsvMIkfWO4jwl57cMtujTFXOe2bA3zi-Lv7u0YzfR-ZDQgj_JU1YySos2RTy4MNOYb4kICXu2xwSUMmVz1Bgi2gQjy26L8WnxaICR8Nn5vSy-vn_3ZfOxvP384WZzfVtapetUSqWRozQwCAX90DQtNwKkrmDdS9NrrZQaGmMMCt4L2XDF14OyBirDhTRWXRavltwphm8zUur2jiyOI3jM13ayFlzW2Vhl9OU_6F2Yo8_XZUqfkuVaZEoulI2BKOLQTdHtIR47wbtTBbqlAl2uQHdfga7Nphfn6Nnssf9j-f3nGVALQFnyW4x_d_8n9hcY78Bk</recordid><startdate>20211001</startdate><enddate>20211001</enddate><creator>Jeong, Hyehyun</creator><creator>Hong, Yong Sang</creator><creator>Kim, Jeong Eun</creator><creator>Lim, Hyeong-Seok</creator><creator>Ahn, Joong Bae</creator><creator>Shin, Sang Joon</creator><creator>Park, Young Suk</creator><creator>Kim, Seung Tae</creator><creator>Han, Sae-Won</creator><creator>Kim, Tae-You</creator><creator>Kim, Tae Won</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>7X8</scope></search><sort><creationdate>20211001</creationdate><title>A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer</title><author>Jeong, Hyehyun ; Hong, Yong Sang ; Kim, Jeong Eun ; Lim, Hyeong-Seok ; Ahn, Joong Bae ; Shin, Sang Joon ; Park, Young Suk ; Kim, Seung Tae ; Han, Sae-Won ; Kim, Tae-You ; Kim, Tae Won</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-237e0e2baf13adf6690b1a274a8d2bd77333f6bbbe10d1260308f3cba4b012bc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>Adverse events</topic><topic>Aged</topic><topic>Angiogenesis</topic><topic>Antiangiogenic agents</topic><topic>Antiangiogenics</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Area Under Curve</topic><topic>Benzophenones - administration & dosage</topic><topic>Benzophenones - adverse effects</topic><topic>Benzophenones - pharmacokinetics</topic><topic>Benzophenones - therapeutic use</topic><topic>Cancer</topic><topic>Chemotherapy</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Cytotoxicity</topic><topic>Diarrhea</topic><topic>Disruption</topic><topic>Dose-Response Relationship, Drug</topic><topic>Expansion</topic><topic>Female</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Intravenous administration</topic><topic>Irinotecan</topic><topic>Irinotecan - therapeutic use</topic><topic>Ischemia</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Maximum Tolerated Dose</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Clearance Rate</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Nausea</topic><topic>Neoplasm Metastasis</topic><topic>Neutropenia</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmacology/Toxicology</topic><topic>Phase I Studies</topic><topic>Progression-Free Survival</topic><topic>Safety</topic><topic>Survival</topic><topic>Thromboembolism</topic><topic>Toxicity</topic><topic>Valine - administration & dosage</topic><topic>Valine - adverse effects</topic><topic>Valine - analogs & derivatives</topic><topic>Valine - pharmacokinetics</topic><topic>Valine - therapeutic use</topic><topic>Vomiting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jeong, Hyehyun</creatorcontrib><creatorcontrib>Hong, Yong Sang</creatorcontrib><creatorcontrib>Kim, Jeong Eun</creatorcontrib><creatorcontrib>Lim, Hyeong-Seok</creatorcontrib><creatorcontrib>Ahn, Joong Bae</creatorcontrib><creatorcontrib>Shin, Sang Joon</creatorcontrib><creatorcontrib>Park, Young Suk</creatorcontrib><creatorcontrib>Kim, Seung Tae</creatorcontrib><creatorcontrib>Han, Sae-Won</creatorcontrib><creatorcontrib>Kim, Tae-You</creatorcontrib><creatorcontrib>Kim, Tae Won</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>Proquest Nursing & Allied Health Source</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>One Business (ProQuest)</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>MEDLINE - Academic</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jeong, Hyehyun</au><au>Hong, Yong Sang</au><au>Kim, Jeong Eun</au><au>Lim, Hyeong-Seok</au><au>Ahn, Joong Bae</au><au>Shin, Sang Joon</au><au>Park, Young Suk</au><au>Kim, Seung Tae</au><au>Han, Sae-Won</au><au>Kim, Tae-You</au><au>Kim, Tae Won</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer</atitle><jtitle>Investigational new drugs</jtitle><stitle>Invest New Drugs</stitle><addtitle>Invest New Drugs</addtitle><date>2021-10-01</date><risdate>2021</risdate><volume>39</volume><issue>5</issue><spage>1335</spage><epage>1347</epage><pages>1335-1347</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><abstract>Summary
Introduction
The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer.
Methods
This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m
2
) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used.
Results
In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m
2
. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively.
Conclusion
This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted.
Trial registration number
NCT03076957 (Registered at March 10, 2017).</abstract><cop>New York</cop><pub>Springer US</pub><pmid>33829355</pmid><doi>10.1007/s10637-021-01110-9</doi><tpages>13</tpages></addata></record> |
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| issn | 0167-6997 1573-0646 |
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| recordid | cdi_proquest_miscellaneous_2510252604 |
| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Adult Adverse events Aged Angiogenesis Antiangiogenic agents Antiangiogenics Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Area Under Curve Benzophenones - administration & dosage Benzophenones - adverse effects Benzophenones - pharmacokinetics Benzophenones - therapeutic use Cancer Chemotherapy Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - pathology Cytotoxicity Diarrhea Disruption Dose-Response Relationship, Drug Expansion Female Half-Life Humans Intravenous administration Irinotecan Irinotecan - therapeutic use Ischemia Kaplan-Meier Estimate Male Maximum Tolerated Dose Medicine Medicine & Public Health Metabolic Clearance Rate Metastases Metastasis Middle Aged Nausea Neoplasm Metastasis Neutropenia Oncology Patients Pharmacology/Toxicology Phase I Studies Progression-Free Survival Safety Survival Thromboembolism Toxicity Valine - administration & dosage Valine - adverse effects Valine - analogs & derivatives Valine - pharmacokinetics Valine - therapeutic use Vomiting |
| title | A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T02%3A58%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20phase%201%20dose-escalation%20and%20dose-expansion%20study%20to%20assess%20the%20safety%20and%20efficacy%20of%20CKD-516,%20a%20novel%20vascular%20disrupting%20agent,%20in%20combination%20with%20Irinotecan%20in%20patients%20with%20previously%20treated%20metastatic%20colorectal%20cancer&rft.jtitle=Investigational%20new%20drugs&rft.au=Jeong,%20Hyehyun&rft.date=2021-10-01&rft.volume=39&rft.issue=5&rft.spage=1335&rft.epage=1347&rft.pages=1335-1347&rft.issn=0167-6997&rft.eissn=1573-0646&rft_id=info:doi/10.1007/s10637-021-01110-9&rft_dat=%3Cproquest_cross%3E2510252604%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2570308281&rft_id=info:pmid/33829355&rfr_iscdi=true |