First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer
A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and...
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| Veröffentlicht in: | Clinical cancer research 2021-12, Vol.27 (24), p.6666-6676 |
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| creator | Yap, Timothy A Vieito, Maria Baldini, Capucine Sepúlveda-Sánchez, Juan Manuel Kondo, Shunsuke Simonelli, Matteo Cosman, Rasha van der Westhuizen, Andre Atkinson, Victoria Carpentier, Antoine F Löhr, Mario Redman, Rebecca Mason, Warren Cervantes, Andres Le Rhun, Emilie Ochsenreither, Sebastian Warren, Louise Zhao, Yumin Callies, Sophie Estrem, Shawn T Man, Michael Gandhi, Leena Avsar, Emin Melisi, Davide |
| description | A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer.
This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation).
Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (
= 3) or LY3200882-LY3300054 combination therapy (
= 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel.
LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted. |
| doi_str_mv | 10.1158/1078-0432.CCR-21-1504 |
| format | Article |
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This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation).
Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (
= 3) or LY3200882-LY3300054 combination therapy (
= 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel.
LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.</description><identifier>ISSN: 1078-0432</identifier><identifier>ISSN: 1557-3265</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-21-1504</identifier><identifier>PMID: 34548321</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Antineoplastic Agents - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Clinical Trials: Targeted Therapy ; Head and Neck Neoplasms ; Humans ; Life Sciences ; Maximum Tolerated Dose ; Paclitaxel - therapeutic use ; Pancreatic Neoplasms - drug therapy ; Transforming Growth Factor beta</subject><ispartof>Clinical cancer research, 2021-12, Vol.27 (24), p.6666-6676</ispartof><rights>2021 The Authors; Published by the American Association for Cancer Research.</rights><rights>Attribution - NonCommercial - NoDerivatives</rights><rights>2021 The Authors; Published by the American Association for Cancer Research 2021 American Association for Cancer Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3424-a32ece2649b84ee4848be82b71d9dfa81d4b510822fbe1b1288c2722313e231c3</citedby><cites>FETCH-LOGICAL-c3424-a32ece2649b84ee4848be82b71d9dfa81d4b510822fbe1b1288c2722313e231c3</cites><orcidid>0000-0002-5264-1251 ; 0000-0002-9365-1288 ; 0000-0002-2154-3309 ; 0000-0003-3806-3691 ; 0000-0002-4031-7585 ; 0000-0001-6024-4312</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3354,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34548321$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.univ-lille.fr/hal-04038783$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Yap, Timothy A</creatorcontrib><creatorcontrib>Vieito, Maria</creatorcontrib><creatorcontrib>Baldini, Capucine</creatorcontrib><creatorcontrib>Sepúlveda-Sánchez, Juan Manuel</creatorcontrib><creatorcontrib>Kondo, Shunsuke</creatorcontrib><creatorcontrib>Simonelli, Matteo</creatorcontrib><creatorcontrib>Cosman, Rasha</creatorcontrib><creatorcontrib>van der Westhuizen, Andre</creatorcontrib><creatorcontrib>Atkinson, Victoria</creatorcontrib><creatorcontrib>Carpentier, Antoine F</creatorcontrib><creatorcontrib>Löhr, Mario</creatorcontrib><creatorcontrib>Redman, Rebecca</creatorcontrib><creatorcontrib>Mason, Warren</creatorcontrib><creatorcontrib>Cervantes, Andres</creatorcontrib><creatorcontrib>Le Rhun, Emilie</creatorcontrib><creatorcontrib>Ochsenreither, Sebastian</creatorcontrib><creatorcontrib>Warren, Louise</creatorcontrib><creatorcontrib>Zhao, Yumin</creatorcontrib><creatorcontrib>Callies, Sophie</creatorcontrib><creatorcontrib>Estrem, Shawn T</creatorcontrib><creatorcontrib>Man, Michael</creatorcontrib><creatorcontrib>Gandhi, Leena</creatorcontrib><creatorcontrib>Avsar, Emin</creatorcontrib><creatorcontrib>Melisi, Davide</creatorcontrib><title>First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer.
This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation).
Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (
= 3) or LY3200882-LY3300054 combination therapy (
= 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel.
LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.</description><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Clinical Trials: Targeted Therapy</subject><subject>Head and Neck Neoplasms</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Maximum Tolerated Dose</subject><subject>Paclitaxel - therapeutic use</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Transforming Growth Factor beta</subject><issn>1078-0432</issn><issn>1557-3265</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc9u1DAQxiMEoqXwCCAfQVoXz9huvBekVcT-kVYUlXLgZDnJhDXaTbZ2stAbz8SD8Ew42rYCLp6R_X3fePTLspcgzgG0eQsiN1woiedFccUROGihHmWnoHXOJV7ox6m_15xkz2L8JgQoEOppdiKVVkYinGY_5z7Enq9avhx2rmUfNy4SW7FP_VDfsq5hjn2gHz1fUEvB9b5rJ-wyuO2EXS_mv3-xK6po33eBAVu1G1_61E_Y-otEIYzBCfMpM_mo7SP77vsNm9UH11ZUs2Is4Xn2pHHbSC_u6ln2ef7-uljy9eViVczWvJIKFXcS0yS8UNPSKCJllCnJYJlDPa0bZ6BWpQZhEJuSoAQ0psIcUYKkdFTyLHt3zN0P5Y7qKn0orWH3we9cuLWd8_bfl9Zv7NfuYKcKFOYyBbw5Bmz-sy1nazveCSWkyY08QNK-vhsWupuBYm93Pla03bqWuiFa1LmWeaKjk1QfpVXoYgzUPGSDsCNpO1K0I0WbSFsEO5JOvld_7_Pgukcr_wAlbKIf</recordid><startdate>20211215</startdate><enddate>20211215</enddate><creator>Yap, Timothy A</creator><creator>Vieito, Maria</creator><creator>Baldini, Capucine</creator><creator>Sepúlveda-Sánchez, Juan Manuel</creator><creator>Kondo, Shunsuke</creator><creator>Simonelli, Matteo</creator><creator>Cosman, Rasha</creator><creator>van der Westhuizen, Andre</creator><creator>Atkinson, Victoria</creator><creator>Carpentier, Antoine F</creator><creator>Löhr, Mario</creator><creator>Redman, Rebecca</creator><creator>Mason, Warren</creator><creator>Cervantes, Andres</creator><creator>Le Rhun, Emilie</creator><creator>Ochsenreither, Sebastian</creator><creator>Warren, Louise</creator><creator>Zhao, Yumin</creator><creator>Callies, Sophie</creator><creator>Estrem, Shawn T</creator><creator>Man, Michael</creator><creator>Gandhi, Leena</creator><creator>Avsar, Emin</creator><creator>Melisi, Davide</creator><general>American Association for Cancer Research</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>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5264-1251</orcidid><orcidid>https://orcid.org/0000-0002-9365-1288</orcidid><orcidid>https://orcid.org/0000-0002-2154-3309</orcidid><orcidid>https://orcid.org/0000-0003-3806-3691</orcidid><orcidid>https://orcid.org/0000-0002-4031-7585</orcidid><orcidid>https://orcid.org/0000-0001-6024-4312</orcidid></search><sort><creationdate>20211215</creationdate><title>First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer</title><author>Yap, Timothy A ; Vieito, Maria ; Baldini, Capucine ; Sepúlveda-Sánchez, Juan Manuel ; Kondo, Shunsuke ; Simonelli, Matteo ; Cosman, Rasha ; van der Westhuizen, Andre ; Atkinson, Victoria ; Carpentier, Antoine F ; Löhr, Mario ; Redman, Rebecca ; Mason, Warren ; Cervantes, Andres ; Le Rhun, Emilie ; Ochsenreither, Sebastian ; Warren, Louise ; Zhao, Yumin ; Callies, Sophie ; Estrem, Shawn T ; Man, Michael ; Gandhi, Leena ; Avsar, Emin ; Melisi, Davide</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3424-a32ece2649b84ee4848be82b71d9dfa81d4b510822fbe1b1288c2722313e231c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Clinical Trials: Targeted Therapy</topic><topic>Head and Neck Neoplasms</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Maximum Tolerated Dose</topic><topic>Paclitaxel - therapeutic use</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Transforming Growth Factor beta</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yap, Timothy A</creatorcontrib><creatorcontrib>Vieito, Maria</creatorcontrib><creatorcontrib>Baldini, Capucine</creatorcontrib><creatorcontrib>Sepúlveda-Sánchez, Juan Manuel</creatorcontrib><creatorcontrib>Kondo, Shunsuke</creatorcontrib><creatorcontrib>Simonelli, Matteo</creatorcontrib><creatorcontrib>Cosman, Rasha</creatorcontrib><creatorcontrib>van der Westhuizen, Andre</creatorcontrib><creatorcontrib>Atkinson, Victoria</creatorcontrib><creatorcontrib>Carpentier, Antoine F</creatorcontrib><creatorcontrib>Löhr, Mario</creatorcontrib><creatorcontrib>Redman, Rebecca</creatorcontrib><creatorcontrib>Mason, Warren</creatorcontrib><creatorcontrib>Cervantes, Andres</creatorcontrib><creatorcontrib>Le Rhun, Emilie</creatorcontrib><creatorcontrib>Ochsenreither, Sebastian</creatorcontrib><creatorcontrib>Warren, Louise</creatorcontrib><creatorcontrib>Zhao, Yumin</creatorcontrib><creatorcontrib>Callies, Sophie</creatorcontrib><creatorcontrib>Estrem, Shawn T</creatorcontrib><creatorcontrib>Man, Michael</creatorcontrib><creatorcontrib>Gandhi, Leena</creatorcontrib><creatorcontrib>Avsar, Emin</creatorcontrib><creatorcontrib>Melisi, Davide</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yap, Timothy A</au><au>Vieito, Maria</au><au>Baldini, Capucine</au><au>Sepúlveda-Sánchez, Juan Manuel</au><au>Kondo, Shunsuke</au><au>Simonelli, Matteo</au><au>Cosman, Rasha</au><au>van der Westhuizen, Andre</au><au>Atkinson, Victoria</au><au>Carpentier, Antoine F</au><au>Löhr, Mario</au><au>Redman, Rebecca</au><au>Mason, Warren</au><au>Cervantes, Andres</au><au>Le Rhun, Emilie</au><au>Ochsenreither, Sebastian</au><au>Warren, Louise</au><au>Zhao, Yumin</au><au>Callies, Sophie</au><au>Estrem, Shawn T</au><au>Man, Michael</au><au>Gandhi, Leena</au><au>Avsar, Emin</au><au>Melisi, Davide</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2021-12-15</date><risdate>2021</risdate><volume>27</volume><issue>24</issue><spage>6666</spage><epage>6676</epage><pages>6666-6676</pages><issn>1078-0432</issn><issn>1557-3265</issn><eissn>1557-3265</eissn><abstract>A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer.
This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation).
Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (
= 3) or LY3200882-LY3300054 combination therapy (
= 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel.
LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>34548321</pmid><doi>10.1158/1078-0432.CCR-21-1504</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-5264-1251</orcidid><orcidid>https://orcid.org/0000-0002-9365-1288</orcidid><orcidid>https://orcid.org/0000-0002-2154-3309</orcidid><orcidid>https://orcid.org/0000-0003-3806-3691</orcidid><orcidid>https://orcid.org/0000-0002-4031-7585</orcidid><orcidid>https://orcid.org/0000-0001-6024-4312</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2021-12, Vol.27 (24), p.6666-6676 |
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| language | eng |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Antineoplastic Agents - adverse effects Antineoplastic Combined Chemotherapy Protocols - adverse effects Clinical Trials: Targeted Therapy Head and Neck Neoplasms Humans Life Sciences Maximum Tolerated Dose Paclitaxel - therapeutic use Pancreatic Neoplasms - drug therapy Transforming Growth Factor beta |
| title | First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer |
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