Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/I...
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| Veröffentlicht in: | Clinical cancer research 2020-12, Vol.26 (24), p.6429-6436 |
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| creator | Le Tourneau, Christophe Tao, Yungan Gomez-Roca, Carlos Cristina, Valerie Borcoman, Edith Deutsch, Eric Bahleda, Rastislav Calugaru, Valentin Modesto, Anouchka Rouits, Elisabeth Gollmer, Kathrin Vuagniaux, Gregoire Crompton, Philippa Zanna, Claudio Szyldergemajn, Sergio Delord, Jean-Pierre Bourhis, Jean |
| description | Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.
Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.
Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.
The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development. |
| doi_str_mv | 10.1158/1078-0432.CCR-20-0425 |
| format | Article |
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Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.
Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.
The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-20-0425</identifier><identifier>PMID: 32994295</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Life Sciences</subject><ispartof>Clinical cancer research, 2020-12, Vol.26 (24), p.6429-6436</ispartof><rights>2020 American Association for Cancer Research.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-3e4cce995986774c60aa5d61e28c95364bb542d15bf390916aa6ef5431160dcd3</citedby><cites>FETCH-LOGICAL-c390t-3e4cce995986774c60aa5d61e28c95364bb542d15bf390916aa6ef5431160dcd3</cites><orcidid>0000-0001-9772-4686 ; 0000-0002-8043-2529 ; 0000-0002-7156-9750 ; 0000-0002-8223-3697 ; 0000-0001-7305-5561</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32994295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04525145$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Le Tourneau, Christophe</creatorcontrib><creatorcontrib>Tao, Yungan</creatorcontrib><creatorcontrib>Gomez-Roca, Carlos</creatorcontrib><creatorcontrib>Cristina, Valerie</creatorcontrib><creatorcontrib>Borcoman, Edith</creatorcontrib><creatorcontrib>Deutsch, Eric</creatorcontrib><creatorcontrib>Bahleda, Rastislav</creatorcontrib><creatorcontrib>Calugaru, Valentin</creatorcontrib><creatorcontrib>Modesto, Anouchka</creatorcontrib><creatorcontrib>Rouits, Elisabeth</creatorcontrib><creatorcontrib>Gollmer, Kathrin</creatorcontrib><creatorcontrib>Vuagniaux, Gregoire</creatorcontrib><creatorcontrib>Crompton, Philippa</creatorcontrib><creatorcontrib>Zanna, Claudio</creatorcontrib><creatorcontrib>Szyldergemajn, Sergio</creatorcontrib><creatorcontrib>Delord, Jean-Pierre</creatorcontrib><creatorcontrib>Bourhis, Jean</creatorcontrib><title>Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.
Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.
Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.
The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. 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Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.
Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.
Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.
The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>32994295</pmid><doi>10.1158/1078-0432.CCR-20-0425</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9772-4686</orcidid><orcidid>https://orcid.org/0000-0002-8043-2529</orcidid><orcidid>https://orcid.org/0000-0002-7156-9750</orcidid><orcidid>https://orcid.org/0000-0002-8223-3697</orcidid><orcidid>https://orcid.org/0000-0001-7305-5561</orcidid><oa>free_for_read</oa></addata></record> |
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| source | American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Life Sciences |
| title | Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck |
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