CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study
Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalim...
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| creator | O'Hara, Mark H O'Reilly, Eileen M Varadhachary, Gauri Wolff, Robert A Wainberg, Zev A Ko, Andrew H Fisher, George Rahma, Osama Lyman, Jaclyn P Cabanski, Christopher R Mick, Rosemarie Gherardini, Pier Federico Kitch, Lacey J Xu, Jingying Samuel, Theresa Karakunnel, Joyson Fairchild, Justin Bucktrout, Samantha LaVallee, Theresa M Selinsky, Cheryl Till, Jacob E Carpenter, Erica L Alanio, Cécile Byrne, Katelyn T Chen, Richard O Trifan, Ovid C Dugan, Ute Horak, Christine Hubbard-Lucey, Vanessa M Wherry, E John Ibrahim, Ramy Vonderheide, Robert H |
| description | Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (fou |
| doi_str_mv | 10.1016/S1470-2045(20)30532-5 |
| format | Article |
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This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(20)30532-5</identifier><identifier>PMID: 33387490</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject><![CDATA[Adenocarcinoma ; Adenocarcinoma - drug therapy ; Adenocarcinoma - immunology ; Adenocarcinoma - secondary ; Aged ; Albumins - administration & dosage ; Albumins - adverse effects ; Antigens ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Cancer immunotherapy ; Cancer therapies ; CD40 antigen ; CD40 Antigens - antagonists & inhibitors ; CD40 Antigens - immunology ; Cell number ; Chemotherapy ; Clinical trials ; Deoxycytidine - administration & dosage ; Deoxycytidine - adverse effects ; Deoxycytidine - analogs & derivatives ; Drug dosages ; Female ; Fever ; Gemcitabine ; Humans ; Immunotherapy ; Intravenous administration ; Lymphocytes T ; Male ; Metastases ; Metastasis ; Middle Aged ; Monoclonal antibodies ; Neutropenia ; Nivolumab - administration & dosage ; Nivolumab - adverse effects ; Oncology ; Paclitaxel ; Paclitaxel - administration & dosage ; Paclitaxel - adverse effects ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - immunology ; Pancreatic Neoplasms - pathology ; Patients ; Pharmacodynamics ; Sepsis ; Septic shock ; Solid tumors ; Targeted cancer therapy ; Time Factors ; Treatment Outcome ; United States]]></subject><ispartof>The lancet oncology, 2021-01, Vol.22 (1), p.118-131</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><rights>2021. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-249e049d4b5ed55aed18ea3adfaa367eaa7624b7d6192518b9f80dcc692bae4d3</citedby><cites>FETCH-LOGICAL-c445t-249e049d4b5ed55aed18ea3adfaa367eaa7624b7d6192518b9f80dcc692bae4d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2474172570?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995,64385,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33387490$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>O'Hara, Mark H</creatorcontrib><creatorcontrib>O'Reilly, Eileen M</creatorcontrib><creatorcontrib>Varadhachary, Gauri</creatorcontrib><creatorcontrib>Wolff, Robert A</creatorcontrib><creatorcontrib>Wainberg, Zev A</creatorcontrib><creatorcontrib>Ko, Andrew H</creatorcontrib><creatorcontrib>Fisher, George</creatorcontrib><creatorcontrib>Rahma, Osama</creatorcontrib><creatorcontrib>Lyman, Jaclyn P</creatorcontrib><creatorcontrib>Cabanski, Christopher R</creatorcontrib><creatorcontrib>Mick, Rosemarie</creatorcontrib><creatorcontrib>Gherardini, Pier Federico</creatorcontrib><creatorcontrib>Kitch, Lacey J</creatorcontrib><creatorcontrib>Xu, Jingying</creatorcontrib><creatorcontrib>Samuel, Theresa</creatorcontrib><creatorcontrib>Karakunnel, Joyson</creatorcontrib><creatorcontrib>Fairchild, Justin</creatorcontrib><creatorcontrib>Bucktrout, Samantha</creatorcontrib><creatorcontrib>LaVallee, Theresa M</creatorcontrib><creatorcontrib>Selinsky, Cheryl</creatorcontrib><creatorcontrib>Till, Jacob E</creatorcontrib><creatorcontrib>Carpenter, Erica L</creatorcontrib><creatorcontrib>Alanio, Cécile</creatorcontrib><creatorcontrib>Byrne, Katelyn T</creatorcontrib><creatorcontrib>Chen, Richard O</creatorcontrib><creatorcontrib>Trifan, Ovid C</creatorcontrib><creatorcontrib>Dugan, Ute</creatorcontrib><creatorcontrib>Horak, Christine</creatorcontrib><creatorcontrib>Hubbard-Lucey, Vanessa M</creatorcontrib><creatorcontrib>Wherry, E John</creatorcontrib><creatorcontrib>Ibrahim, Ramy</creatorcontrib><creatorcontrib>Vonderheide, Robert H</creatorcontrib><title>CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - immunology</subject><subject>Adenocarcinoma - secondary</subject><subject>Aged</subject><subject>Albumins - administration & dosage</subject><subject>Albumins - adverse effects</subject><subject>Antigens</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Cancer immunotherapy</subject><subject>Cancer therapies</subject><subject>CD40 antigen</subject><subject>CD40 Antigens - antagonists & inhibitors</subject><subject>CD40 Antigens - immunology</subject><subject>Cell number</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - adverse effects</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Drug dosages</subject><subject>Female</subject><subject>Fever</subject><subject>Gemcitabine</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Intravenous administration</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Neutropenia</subject><subject>Nivolumab - administration & dosage</subject><subject>Nivolumab - adverse effects</subject><subject>Oncology</subject><subject>Paclitaxel</subject><subject>Paclitaxel - administration & dosage</subject><subject>Paclitaxel - adverse effects</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - immunology</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Patients</subject><subject>Pharmacodynamics</subject><subject>Sepsis</subject><subject>Septic shock</subject><subject>Solid tumors</subject><subject>Targeted cancer therapy</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>United 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nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study</title><author>O'Hara, Mark H ; O'Reilly, Eileen M ; Varadhachary, Gauri ; Wolff, Robert A ; Wainberg, Zev A ; Ko, Andrew H ; Fisher, George ; Rahma, Osama ; Lyman, Jaclyn P ; Cabanski, Christopher R ; Mick, Rosemarie ; Gherardini, Pier Federico ; Kitch, Lacey J ; Xu, Jingying ; Samuel, Theresa ; Karakunnel, Joyson ; Fairchild, Justin ; Bucktrout, Samantha ; LaVallee, Theresa M ; Selinsky, Cheryl ; Till, Jacob E ; Carpenter, Erica L ; Alanio, Cécile ; Byrne, Katelyn T ; Chen, Richard O ; Trifan, Ovid C ; Dugan, Ute ; Horak, Christine ; Hubbard-Lucey, Vanessa M ; Wherry, E John ; Ibrahim, Ramy ; Vonderheide, Robert H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-249e049d4b5ed55aed18ea3adfaa367eaa7624b7d6192518b9f80dcc692bae4d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - immunology</topic><topic>Adenocarcinoma - secondary</topic><topic>Aged</topic><topic>Albumins - administration & dosage</topic><topic>Albumins - adverse effects</topic><topic>Antigens</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Cancer immunotherapy</topic><topic>Cancer therapies</topic><topic>CD40 antigen</topic><topic>CD40 Antigens - antagonists & inhibitors</topic><topic>CD40 Antigens - immunology</topic><topic>Cell number</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Deoxycytidine - administration & dosage</topic><topic>Deoxycytidine - adverse effects</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Drug dosages</topic><topic>Female</topic><topic>Fever</topic><topic>Gemcitabine</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Intravenous administration</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Neutropenia</topic><topic>Nivolumab - administration & dosage</topic><topic>Nivolumab - adverse effects</topic><topic>Oncology</topic><topic>Paclitaxel</topic><topic>Paclitaxel - administration & dosage</topic><topic>Paclitaxel - adverse effects</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - immunology</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Patients</topic><topic>Pharmacodynamics</topic><topic>Sepsis</topic><topic>Septic shock</topic><topic>Solid tumors</topic><topic>Targeted cancer therapy</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>United States</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>O'Hara, Mark H</creatorcontrib><creatorcontrib>O'Reilly, Eileen M</creatorcontrib><creatorcontrib>Varadhachary, Gauri</creatorcontrib><creatorcontrib>Wolff, Robert A</creatorcontrib><creatorcontrib>Wainberg, Zev A</creatorcontrib><creatorcontrib>Ko, Andrew H</creatorcontrib><creatorcontrib>Fisher, George</creatorcontrib><creatorcontrib>Rahma, Osama</creatorcontrib><creatorcontrib>Lyman, Jaclyn P</creatorcontrib><creatorcontrib>Cabanski, Christopher R</creatorcontrib><creatorcontrib>Mick, Rosemarie</creatorcontrib><creatorcontrib>Gherardini, Pier Federico</creatorcontrib><creatorcontrib>Kitch, Lacey J</creatorcontrib><creatorcontrib>Xu, Jingying</creatorcontrib><creatorcontrib>Samuel, Theresa</creatorcontrib><creatorcontrib>Karakunnel, Joyson</creatorcontrib><creatorcontrib>Fairchild, Justin</creatorcontrib><creatorcontrib>Bucktrout, Samantha</creatorcontrib><creatorcontrib>LaVallee, Theresa M</creatorcontrib><creatorcontrib>Selinsky, Cheryl</creatorcontrib><creatorcontrib>Till, Jacob E</creatorcontrib><creatorcontrib>Carpenter, Erica L</creatorcontrib><creatorcontrib>Alanio, Cécile</creatorcontrib><creatorcontrib>Byrne, Katelyn T</creatorcontrib><creatorcontrib>Chen, Richard O</creatorcontrib><creatorcontrib>Trifan, Ovid C</creatorcontrib><creatorcontrib>Dugan, Ute</creatorcontrib><creatorcontrib>Horak, Christine</creatorcontrib><creatorcontrib>Hubbard-Lucey, Vanessa M</creatorcontrib><creatorcontrib>Wherry, E John</creatorcontrib><creatorcontrib>Ibrahim, Ramy</creatorcontrib><creatorcontrib>Vonderheide, Robert H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</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 China</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>O'Hara, Mark H</au><au>O'Reilly, Eileen M</au><au>Varadhachary, Gauri</au><au>Wolff, Robert A</au><au>Wainberg, Zev A</au><au>Ko, Andrew H</au><au>Fisher, George</au><au>Rahma, Osama</au><au>Lyman, Jaclyn P</au><au>Cabanski, Christopher R</au><au>Mick, Rosemarie</au><au>Gherardini, Pier Federico</au><au>Kitch, Lacey J</au><au>Xu, Jingying</au><au>Samuel, Theresa</au><au>Karakunnel, Joyson</au><au>Fairchild, Justin</au><au>Bucktrout, Samantha</au><au>LaVallee, Theresa M</au><au>Selinsky, Cheryl</au><au>Till, Jacob E</au><au>Carpenter, Erica L</au><au>Alanio, Cécile</au><au>Byrne, Katelyn T</au><au>Chen, Richard O</au><au>Trifan, Ovid C</au><au>Dugan, Ute</au><au>Horak, Christine</au><au>Hubbard-Lucey, Vanessa M</au><au>Wherry, E John</au><au>Ibrahim, Ramy</au><au>Vonderheide, Robert H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2021-01</date><risdate>2021</risdate><volume>22</volume><issue>1</issue><spage>118</spage><epage>131</epage><pages>118-131</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><abstract>Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33387490</pmid><doi>10.1016/S1470-2045(20)30532-5</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2021-01, Vol.22 (1), p.118-131 |
| issn | 1470-2045 1474-5488 |
| language | eng |
| recordid | cdi_proquest_journals_2474172570 |
| source | MEDLINE; Access via ScienceDirect (Elsevier); ProQuest Central UK/Ireland |
| subjects | Adenocarcinoma Adenocarcinoma - drug therapy Adenocarcinoma - immunology Adenocarcinoma - secondary Aged Albumins - administration & dosage Albumins - adverse effects Antigens Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Cancer immunotherapy Cancer therapies CD40 antigen CD40 Antigens - antagonists & inhibitors CD40 Antigens - immunology Cell number Chemotherapy Clinical trials Deoxycytidine - administration & dosage Deoxycytidine - adverse effects Deoxycytidine - analogs & derivatives Drug dosages Female Fever Gemcitabine Humans Immunotherapy Intravenous administration Lymphocytes T Male Metastases Metastasis Middle Aged Monoclonal antibodies Neutropenia Nivolumab - administration & dosage Nivolumab - adverse effects Oncology Paclitaxel Paclitaxel - administration & dosage Paclitaxel - adverse effects Pancreas Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - immunology Pancreatic Neoplasms - pathology Patients Pharmacodynamics Sepsis Septic shock Solid tumors Targeted cancer therapy Time Factors Treatment Outcome United States |
| title | CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study |
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