Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring
Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition. We conduct...
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| Veröffentlicht in: | Clinical cancer research 2022-01, Vol.28 (1), p.45-56 |
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| creator | Stewart, Caitlin M Michaud, Laure Whiting, Karissa Nakajima, Reiko Nichols, Chelsea De Frank, Stephanie Hamlin, Jr, Paul A Matasar, Matthew J Gerecitano, John F Drullinsky, Pamela Hamilton, Audrey Straus, David Horwitz, Steven M Kumar, Anita Moskowitz, Craig H Moskowitz, Alison Zelenetz, Andrew D Rademaker, Jurgen Salles, Gilles Seshan, Venkatraman Schöder, Heiko Younes, Anas Tsui, Dana W Y Batlevi, Connie Lee |
| description | Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.
We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.
Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.
BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma. |
| doi_str_mv | 10.1158/1078-0432.CCR-21-2183 |
| format | Article |
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We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.
Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.
BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-21-2183</identifier><identifier>PMID: 34615723</identifier><language>eng</language><publisher>United States</publisher><subject>Adenine - analogs & derivatives ; Adult ; Aminopyridines ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Cell-Free Nucleic Acids ; Humans ; Lymphoma, Large B-Cell, Diffuse - drug therapy ; Lymphoma, Mantle-Cell - drug therapy ; Lymphoma, Mantle-Cell - genetics ; Lymphoma, Mantle-Cell - pathology ; Morpholines ; Phosphatidylinositol 3-Kinases ; Piperidines ; Pyrazoles ; Pyrimidines</subject><ispartof>Clinical cancer research, 2022-01, Vol.28 (1), p.45-56</ispartof><rights>2021 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-b8912841757533ebc82bd750b7b4a0f0e1e04f56997adf82f37aee35e4747e5b3</citedby><cites>FETCH-LOGICAL-c463t-b8912841757533ebc82bd750b7b4a0f0e1e04f56997adf82f37aee35e4747e5b3</cites><orcidid>0000-0002-4683-1868 ; 0000-0002-5070-4810 ; 0000-0002-9541-8666 ; 0000-0002-5170-4185 ; 0000-0001-9500-1804</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/34615723$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stewart, Caitlin M</creatorcontrib><creatorcontrib>Michaud, Laure</creatorcontrib><creatorcontrib>Whiting, Karissa</creatorcontrib><creatorcontrib>Nakajima, Reiko</creatorcontrib><creatorcontrib>Nichols, Chelsea</creatorcontrib><creatorcontrib>De Frank, Stephanie</creatorcontrib><creatorcontrib>Hamlin, Jr, Paul A</creatorcontrib><creatorcontrib>Matasar, Matthew J</creatorcontrib><creatorcontrib>Gerecitano, John F</creatorcontrib><creatorcontrib>Drullinsky, Pamela</creatorcontrib><creatorcontrib>Hamilton, Audrey</creatorcontrib><creatorcontrib>Straus, David</creatorcontrib><creatorcontrib>Horwitz, Steven M</creatorcontrib><creatorcontrib>Kumar, Anita</creatorcontrib><creatorcontrib>Moskowitz, Craig H</creatorcontrib><creatorcontrib>Moskowitz, Alison</creatorcontrib><creatorcontrib>Zelenetz, Andrew D</creatorcontrib><creatorcontrib>Rademaker, Jurgen</creatorcontrib><creatorcontrib>Salles, Gilles</creatorcontrib><creatorcontrib>Seshan, Venkatraman</creatorcontrib><creatorcontrib>Schöder, Heiko</creatorcontrib><creatorcontrib>Younes, Anas</creatorcontrib><creatorcontrib>Tsui, Dana W Y</creatorcontrib><creatorcontrib>Batlevi, Connie Lee</creatorcontrib><title>Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.
We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.
Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.
BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.</description><subject>Adenine - analogs & derivatives</subject><subject>Adult</subject><subject>Aminopyridines</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Cell-Free Nucleic Acids</subject><subject>Humans</subject><subject>Lymphoma, Large B-Cell, Diffuse - drug therapy</subject><subject>Lymphoma, Mantle-Cell - drug therapy</subject><subject>Lymphoma, Mantle-Cell - genetics</subject><subject>Lymphoma, Mantle-Cell - pathology</subject><subject>Morpholines</subject><subject>Phosphatidylinositol 3-Kinases</subject><subject>Piperidines</subject><subject>Pyrazoles</subject><subject>Pyrimidines</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd1u1DAQhS0EakvpI4B8yQVp_Rt7b5DatAsrpVB1y7VlJ-PGKJts7QS0r9CnbtI_gWTLHp0zx2N9CH2k5JhSqU8oUTojgrPjorjOGJ2W5m_QAZVSZZzl8u10f_Hso_cp_SaECkrEHtrnIqdSMX6A7q8amwCvTlYOr4ex3uHe46EBfOF9qGy1w7ar8dp6GB6ls3FrYxtScI_CysVxCN1U3TQQ7XaHQ4cvi_ILXk57dpyXZ0WJ_4ahwWuIwba4gLbNlhEAn_84xZd9F4Y-hu72A3rnbZvg6Pk8RL-WFzfF96z8-W1VnJZZJXI-ZE4vKNOCKqkk5-AqzVytJHHKCUs8AQpEeJkvFsrWXjPPlQXgEoQSCqTjh-jrU-52dBuoK-iGaFuzjWFj4870Npj_lS405rb_Y7SmTDExBXx-Doj93QhpMJuQqulXtoN-TIZJTQjLFSeTVT5Zq9inFMG_PkOJmTmamZGZGZmJo2HUzBynvk__zvja9QKOPwCmMJgc</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>Stewart, Caitlin M</creator><creator>Michaud, Laure</creator><creator>Whiting, Karissa</creator><creator>Nakajima, Reiko</creator><creator>Nichols, Chelsea</creator><creator>De Frank, Stephanie</creator><creator>Hamlin, Jr, Paul A</creator><creator>Matasar, Matthew J</creator><creator>Gerecitano, John F</creator><creator>Drullinsky, Pamela</creator><creator>Hamilton, Audrey</creator><creator>Straus, David</creator><creator>Horwitz, Steven M</creator><creator>Kumar, Anita</creator><creator>Moskowitz, Craig H</creator><creator>Moskowitz, Alison</creator><creator>Zelenetz, Andrew D</creator><creator>Rademaker, Jurgen</creator><creator>Salles, Gilles</creator><creator>Seshan, Venkatraman</creator><creator>Schöder, Heiko</creator><creator>Younes, Anas</creator><creator>Tsui, Dana W Y</creator><creator>Batlevi, Connie Lee</creator><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>5PM</scope><orcidid>https://orcid.org/0000-0002-4683-1868</orcidid><orcidid>https://orcid.org/0000-0002-5070-4810</orcidid><orcidid>https://orcid.org/0000-0002-9541-8666</orcidid><orcidid>https://orcid.org/0000-0002-5170-4185</orcidid><orcidid>https://orcid.org/0000-0001-9500-1804</orcidid></search><sort><creationdate>20220101</creationdate><title>Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring</title><author>Stewart, Caitlin M ; Michaud, Laure ; Whiting, Karissa ; Nakajima, Reiko ; Nichols, Chelsea ; De Frank, Stephanie ; Hamlin, Jr, Paul A ; Matasar, Matthew J ; Gerecitano, John F ; Drullinsky, Pamela ; Hamilton, Audrey ; Straus, David ; Horwitz, Steven M ; Kumar, Anita ; Moskowitz, Craig H ; Moskowitz, Alison ; Zelenetz, Andrew D ; Rademaker, Jurgen ; Salles, Gilles ; Seshan, Venkatraman ; Schöder, Heiko ; Younes, Anas ; Tsui, Dana W Y ; Batlevi, Connie Lee</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-b8912841757533ebc82bd750b7b4a0f0e1e04f56997adf82f37aee35e4747e5b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adult</topic><topic>Aminopyridines</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Cell-Free Nucleic Acids</topic><topic>Humans</topic><topic>Lymphoma, Large B-Cell, Diffuse - drug therapy</topic><topic>Lymphoma, Mantle-Cell - drug therapy</topic><topic>Lymphoma, Mantle-Cell - genetics</topic><topic>Lymphoma, Mantle-Cell - pathology</topic><topic>Morpholines</topic><topic>Phosphatidylinositol 3-Kinases</topic><topic>Piperidines</topic><topic>Pyrazoles</topic><topic>Pyrimidines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stewart, Caitlin M</creatorcontrib><creatorcontrib>Michaud, Laure</creatorcontrib><creatorcontrib>Whiting, Karissa</creatorcontrib><creatorcontrib>Nakajima, Reiko</creatorcontrib><creatorcontrib>Nichols, Chelsea</creatorcontrib><creatorcontrib>De Frank, Stephanie</creatorcontrib><creatorcontrib>Hamlin, Jr, Paul A</creatorcontrib><creatorcontrib>Matasar, Matthew J</creatorcontrib><creatorcontrib>Gerecitano, John F</creatorcontrib><creatorcontrib>Drullinsky, Pamela</creatorcontrib><creatorcontrib>Hamilton, Audrey</creatorcontrib><creatorcontrib>Straus, David</creatorcontrib><creatorcontrib>Horwitz, Steven M</creatorcontrib><creatorcontrib>Kumar, Anita</creatorcontrib><creatorcontrib>Moskowitz, Craig H</creatorcontrib><creatorcontrib>Moskowitz, Alison</creatorcontrib><creatorcontrib>Zelenetz, Andrew D</creatorcontrib><creatorcontrib>Rademaker, Jurgen</creatorcontrib><creatorcontrib>Salles, Gilles</creatorcontrib><creatorcontrib>Seshan, Venkatraman</creatorcontrib><creatorcontrib>Schöder, Heiko</creatorcontrib><creatorcontrib>Younes, Anas</creatorcontrib><creatorcontrib>Tsui, Dana W Y</creatorcontrib><creatorcontrib>Batlevi, Connie Lee</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>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stewart, Caitlin M</au><au>Michaud, Laure</au><au>Whiting, Karissa</au><au>Nakajima, Reiko</au><au>Nichols, Chelsea</au><au>De Frank, Stephanie</au><au>Hamlin, Jr, Paul A</au><au>Matasar, Matthew J</au><au>Gerecitano, John F</au><au>Drullinsky, Pamela</au><au>Hamilton, Audrey</au><au>Straus, David</au><au>Horwitz, Steven M</au><au>Kumar, Anita</au><au>Moskowitz, Craig H</au><au>Moskowitz, Alison</au><au>Zelenetz, Andrew D</au><au>Rademaker, Jurgen</au><au>Salles, Gilles</au><au>Seshan, Venkatraman</au><au>Schöder, Heiko</au><au>Younes, Anas</au><au>Tsui, Dana W Y</au><au>Batlevi, Connie Lee</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>28</volume><issue>1</issue><spage>45</spage><epage>56</epage><pages>45-56</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Activation of Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K) represent parallel, synergistic pathways in lymphoma pathogenesis. As predominant PI3Kδ inhibition is a possible mechanism of tumor escape, we proposed a clinical trial of dual BTK and pan-PI3K inhibition.
We conducted a single-center phase I/Ib trial combining a BTK inhibitor (ibrutinib) and a pan-PI3K inhibitor (buparlisib) in 37 patients with relapsed/refractory (R/R) B-cell lymphoma. Buparlisib and ibrutinib were administered orally, once daily in 28-day cycles until progression or unacceptable toxicity. The clinical trial is registered with clinicaltrials.gov, NCT02756247.
Patients with mantle cell lymphoma (MCL) receiving the combination had a 94% overall response rate (ORR) and 33-month median progression-free survival; ORR of 31% and 20% were observed in patients with diffuse large B-cell lymphoma and follicular lymphoma, respectively. The maximum tolerated dose was ibrutinib 560 mg plus buparlisib 100 mg and the recommended phase II dose was ibrutinib 560 mg plus buparlisib 80 mg. The most common grade 3 adverse events were rash/pruritis/dermatitis (19%), diarrhea (11%), hyperglycemia (11%), and hypertension (11%). All grade mood disturbances ranging from anxiety, depression, to agitation were observed in 22% of patients. Results from serial monitoring of cell-free DNA samples corresponded to radiographic resolution of disease and tracked the emergence of mutations known to promote BTK inhibitor resistance.
BTK and pan-PI3K inhibition in mantle cell lymphoma demonstrates a promising efficacy signal. Addition of BCL2 inhibitors to a BTK and pan-PI3K combination remain suitable for further development in mantle cell lymphoma.</abstract><cop>United States</cop><pmid>34615723</pmid><doi>10.1158/1078-0432.CCR-21-2183</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-4683-1868</orcidid><orcidid>https://orcid.org/0000-0002-5070-4810</orcidid><orcidid>https://orcid.org/0000-0002-9541-8666</orcidid><orcidid>https://orcid.org/0000-0002-5170-4185</orcidid><orcidid>https://orcid.org/0000-0001-9500-1804</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2022-01, Vol.28 (1), p.45-56 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8812724 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adenine - analogs & derivatives Adult Aminopyridines Antineoplastic Combined Chemotherapy Protocols - adverse effects Cell-Free Nucleic Acids Humans Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Mantle-Cell - drug therapy Lymphoma, Mantle-Cell - genetics Lymphoma, Mantle-Cell - pathology Morpholines Phosphatidylinositol 3-Kinases Piperidines Pyrazoles Pyrimidines |
| title | Phase I/Ib Study of the Efficacy and Safety of Buparlisib and Ibrutinib Therapy in MCL, FL, and DLBCL with Serial Cell-Free DNA Monitoring |
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