Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma
Abstract There is a need for additional treatment options for patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC‐122), the selective, ATP‐com...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-02-01
|
| Series: | eJHaem |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jha2.375 |
| _version_ | 1797740058189496320 |
|---|---|
| author | Vincent Ribrag Julio C. Chavez Carola Boccomini Jason Kaplan Jason C. Chandler Armando Santoro Paolo Corradini Ian W. Flinn Ranjana Advani Philippe A. Cassier Randeep Sangha Vaishalee P. Kenkre Iris Isufi Shailaja Uttamsingh Patrick R. Hagner Anita K. Gandhi Frank Shen Sophie Michelliza Harald Haeske Kristen Hege Michael Pourdehnad John Kuruvilla |
| author_facet | Vincent Ribrag Julio C. Chavez Carola Boccomini Jason Kaplan Jason C. Chandler Armando Santoro Paolo Corradini Ian W. Flinn Ranjana Advani Philippe A. Cassier Randeep Sangha Vaishalee P. Kenkre Iris Isufi Shailaja Uttamsingh Patrick R. Hagner Anita K. Gandhi Frank Shen Sophie Michelliza Harald Haeske Kristen Hege Michael Pourdehnad John Kuruvilla |
| author_sort | Vincent Ribrag |
| collection | DOAJ |
| description | Abstract There is a need for additional treatment options for patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC‐122), the selective, ATP‐competitive mammalian target of rapamycin kinase inhibitor CC‐223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC‐292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC‐122‐DLBCL‐001 study (NCT02031419), the dose‐escalation portion explored combinations of CC‐122, CC‐223, and CC‐292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose‐limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24–84 years), and patients had a median of 3 (range 1–10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any‐grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC‐122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC‐122 plus rituximab was considered suitable for dose expansion, whereas CC‐223 and CC‐292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC‐122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi‐arm dose‐finding design. |
| first_indexed | 2024-03-12T14:06:49Z |
| format | Article |
| id | doaj.art-96c484da7911405ebd05aa9e00d581f2 |
| institution | Directory Open Access Journal |
| issn | 2688-6146 |
| language | English |
| last_indexed | 2024-03-12T14:06:49Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj.art-96c484da7911405ebd05aa9e00d581f22023-08-21T14:05:38ZengWileyeJHaem2688-61462022-02-013113915310.1002/jha2.375Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphomaVincent Ribrag0Julio C. Chavez1Carola Boccomini2Jason Kaplan3Jason C. Chandler4Armando Santoro5Paolo Corradini6Ian W. Flinn7Ranjana Advani8Philippe A. Cassier9Randeep Sangha10Vaishalee P. Kenkre11Iris Isufi12Shailaja Uttamsingh13Patrick R. Hagner14Anita K. Gandhi15Frank Shen16Sophie Michelliza17Harald Haeske18Kristen Hege19Michael Pourdehnad20John Kuruvilla21Institut Gustave Roussy Villejuif FranceH. Lee Moffitt Cancer Center & Research Institute Tampa Florida USACandiolo Cancer Institute FPO‐IRCCS Turin ItalyFeinberg School of Medicine Northwestern University Chicago Illinois USAWest Cancer Center Memphis Tennessee USAHumanitas Clinical and Research Center IRCCS Humanitas University Rozzano‐Milano ItalyIRCCS Istituto Nazionale dei Tumori University of Milano Milano ItalySarah Cannon Research Institute Nashville Tennessee USAStanford Cancer Institute Stanford California USACentre Leon Berard Lyon FranceCross Cancer Institute Edmonton CanadaDivision of Hematology/Oncology University of Wisconsin Madison Wisconsin USAYale Cancer Center New Haven Connecticut USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USABristol Myers Squibb Princeton New Jersey USADivision of Medical Oncology and Hematology Princess Margaret Cancer Centre University of Toronto Toronto CanadaAbstract There is a need for additional treatment options for patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC‐122), the selective, ATP‐competitive mammalian target of rapamycin kinase inhibitor CC‐223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC‐292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC‐122‐DLBCL‐001 study (NCT02031419), the dose‐escalation portion explored combinations of CC‐122, CC‐223, and CC‐292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose‐limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24–84 years), and patients had a median of 3 (range 1–10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any‐grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC‐122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC‐122 plus rituximab was considered suitable for dose expansion, whereas CC‐223 and CC‐292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC‐122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi‐arm dose‐finding design.https://doi.org/10.1002/jha2.375new drug developmentnon‐Hodgkin lymphomaphase 1 clinical trials |
| spellingShingle | Vincent Ribrag Julio C. Chavez Carola Boccomini Jason Kaplan Jason C. Chandler Armando Santoro Paolo Corradini Ian W. Flinn Ranjana Advani Philippe A. Cassier Randeep Sangha Vaishalee P. Kenkre Iris Isufi Shailaja Uttamsingh Patrick R. Hagner Anita K. Gandhi Frank Shen Sophie Michelliza Harald Haeske Kristen Hege Michael Pourdehnad John Kuruvilla Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma eJHaem new drug development non‐Hodgkin lymphoma phase 1 clinical trials |
| title | Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma |
| title_full | Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma |
| title_fullStr | Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma |
| title_full_unstemmed | Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma |
| title_short | Phase Ib study of combinations of avadomide (CC‐122), CC‐223, CC‐292, and rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma |
| title_sort | phase ib study of combinations of avadomide cc 122 cc 223 cc 292 and rituximab in patients with relapsed refractory diffuse large b cell lymphoma |
| topic | new drug development non‐Hodgkin lymphoma phase 1 clinical trials |
| url | https://doi.org/10.1002/jha2.375 |
| work_keys_str_mv | AT vincentribrag phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT juliocchavez phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT carolaboccomini phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT jasonkaplan phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT jasoncchandler phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT armandosantoro phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT paolocorradini phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT ianwflinn phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT ranjanaadvani phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT philippeacassier phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT randeepsangha phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT vaishaleepkenkre phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT irisisufi phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT shailajauttamsingh phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT patrickrhagner phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT anitakgandhi phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT frankshen phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT sophiemichelliza phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT haraldhaeske phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT kristenhege phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT michaelpourdehnad phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma AT johnkuruvilla phaseibstudyofcombinationsofavadomidecc122cc223cc292andrituximabinpatientswithrelapsedrefractorydiffuselargebcelllymphoma |