Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial

Andrew D. Zelenetz, Gilles Salles, Kylie D. Mason, Carla Casulo, Steven le Gouill, Laurie H. Sehn, Herve Tilly, Guillaume Cartron, Martine E. D. Chamuleau, Andre Goy, Constantine S. Tam, Pieternella J. Lugtenburg, Adam M. Petrich, Arijit Sinha, Divya Samineni, Sylvia Herter, Ellen Ingalla, Edith Szafer-Glusman, Christian Klein, Deepak Sampath & 3 others Martin Kornacker, Mehrdad Mobasher, Franck Morschhauser

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2 1 and MYC 1 ) DLBCL patients (87.5%; n 5 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study.
Original languageEnglish
Pages (from-to)1964-1976
JournalBlood
Volume133
Issue number18
DOIs
Publication statusPublished - 2019

Cite this

Zelenetz, A. D., Salles, G., Mason, K. D., Casulo, C., le Gouill, S., Sehn, L. H., ... Morschhauser, F. (2019). Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial. Blood, 133(18), 1964-1976. https://doi.org/10.1182/blood-2018-11-880526
Zelenetz, Andrew D. ; Salles, Gilles ; Mason, Kylie D. ; Casulo, Carla ; le Gouill, Steven ; Sehn, Laurie H. ; Tilly, Herve ; Cartron, Guillaume ; Chamuleau, Martine E. D. ; Goy, Andre ; Tam, Constantine S. ; Lugtenburg, Pieternella J. ; Petrich, Adam M. ; Sinha, Arijit ; Samineni, Divya ; Herter, Sylvia ; Ingalla, Ellen ; Szafer-Glusman, Edith ; Klein, Christian ; Sampath, Deepak ; Kornacker, Martin ; Mobasher, Mehrdad ; Morschhauser, Franck. / Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial. In: Blood. 2019 ; Vol. 133, No. 18. pp. 1964-1976.
@article{0e2b1bcdb87247de88932832437cb6e7,
title = "Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial",
abstract = "Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43{\%}) or diffuse large B-cell lymphoma (DLBCL; 32{\%}). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5{\%} (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2{\%} and 78.1{\%}, respectively. Most double-expressor (BCL2 1 and MYC 1 ) DLBCL patients (87.5{\%}; n 5 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study.",
author = "Zelenetz, {Andrew D.} and Gilles Salles and Mason, {Kylie D.} and Carla Casulo and {le Gouill}, Steven and Sehn, {Laurie H.} and Herve Tilly and Guillaume Cartron and Chamuleau, {Martine E. D.} and Andre Goy and Tam, {Constantine S.} and Lugtenburg, {Pieternella J.} and Petrich, {Adam M.} and Arijit Sinha and Divya Samineni and Sylvia Herter and Ellen Ingalla and Edith Szafer-Glusman and Christian Klein and Deepak Sampath and Martin Kornacker and Mehrdad Mobasher and Franck Morschhauser",
year = "2019",
doi = "10.1182/blood-2018-11-880526",
language = "English",
volume = "133",
pages = "1964--1976",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "18",

}

Zelenetz, AD, Salles, G, Mason, KD, Casulo, C, le Gouill, S, Sehn, LH, Tilly, H, Cartron, G, Chamuleau, MED, Goy, A, Tam, CS, Lugtenburg, PJ, Petrich, AM, Sinha, A, Samineni, D, Herter, S, Ingalla, E, Szafer-Glusman, E, Klein, C, Sampath, D, Kornacker, M, Mobasher, M & Morschhauser, F 2019, 'Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial' Blood, vol. 133, no. 18, pp. 1964-1976. https://doi.org/10.1182/blood-2018-11-880526

Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial. / Zelenetz, Andrew D.; Salles, Gilles; Mason, Kylie D.; Casulo, Carla; le Gouill, Steven; Sehn, Laurie H.; Tilly, Herve; Cartron, Guillaume; Chamuleau, Martine E. D.; Goy, Andre; Tam, Constantine S.; Lugtenburg, Pieternella J.; Petrich, Adam M.; Sinha, Arijit; Samineni, Divya; Herter, Sylvia; Ingalla, Ellen; Szafer-Glusman, Edith; Klein, Christian; Sampath, Deepak; Kornacker, Martin; Mobasher, Mehrdad; Morschhauser, Franck.

In: Blood, Vol. 133, No. 18, 2019, p. 1964-1976.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial

AU - Zelenetz, Andrew D.

AU - Salles, Gilles

AU - Mason, Kylie D.

AU - Casulo, Carla

AU - le Gouill, Steven

AU - Sehn, Laurie H.

AU - Tilly, Herve

AU - Cartron, Guillaume

AU - Chamuleau, Martine E. D.

AU - Goy, Andre

AU - Tam, Constantine S.

AU - Lugtenburg, Pieternella J.

AU - Petrich, Adam M.

AU - Sinha, Arijit

AU - Samineni, Divya

AU - Herter, Sylvia

AU - Ingalla, Ellen

AU - Szafer-Glusman, Edith

AU - Klein, Christian

AU - Sampath, Deepak

AU - Kornacker, Martin

AU - Mobasher, Mehrdad

AU - Morschhauser, Franck

PY - 2019

Y1 - 2019

N2 - Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2 1 and MYC 1 ) DLBCL patients (87.5%; n 5 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study.

AB - Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2 1 and MYC 1 ) DLBCL patients (87.5%; n 5 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30850381

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DO - 10.1182/blood-2018-11-880526

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SP - 1964

EP - 1976

JO - Blood

JF - Blood

SN - 0006-4971

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Zelenetz AD, Salles G, Mason KD, Casulo C, le Gouill S, Sehn LH et al. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: Results from the CAVALLI phase 1b trial. Blood. 2019;133(18):1964-1976. https://doi.org/10.1182/blood-2018-11-880526