Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma

Matthew S. Davids, Andrew W. Roberts, John F. Seymour, John M. Pagel, Brad S. Kahl, William G. Wierda, Soham D Puvvada, Thomas J. Kipps, Mary Ann Anderson, Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Franklin Peale, Jeremy A. Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A. Humerickhouse, Gary B. Gordon & 1 others John F. Gerecitano

Research output: Contribution to journalArticle

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Abstract

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatmentemergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was ± months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Original languageEnglish (US)
Pages (from-to)826-833
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number8
DOIs
StatePublished - Mar 10 2017

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Non-Hodgkin's Lymphoma
B-Cell Leukemia
B-Cell Lymphoma
Tumor Lysis Syndrome
Safety
Mantle-Cell Lymphoma
Waldenstrom Macroglobulinemia
Architectural Accessibility
Follicular Lymphoma
Lymphoma, Large B-Cell, Diffuse
B-Cell Chronic Lymphocytic Leukemia
Patient Safety
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Neutropenia
Thrombocytopenia
Disease-Free Survival
Anemia
Lymphoma
Pharmacokinetics
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Davids, M. S., Roberts, A. W., Seymour, J. F., Pagel, J. M., Kahl, B. S., Wierda, W. G., ... Gerecitano, J. F. (2017). Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. Journal of Clinical Oncology, 35(8), 826-833. https://doi.org/10.1200/JCO.2016.70.4320

Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. / Davids, Matthew S.; Roberts, Andrew W.; Seymour, John F.; Pagel, John M.; Kahl, Brad S.; Wierda, William G.; Puvvada, Soham D; Kipps, Thomas J.; Anderson, Mary Ann; Salem, Ahmed Hamed; Dunbar, Martin; Zhu, Ming; Peale, Franklin; Ross, Jeremy A.; Gressick, Lori; Desai, Monali; Kim, Su Young; Verdugo, Maria; Humerickhouse, Rod A.; Gordon, Gary B.; Gerecitano, John F.

In: Journal of Clinical Oncology, Vol. 35, No. 8, 10.03.2017, p. 826-833.

Research output: Contribution to journalArticle

Davids, MS, Roberts, AW, Seymour, JF, Pagel, JM, Kahl, BS, Wierda, WG, Puvvada, SD, Kipps, TJ, Anderson, MA, Salem, AH, Dunbar, M, Zhu, M, Peale, F, Ross, JA, Gressick, L, Desai, M, Kim, SY, Verdugo, M, Humerickhouse, RA, Gordon, GB & Gerecitano, JF 2017, 'Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma', Journal of Clinical Oncology, vol. 35, no. 8, pp. 826-833. https://doi.org/10.1200/JCO.2016.70.4320
Davids, Matthew S. ; Roberts, Andrew W. ; Seymour, John F. ; Pagel, John M. ; Kahl, Brad S. ; Wierda, William G. ; Puvvada, Soham D ; Kipps, Thomas J. ; Anderson, Mary Ann ; Salem, Ahmed Hamed ; Dunbar, Martin ; Zhu, Ming ; Peale, Franklin ; Ross, Jeremy A. ; Gressick, Lori ; Desai, Monali ; Kim, Su Young ; Verdugo, Maria ; Humerickhouse, Rod A. ; Gordon, Gary B. ; Gerecitano, John F. / Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 8. pp. 826-833.
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title = "Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma",
abstract = "Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstr{\"o}m macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatmentemergent adverse events were reported in 103 patients (97{\%}), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56{\%}), and the most common were hematologic, including anemia (15{\%}), neutropenia (11{\%}), and thrombocytopenia (9{\%}). Overall response rate was 44{\%} (MCL, 75{\%}; FL, 38{\%}; DLBCL, 18{\%}). Estimated median progression-free survival was ± months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.",
author = "Davids, {Matthew S.} and Roberts, {Andrew W.} and Seymour, {John F.} and Pagel, {John M.} and Kahl, {Brad S.} and Wierda, {William G.} and Puvvada, {Soham D} and Kipps, {Thomas J.} and Anderson, {Mary Ann} and Salem, {Ahmed Hamed} and Martin Dunbar and Ming Zhu and Franklin Peale and Ross, {Jeremy A.} and Lori Gressick and Monali Desai and Kim, {Su Young} and Maria Verdugo and Humerickhouse, {Rod A.} and Gordon, {Gary B.} and Gerecitano, {John F.}",
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T1 - Phase i first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma

AU - Davids, Matthew S.

AU - Roberts, Andrew W.

AU - Seymour, John F.

AU - Pagel, John M.

AU - Kahl, Brad S.

AU - Wierda, William G.

AU - Puvvada, Soham D

AU - Kipps, Thomas J.

AU - Anderson, Mary Ann

AU - Salem, Ahmed Hamed

AU - Dunbar, Martin

AU - Zhu, Ming

AU - Peale, Franklin

AU - Ross, Jeremy A.

AU - Gressick, Lori

AU - Desai, Monali

AU - Kim, Su Young

AU - Verdugo, Maria

AU - Humerickhouse, Rod A.

AU - Gordon, Gary B.

AU - Gerecitano, John F.

PY - 2017/3/10

Y1 - 2017/3/10

N2 - Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatmentemergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was ± months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

AB - Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatmentemergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was ± months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

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