Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia

Kerry A. Rogers, Ying Huang, Amy S. Ruppert, Farrukh T. Awan, Nyla A. Heerema, Corinne Hoffman, Gerard Lozanski, Kami J. Maddocks, Mollie E. Moran, Mark A. Reid, Margaret Lucas, Jennifer A. Woyach, W. Thomas Whitlow, Jeffrey A. Jones, John C. Byrd

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton’s tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

Original languageEnglish (US)
Pages (from-to)1568-1572
Number of pages5
JournalBlood
Volume132
Issue number15
DOIs
StatePublished - Oct 11 2018
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
Refractory materials
Tumor Lysis Syndrome
Hematologic Agents
Tumors
Bone Marrow
Patient treatment
B-Cell Lymphoma
United States Food and Drug Administration
Toxicity
Bone
Blood
Therapeutics
Monoclonal Antibodies
Cells
Confidence Intervals
Safety
Planning
Recovery
PCI 32765

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Rogers, K. A., Huang, Y., Ruppert, A. S., Awan, F. T., Heerema, N. A., Hoffman, C., ... Byrd, J. C. (2018). Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood, 132(15), 1568-1572. https://doi.org/10.1182/blood-2018-05-853564

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. / Rogers, Kerry A.; Huang, Ying; Ruppert, Amy S.; Awan, Farrukh T.; Heerema, Nyla A.; Hoffman, Corinne; Lozanski, Gerard; Maddocks, Kami J.; Moran, Mollie E.; Reid, Mark A.; Lucas, Margaret; Woyach, Jennifer A.; Thomas Whitlow, W.; Jones, Jeffrey A.; Byrd, John C.

In: Blood, Vol. 132, No. 15, 11.10.2018, p. 1568-1572.

Research output: Contribution to journalArticle

Rogers, KA, Huang, Y, Ruppert, AS, Awan, FT, Heerema, NA, Hoffman, C, Lozanski, G, Maddocks, KJ, Moran, ME, Reid, MA, Lucas, M, Woyach, JA, Thomas Whitlow, W, Jones, JA & Byrd, JC 2018, 'Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia', Blood, vol. 132, no. 15, pp. 1568-1572. https://doi.org/10.1182/blood-2018-05-853564
Rogers, Kerry A. ; Huang, Ying ; Ruppert, Amy S. ; Awan, Farrukh T. ; Heerema, Nyla A. ; Hoffman, Corinne ; Lozanski, Gerard ; Maddocks, Kami J. ; Moran, Mollie E. ; Reid, Mark A. ; Lucas, Margaret ; Woyach, Jennifer A. ; Thomas Whitlow, W. ; Jones, Jeffrey A. ; Byrd, John C. / Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. In: Blood. 2018 ; Vol. 132, No. 15. pp. 1568-1572.
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abstract = "Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton’s tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92{\%} (95{\%} confidence interval, 62{\%}-100{\%}), with 42{\%} (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.",
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AU - Awan, Farrukh T.

AU - Heerema, Nyla A.

AU - Hoffman, Corinne

AU - Lozanski, Gerard

AU - Maddocks, Kami J.

AU - Moran, Mollie E.

AU - Reid, Mark A.

AU - Lucas, Margaret

AU - Woyach, Jennifer A.

AU - Thomas Whitlow, W.

AU - Jones, Jeffrey A.

AU - Byrd, John C.

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