Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma

Michael Robertson, Brad S. Kahl, Julie M. Vose, Sven De Vos, Mary Laughlin, Patrick J. Flynn, Kendrith Rowland, Jose C. Cruz, Stuart L. Goldberg, Luna Musib, Christelle Darstein, Nathan Enas, Jeffery L. Kutok, Jon C. Aster, Donna Neuberg, Kerry J. Savage, Ann LaCasce, Donald Thornton, Christopher A. Slapak, Margaret A. Shipp

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

Purpose: Protein kinase C beta (PKCβ) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCβ, enzastaurin, in patients with relapsed or refractory DLBCL. Patients and Methods: Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for ≥ two cycles (one cycle = 28 days), objective response, and toxicity. Results: Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for ≥ two cycles, and eight patients remained free from progression for ≥ four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry. Conclusion: Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

Original languageEnglish (US)
Pages (from-to)1741-1746
Number of pages6
JournalJournal of Clinical Oncology
Volume25
Issue number13
DOIs
StatePublished - May 1 2007
Externally publishedYes

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Protein Kinase C beta
Lymphoma, Large B-Cell, Diffuse
enzastaurin
Therapeutics
Stem Cell Transplantation
Gene Expression Profiling
Neutropenia
Fatigue
Headache
Disease Progression
Edema

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. / Robertson, Michael; Kahl, Brad S.; Vose, Julie M.; De Vos, Sven; Laughlin, Mary; Flynn, Patrick J.; Rowland, Kendrith; Cruz, Jose C.; Goldberg, Stuart L.; Musib, Luna; Darstein, Christelle; Enas, Nathan; Kutok, Jeffery L.; Aster, Jon C.; Neuberg, Donna; Savage, Kerry J.; LaCasce, Ann; Thornton, Donald; Slapak, Christopher A.; Shipp, Margaret A.

In: Journal of Clinical Oncology, Vol. 25, No. 13, 01.05.2007, p. 1741-1746.

Research output: Contribution to journalArticle

Robertson, M, Kahl, BS, Vose, JM, De Vos, S, Laughlin, M, Flynn, PJ, Rowland, K, Cruz, JC, Goldberg, SL, Musib, L, Darstein, C, Enas, N, Kutok, JL, Aster, JC, Neuberg, D, Savage, KJ, LaCasce, A, Thornton, D, Slapak, CA & Shipp, MA 2007, 'Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma', Journal of Clinical Oncology, vol. 25, no. 13, pp. 1741-1746. https://doi.org/10.1200/JCO.2006.09.3146
Robertson, Michael ; Kahl, Brad S. ; Vose, Julie M. ; De Vos, Sven ; Laughlin, Mary ; Flynn, Patrick J. ; Rowland, Kendrith ; Cruz, Jose C. ; Goldberg, Stuart L. ; Musib, Luna ; Darstein, Christelle ; Enas, Nathan ; Kutok, Jeffery L. ; Aster, Jon C. ; Neuberg, Donna ; Savage, Kerry J. ; LaCasce, Ann ; Thornton, Donald ; Slapak, Christopher A. ; Shipp, Margaret A. / Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 13. pp. 1741-1746.
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abstract = "Purpose: Protein kinase C beta (PKCβ) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCβ, enzastaurin, in patients with relapsed or refractory DLBCL. Patients and Methods: Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for ≥ two cycles (one cycle = 28 days), objective response, and toxicity. Results: Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22{\%}; 95{\%} CI, 13{\%} to 46{\%}) experienced FFP for ≥ two cycles, and eight patients remained free from progression for ≥ four cycles (15{\%}; 95{\%} CI, 6{\%} to 27{\%}). Four patients (7{\%}; 95{\%} CI, 2{\%} to 18{\%}), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry. Conclusion: Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.",
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T1 - Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma

AU - Robertson, Michael

AU - Kahl, Brad S.

AU - Vose, Julie M.

AU - De Vos, Sven

AU - Laughlin, Mary

AU - Flynn, Patrick J.

AU - Rowland, Kendrith

AU - Cruz, Jose C.

AU - Goldberg, Stuart L.

AU - Musib, Luna

AU - Darstein, Christelle

AU - Enas, Nathan

AU - Kutok, Jeffery L.

AU - Aster, Jon C.

AU - Neuberg, Donna

AU - Savage, Kerry J.

AU - LaCasce, Ann

AU - Thornton, Donald

AU - Slapak, Christopher A.

AU - Shipp, Margaret A.

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N2 - Purpose: Protein kinase C beta (PKCβ) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCβ, enzastaurin, in patients with relapsed or refractory DLBCL. Patients and Methods: Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for ≥ two cycles (one cycle = 28 days), objective response, and toxicity. Results: Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for ≥ two cycles, and eight patients remained free from progression for ≥ four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry. Conclusion: Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

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