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Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse
Michael J Robertson1, Brad S Kahl, Julie M Vose
1Indiana University Medical Center, Indianapolis, IN, USA.
Purpose:
Protein kinase C beta (PKCbeta) 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 PKCbeta, 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 > or= 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.
Insights
Enzastaurin, a protein kinase C beta inhibitor, showed good tolerability in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). A subset of patients experienced prolonged freedom from progression, warranting further investigation.
Area of Science:
- Oncology
- Pharmacology
Background:
- Protein kinase C beta (PKCbeta) is a validated therapeutic target in diffuse large B-cell lymphoma (DLBCL).
- Gene-expression profiling and immunohistochemical analysis identified PKCbeta as a key target in DLBCL.
Purpose of the Study:
- To evaluate the efficacy and safety of enzastaurin, a potent PKCbeta inhibitor, in patients with relapsed or refractory DLBCL.
- To assess freedom from progression (FFP), objective response, and toxicity in a phase II multicenter study.
Main Methods:
- Oral administration of enzastaurin once daily until disease progression or unacceptable toxicity.
- Enrollment of 55 patients with relapsed or refractory DLBCL, with a median of two prior therapies.
- Key endpoints included FFP for ≥2 cycles, objective response, and toxicity assessment.
Main Results:
- Enzastaurin was well-tolerated, with only one grade 4 toxicity (hypomagnesemia) reported.
- Grade 3 toxicities were infrequent and included fatigue, edema, headache, motor neuropathy, and thrombocytopenia.
- Twelve of 55 patients (22%) achieved FFP for two cycles; eight patients (15%) remained progression-free for four cycles. Four patients (7%) experienced prolonged FFP (20+ to 50+ months).
Conclusions:
- Enzastaurin demonstrated a favorable safety profile in patients with relapsed or refractory DLBCL.
- A subset of patients experienced prolonged freedom from progression, suggesting potential efficacy.
- Further clinical studies of enzastaurin for DLBCL are warranted.
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