title: Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Indiana University Medical Center, Indianapolis, IN, USA.
authors: Michael J
authors: MJ
authors: Robertson
authors: Brad S
authors: BS
authors: Kahl
authors: Julie M
authors: JM
authors: Vose
authors: Sven
authors: S
authors: de Vos
authors: Mary
authors: M
authors: Laughlin
authors: Patrick J
authors: PJ
authors: Flynn
authors: Kendrith
authors: K
authors: Rowland
authors: Jose C
authors: JC
authors: Cruz
authors: Stuart L
authors: SL
authors: Goldberg
authors: Luna
authors: L
authors: Musib
authors: Christelle
authors: C
authors: Darstein
authors: Nathan
authors: N
authors: Enas
authors: Jeffery L
authors: JL
authors: Kutok
authors: Jon C
authors: JC
authors: Aster
authors: Donna
authors: D
authors: Neuberg
authors: Kerry J
authors: KJ
authors: Savage
authors: Ann
authors: A
authors: LaCasce
authors: Donald
authors: D
authors: Thornton
authors: Christopher A
authors: CA
authors: Slapak
authors: Margaret A
authors: MA
authors: Shipp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin