A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma.
BACKGROUND
Protein kinase C beta (PKCbeta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCbeta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis.


METHODS
Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily.


RESULTS
Sixty patients, median age 66 years (range 45-85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3-5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for > or =3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months.


CONCLUSIONS
Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.
Morschhauser
F
F
Hematology, Hopital C. Huriez Centre Hospitalier Universitaire, Lille, France. f-morschhauser@chru-lille.fr
Seymour
J F
JF
Kluin-Nelemans
H C
HC
Grigg
A
A
Wolf
M
M
Pfreundschuh
M
M
Tilly
H
H
Raemaekers
J
J
van 't Veer
M B
MB
Milpied
N
N
Cartron
G
G
Pezzutto
A
A
Spencer
A
A
Reyes
F
F
Dreyling
M
M
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D011493:Protein Kinase C / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome
D007211:Indoles; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C504878:enzastaurin