Résumé
Protein kinase C beta (PKCβ), a pivotal enzyme in B-cell signaling and survival, has been identified as a therapeutic target in B-cell malignancies. Recent studies show that PKCβ is overexpressed in a majority of patients (pts) with mantle cell lymphoma (MCL). Other studies implicate overactivation of the PI3K/AKT pathway in the pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. The primary objective of this phase II, single-arm, multicenter trial was to determine the rate of freedom from progression (FFP) for ≥3 cycles (1 cycle = 28 days). Secondary endpoints included objective response rate (complete + partial) and toxicity. Pts with previously relapsed/refractory MCL, with no more than 4 prior regimens of therapy, received 500 mg enzastaurin orally, once daily, until disease progression or unacceptable toxicity. A total of 60 pts (18 female; 42 male), median age of 66 years (range: 45–85), median international prognostic index of 2 (range: 0–5), and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. All pts had CD20 + MCL and failed multiple prior therapies (median = 2, range: 1–5). Most pts had received CHOP-based chemotherapy and/or rituximab. All enrolled pts received at least 1 dose of enzastaurin and were included in the safety and efficacy analysis. Three pts discontinued due to adverse events possibly related to study drug (diarrhea, renal impairment, and syncope). There were no drug-related deaths or grade (Gr) 4 toxicities. No drug-related bone-marrow toxicities, except Gr 3 anemia (1 pt), were reported. There was 1 case each of drug-related Gr 3 diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue (Gr ≤2) was the most common toxicity (n = 5). No objective tumor responses were recorded. 22 of 60 enrolled pts (36.7%, 95% CI: 24.5%–48.9%) were FFP for ≥3 cycles. Six of these pts, who had failed prior chemotherapy and/or immunotherapy, achieved stable disease for ≥ 6 months. One pt was FFP for 22 months, and 2 pts are still on treatment for 8+ and 12+ months, respectively. Although no objective tumor responses occurred, 6 pts were FFP for 6 to 22 months. Oral enzastaurin was well tolerated for extended durations, suggesting it may be used as continuous or maintenance therapy after induction therapy and warrants further investigation in MCL.