Enzastaurin in Patients with Non-Hodgkin Lymphomas: A Multicenter, Open-Label, Screening Study.

Enzastaurin, an oral serine/threonine kinase inhibitor, targets the PKCβ and PI3K/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis. At a clinically achievable concentration, enzastaurin suppressed growth and induced apoptosis in B-cell lymphoma (BCL) cell lines and induced apoptosis through AKT signaling in cutaneous T-cell lymphoma (CTCL) cell lines. Enzastaurin has demonstrated clinical activity in patients with relapsed/refractory diffuse large B-cell lymphoma. A screening study was initiated to evaluate the activity (response) of enzastaurin in relapsed peripheral TCL (PTCL), CTCL, and indolent and aggressive BCLs (IBCL and ABCL). Secondary objectives included determination of progression-free survival (PFS) and safety.

In this open-label, three (parallel) arm, non-comparative screening study, patients with relapsed TCL or BCL received 250 mg oral enzastaurin, twice daily (1125-mg loading dose on day 1), in 28-day cycles, for up to 2 years. TCL cohort consisted of patients who had histologically/cytologically confirmed PTCL and or histologically confirmed stage IB-IVB CTCL (including mycosis fungoides or Sézary syndrome). IBCL cohort had patients with stage II-IV, histologically confirmed small lymphocytic lymphoma (SLL) and grade 1/2 follicular lymphoma (FL) or marginal zone lymphoma (MZ: splenic, extranodal, or nodal). ABCL cohort included patients who had histologically confirmed grade 3a/b FL or aggressive lymphoma with prior clinical history of indolent lymphoma. Patients must have failed ≥1 prior systemic treatment (1 for TCL and IBCL; 2 for ABCL). Response was assessed using the modified Severity-Weighted Assessment Tool (mSWAT) in CTCL patients and the International Workshop criteria in all other patients. Safety was assessed using the Common Terminology Criteria for Adverse Events, version 3.0.

A total of 58 patients were enrolled into the study: 24 in the TCL cohort, 19 in the IBCL cohort and 15 in the ABCL cohort. Patient characteristics and efficacy results at the interim analysis are summarized in the table. None of the patients had a complete response. Partial responses were observed in 1 patient each with CTCL, SLL, grade 1/2 FL, and grade 3a/3b FL. Eleven patients are ongoing treatment for >6 cycles (8 patients ≥12 cycles). Three patients (5%) discontinued due to drug-related toxicities: 1 due to grade (G) 3 hallucination, 1 due to G1 erectile dysfunction, and 1 due to G3 pruritus. One patient had drug-related G3 diarrhea and jaundice and G4 edema. Other 'G3 toxicities, regardless of causality, reported in >1 patient were: anemia (n=4), thrombocytopenia (n=2), and sepsis (n=3) in TCL patients; anemia (n=4) in IBCL patients; and pneumonia (n=2) in ABCL patients. There were no drug-related deaths.

These preliminary results indicate that enzastaurin appears to have activity and is well tolerated in patients with indolent lymphomas, grade 3a/3b FL, and CTCL.

Eliadis:HOCA Employee: Employment, Membership on an entity's Board of Directors or advisory committees. Crespo-Solis:Eli Lilly and Company: Honoraria. Pereira:Fundacao Faculdade de Medicina da Universidade de Sao Paulo: Employment. Roberson:Eli Lilly and Company: Employment. Hamid:Eli Lilly and Company: Employment. Smith:Eli Lilly and Company: Employment.