Phase I Study of mTOR Inhibitor Everolimus Plus CHOP in Patients with Advanced, Aggressive T-Cell lymphomas

Advanced stage T-cell lymphomas usually follow aggressive clinical course and their treatment outcomes are worse than B-cell non-Hodgkin lymphoma. Furthermore, the optimal treatment regimen is still not established for these disease entities. Thus, cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens are still used as a primary treatment even though their efficacy is not satisfactory. This unmet need of T-cell lymphomas has required the development of more effective regimen. Thus, we incorporated an oral mTOR inhibitor, everolimus (RAD001, Afinitor®) into CHOP regimen to improve its efficacy. The mTOR complex is one of emerging targets in the lymphoma treatment because mTOR signal pathway is used by malignant cells to promote growth and survival. Previous studies demonstrated a single agent activity of mTOR inhibitor against relapsed or refractory lymphomas. Furthermore, several animal study results suggested that the mTOR inhibitor might enhance the effects of vincristine and cyclophosphamide when it was tried in combination with these drugs. Thus, we performed the phase I study to evaluate the feasibility and safety of everolimus plus CHOP chemotherapy for advanced stage, aggressive T-cell lymphomas.

We enrolled patients with newly diagnosed T cell lymphomas including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALCL) and cutaneous T-cell lymphoma (CTCL). Extranodal NK/T-cell lymphoma was excluded because it is resistant to anthracycline-based chemotherapy, and mycosis fungoides was also excluded due to its indolent nature. All patients were Ann Arbor stage III/IV and had adequate organ function. Patients received everolimus from day 1 to day 15 (once daily schedule of four dose levels, 2.5, 5, 7.5, and 10mg/dose) in addition to 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5. Six cycles of therapy administered every 21 days were planned. As a pharmacokinetic study, steady state trough concentrations of everolimus were measured at the end of cycle 1 and 2. All patients provided written informed consents and this trial was registered at www.ClinicalTrials.gov (NCT01198665).

Fifteen patients were enrolled between October 2010 and April 2011 including PTCL-NOS (n = 8), AITL (n = 4), ALCL (n = 1) and CTCL (n = 2). Ten patients presented as stage IV (66.7%) and the majority of patients showed serum LDH elevation (n = 13, 86.7%). Thus, the International Prognostic Index risk was dominantly high or high-intermediate (n = 9, 60.0%). There was no dose-limiting toxicity (DLT) at the level I (2.5mg/dose of everolimus) while one patient experienced hematologic DLT (grade IV thrombocytopenia) at the level II (5mg/dose). Thus, after patients were enrolled up to six at the level II, dose of everolimus was escalated to 7.5mg (level III). At the level III, two patients experienced DLT (grade IV thrombocytopenia and febrile neutropenia) among six patients enrolled. Therefore, the maximum tolerated dose for everolimus was determined as 5mg. In the evaluation of pharmacokinetic profile, there were no differences in the trough concentrations of everolimus between cycle 1 and 2 for all of these three dose groups. There was no dose-limiting non-hematologic toxicity in the all three dose levels. Although the main toxicity of everolimus was hematologic toxicity and it was overlapped with the toxicity of CHOP regimen, these hematologic toxicities were manageable. Among 15 patients, 14 patients responded to the treatment including 7 complete responses and 7 partial responses. However, five patients relapsed or progressed during follow-up.

Everolimus can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II study of everolimus plus CHOP is 5 mg/dose of everolimus once daily for 15 days as first-line treatment.

No relevant conflicts of interest to declare.