Phase I study of the oral mammalian target of rapamycin inhibitor everolimus (RAD001) in Japanese patients with relapsed or refractory non-Hodgkin lymphoma.
Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10 mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model. DLTs were evaluated in six patients at each dose level during the initial 28 days of study treatment. A total of 13 patients were enrolled; 5 mg (seven) and 10 mg (six). No DLTs were observed at either dose level. Frequently observed potentially drug-related adverse events included leukopenia (8/13), thrombocytopenia (8/13), elevated hepatic transaminase (9/13), stomatitis (7/13), anemia (6/13), and nasopharyngitis (6/13). All adverse events were reversible. Non-infectious pneumonitis (grade 1) in one patient resolved following discontinuation of everolimus. Two patients with diffuse large B cell lymphoma and two patients with follicular lymphomas achieved objective responses with an overall response rate of 31% (4/13). The pharmacokinetic profiles were not different from those in non-Japanese patients. Everolimus was well tolerated at doses up to 10 mg/day and showed potential efficacy in relapsed or refractory NHL, warranting further investigation.
Tobinai
Kensei
K
Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. ktobinai@ncc.go.jp
Ogura
Michinori
M
Maruyama
Dai
D
Uchida
Toshiki
T
Uike
Naokuni
N
Choi
Ilseung
I
Ishizawa
Kenichi
K
Itoh
Kuniaki
K
Ando
Kiyoshi
K
Taniwaki
Masafumi
M
Shimada
Naomi
N
Kobayashi
Ken
K
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007564:Japan; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus