Phase I and Pharmacokinetic (PK) Study of Everolimus (RAD001) in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL).

Abstract 1712

Poster Board I-738

[Background and Purpose] Everolimus (RAD001), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR) serine-threonine kinase, which plays a key role in regulating cell growth and proliferation. Although anti-lymphoma effects of RAD001 have been shown in preclinical studies and one phase II clinical study in NHL, there is no PK data in NHL patients (pts). A phase I (P1) study was conducted to evaluate safety, PK profile, and efficacy of RAD001 in Japanese pts with relapsed and/or refractory NHL.

[Patients and Methods] Pts with relapsed or refractory NHL, age ≥20, and PS 0-2 (ECOG) were enrolled and treated with RAD001, administered orally once daily at either 5 or 10 mg. Dose escalation was based on the clinical assessment of safety, incidence of dose-limiting toxicity (DLT), and probability of incidence of DLT. The latter probability distribution was estimated by a Bayesian logistic model, using prior information from other P1 trials with this agent in solid tumors. DLTs were evaluated in 6 pts at each dose level during the initial 28 days of study treatment (cycle 1). PK parameters were evaluated on days 1 and 15 of cycle 1. Response was assessed according to the International Workshop Criteria for NHL (1999).

[Results] A total of 13 pts were enrolled into 2 cohorts as follows; 5 mg (7 pts, DLBCL: 2; MCL: 1; FL: 1; PTCL: 1; CTCL: 1; ALCL: 1) and 10 mg (6 pts, FL: 4; MCL: 1; ALCL: 1). 12 pts were evaluable for DLTs. 1 pt in the 5 mg cohort was inevaluable for DLTs due to early disease progression. No DLTs were observed at either dose level. Frequently encountered potentially drug-related adverse events (AEs) (≥40%) include leukopenia (8/13, 62%), thrombocytopenia (8/13, 62%), elevated AST (9/13, 69%), stomatitis (7/13, 54%), anemia (6/13, 46%), nasopharyngitis (6/13, 46%), and elevated ALT (6/13, 46%). Potentially drug-related Gr 3 or 4 toxicities include anemia (Gr 4 : 1), thrombocytopenia (Gr 4 : 1; Gr 3: 1), lymphopenia (Gr 4 : 1; Gr 3: 3), elevated LDH (Gr 3: 1), anorexia (Gr 3: 1), hyperglycemia (Gr 3: 1), fatigue (Gr 3: 1), hepatic function abnormal (Gr 3: 1), P. jiroveci pneumonia (Gr 3: 1), hyperkalemia (Gr 3: 1), and hypokalemia (Gr 3: 1). All toxicities cited above were transient and reversible. Non-infectious pneumonitis (Gr 1) was observed in 1 pt but resolved following discontinuation of RAD001 without additional therapy. T_max was achieved within 4 hours, and C_max and AUC_tau both showed dose-proportional increases. The accumulation ratio after daily administration was approximately 2-fold. These data are consistent with those from a previous P1 study in solid tumors. A total of 4 objective responses (OR) were observed (summarized below):

[Conclusions] RAD001 is well tolerated in this pt population at doses up to 10 mg/day and shows preliminary evidence of activity in relapsed or refractory NHL. The PK profile in pts with NHL is similar to that in pts with solid tumors. A global randomized phase III study to determine efficacy of RAD001 as adjuvant therapy following front-line R-CHOP induction in poor-risk DLBCL is currently ongoing. The data from this P1 study led directly to Japan's decision to participate in the global phase III study.