Phase I study of lenalidomide, a novel thalidomide analog, in patients with refractory metastatic cancer

13038 Background: Lenalidomide (L), CC5013, is a thalidomide (T) analog that has shown activity in multiple myeloma and myelodysplastic syndromes (MDS); including activity in pts refractory to T. Preclinical studies suggest L has more potent immunomodulatory and antiangiogenic activity than T. We have conducted a phase I clinical trial of L to determine the maximum-tolerated dose (MTD), characterize the side-effects, characterize pharmacokinetics (PK) in pts with solid tumors. Methods: Pts with refractory metastatic cancer were treated on a modified Fibonacci dose-escalation scheme with an oral daily dose of L. Therapy was continued until MTD or disease progression. Results: Forty-five pts have been enrolled (M/F: 37/8). Median age 68 yrs (range, 25–89 yrs). Tumor types include prostate cancer (36 pts), adrenal carcinoma (3 pt), renal cell carcinoma (1 pt), choleangiocarcinoma (1 pt), small intestine cancer (1 pt), colon cancer (2 pt), and melanoma (1 pt). Dose levels were: 5 mg (n = 3), 10 mg (n = 6), 15 mg (n = 3), 20 mg (n = 3 + 7), 25 mg (n = 6), 30 mg (n = 8), 35 mg (n = 6) and 40 mg (n = 3). Due to side effects the dosing schedule was modified from daily dosing to daily dosing for 21 out of 28 days. Therapy has been well tolerated with most frequent gr 1 and gr 2 toxicities include nausea (43%), myalgia (38%), pruritis/rash (54%), and fatigue (38%), neutropenia (30%) with gr 3 diarrhea (n = 1), hypotension (n = 1), pulmonary effusions (n = 1), thromboses (n = 2) and gr 4 neutropenia (n = 2), arrhythmias (n = 1), hemolysis (n = 1). Dose escalation continues. There were no differences observed between dose levels for either oral clearance values (p = 0.47) or the apparent volume of distribution (Vz) values (p = 0.23). Dose-normalized AUC(0-∞), dose-normalized peak concentrations (Cmax), or half-life (t1/2) did not vary between dose levels (p > 0.12). Conclusion: L has been well tolerated up to 35 mg/d (21 days on; 7 days off), doses higher than the recently FDA-approved doses of 5 and 10 mg/d. In this dose range L exhibits linear PK. Tolerability to myelosuppression the dose-limiting toxicity in pts with MDS may therefore be improved in pts without hematological malignancies. No significant financial relationships to disclose.