Phase i clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer

Background Lenalidomide, an immunomodulatory and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers. Patients and methods A "3 + 3" study design was used. During the escalation phase, lenalidomide (orally, days 1-21) and temsirolimus (intravenously, once a week) were given at the following respective doses: level 1 (10 mg, 15 mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Results Forty-three patients were treated (median age: 58 years (range, 21-80); male/female: 26/17). The most common diagnoses were colorectal cancer (N = 5), sarcoma (N = 5), neuroendocrine carcinoma (N = 4) and adenoid cystic carcinoma (N = 4). Overall, 121 cycles (median: 2) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related hematologic toxicities (all reversible) were seen in 19 (72 %) patients and included neutropenia (N = 12), thrombocytopenia (N = 6), and infection (N = 1). Grade 3 hyperglycemia and Grade 3 hypertriglyceridemia were noted in 21 % and 20 % of patients, respectively. Of 43 patients, 30 (70 %) received prophylactic anticoagulation. There were no thrombotic events. Response was evaluable in 40 patients: one (2.5 %) patient had a partial response and 19 (48 %) had stable disease (SD), with SD ≥ 6 months in 6 (15 %) patients. Tumor types with SD ≥ 6 months were soft tissue sarcoma (2/5; 40 %), adenoid cystic carcinoma (1/4; 25 %), parotid adenocarcinoma (1/2; 50 %), adrenocortical carcinoma (1/3; 33 %), and neuroendocrine carcinoma (1/4; 25 %). The median progression-free survival duration was 2.2 months (95 % CI, 1.5-2.9), and the median overall survival duration was 7.8 months (95 % CI, 5.1-10.6). Conclusions Lenalidomide and temsirolimus combination therapy was well tolerated and associated with clinical benefit in patients with soft tissue sarcoma, adenoid cystic carcinoma, neuroendocrine carcinoma, parotid carcinoma, and adrenocortical carcinoma.