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

• Published in: Investigational new drugs 2013-12, Vol.31 (6), p.1505-1513
• Main Authors: Ganesan, Prasanth, Piha-Paul, Sarina, Naing, Aung, Falchook, Gerald, Wheler, Jennifer, Janku, Filip, Zinner, Ralph, Laday, Shell, Kies, Merrill, Tsimberidou, Apostolia M.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Angina pectoris; Angiogenesis Inhibitors - administration & dosage; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; Blood pressure; Bone marrow; Cancer; Cancer therapies; Chemotherapy; Clinical trials; Cytotoxicity; Drug Administration Schedule; Drug dosages; Drug therapy; Female; General aspects; Humans; Kinases; Lymphoma; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple myeloma; Neoplasms - drug therapy; Neutropenia; Oncology; Patients; Pharmaceuticals; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; Protein Kinase Inhibitors - administration & dosage; Sarcoma; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Studies; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; TOR Serine-Threonine Kinases - antagonists & inhibitors; Toxicity; Tumors; Young Adult
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-013-0013-1

Summary 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.