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

Abstract

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.

• Authors: Prasanth Ganesan, Sarina Piha-Paul, Aung Naing, Gerald Falchook, Jennifer Wheler, Filip Janku, Ralph Zinner, Shell Laday, Merrill Kies, Apostolia M Tsimberidou
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 6 Pg. 1505-13 (Dec 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 23982248 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Protein Kinase Inhibitors
• Thalidomide
• temsirolimus
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Lenalidomide
• Sirolimus

Topics

• Adult
• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Drug Administration Schedule
• Female
• Humans
• Lenalidomide
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (administration & dosage)
• Sirolimus (administration & dosage, analogs & derivatives)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Thalidomide (administration & dosage, analogs & derivatives)
• Young Adult