Phase I Trial of Lenalidomide and CCI-779 in Patients With Relapsed Multiple Myeloma: Evidence for Lenalidomide–CCI-779 Interaction via P-Glycoprotein

• Published in: Journal of clinical oncology Vol. 29; no. 25; pp. 3427 - 3434
• Main Authors: HOFMEISTER, Craig C, XIAOXIA YANG, JIA JI, SCHAAF, Larry J, BENSON, Don M, KRAUT, Eric H, HICKS, William J, CHAN, Kenneth K, CHEN, Ching-Shih, FARAG, Sherif S, GREVER, Michael R, BYRD, John C, PICHIORRI, Flavia, PHELPS, Mitch A, PING CHEN, ROZEWSKI, Darlene M, JOHNSON, Amy J, LEE, Seungsoo, ZHONGFA LIU, GARR, Celia L, HADE, Erinn M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01-09-2011
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Blotting, Western; Drug Interactions; Faze; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Maximum Tolerated Dose; Medical sciences; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Original Reports; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Survival Rate; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; Tissue Distribution; Treatment Outcome; Tumors; Antineoplastic agent; Human; Immunopathology; Relapse; Lenalidomide; P Glycoprotein; Malignant hemopathy; Myeloma; Cancerology; Immunoglobulinopathy; Lymphoproliferative syndrome; Phase I trial; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2010.32.4962

Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM.
A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions.
Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate.
The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.