Originally published as JCO Early Release 10.1200/JCO.2005.13.466 on June 27 2005
Journal of Clinical Oncology, Vol 23, No 23 (August 10), 2005: pp. 5347-5356
© 2005 American Society of Clinical Oncology.
Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma
Thomas E. Witzig,
Susan M. Geyer,
Irene Ghobrial,
David J. Inwards,
Rafael Fonseca,
Paul Kurtin,
Stephen M. Ansell,
Ronnie Luyun,
Patrick J. Flynn,
Roscoe F. Morton,
Shaker R. Dakhil,
Howard Gross,
Scott H. Kaufmann
From the Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN; Scottsdale CCOP, Scottsdale, AZ; Carle Cancer Center CCOP, Urbana, IL; Metro-Minnesota Community Clinical Oncology Program, St Louis Park, MN; Iowa Oncology Research Association CCOP, Des Moines, IA; Wichita Community Clinical Oncology Program, Wichita, KS; and Hematology & Oncology of Dayton Inc, Dayton, OH
Address reprint requests to Thomas E. Witzig, MD, Mayo Clinic, Stabile 628, 200 First St SW, Rochester, MN 55905; e-mail: witzig{at}mayo.edu.
PURPOSE: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL.
PATIENTS AND METHODS: Patients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance.
RESULTS: Thirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week.
CONCLUSIONS: Single-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.
Supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-63826, CA-35195, CA-35267, CA-35101, CS-35431, CA-35090, CA-35113, CA-35415, CA-60276, CA-35448, and CA-63848, and grant CA97274 from the National Cancer Institute, Department of Heath and Human Services, Bethesda, MD.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Additional participating institutions include Medcenter One Health Systems, Bismarck, ND (Edward Wos, MD); Illinois Oncology Research Association CCOP, Peoria, IL (John W. Kugler, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (Paul L. Schaefer, MD); Scottsdale CCOP, Scottsdale, AZ (Tom R. Fitch, MD); Geisinger Clinic & Medical Center CCOP, Danville, PA (Albert Bernath, MD); and Ann Arbor Regional CCOP, Ann Arbor, MI (Philip J. Stella, MD).
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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