Phase 4 Trial to Compare Efficacy, Tolerability of Temsirolimus With and Without Elevated Starting Dose in Mantle Cell Lymphoma

CHICAGO—A Phase 3 study of temsirolimus showed significantly longer progression-free survival (PFS) in patients with relapsed, refractory mantle cell lymphoma (MCL). Investigators Georg Hess, MD, Johannes Gutenberg University, Mainz, Germany, and colleagues now want to determine via a Phase 4 trial if that efficacy can be maintained while minimizing the high incidence of adverse events associated with the 175mg starting dose used in the earlier study by eliminating the starting dose, according to information presented at the American Society of Clinical Oncology’s 2011 Annual Meeting. 

In the randomized Phase 3 study,1 patients with relapsed, refractory MCL were treated with temsirolimus 175mg IV for the first 3 weeks followed by 75mg weekly (175/75). The study participants had significantly longer progression-free survival (PFS) compared with those receiving investigator’s choice of therapy. However, the starting dose of 175mg was associated with a higher incidence of adverse events relative to investigator’s choice and to that observed with temsirolimus at lower doses. These included thrombocytopenia, asthenia, anemia, diarrhea, fever, anorexia, mucositis, epistaxis, and rash.

In this global, multicenter, open-label study, which began recruitment in January 2011, patients with relapsed, refractory MCL who received two to seven prior therapies—which may include hematopoietic stem cell transplant—are eligible for enrollment. Patients are randomized (1:1) to receive temsirolimus 175/75 or 75mg weekly and are stratified by histologic subtype (blastoid vs. nonblastoid vs. unknown histology). The primary endpoint is PFS based on independent tumor assessments; the hazard ratio comparing PFS for the two dosages will be estimated using an unstratified Cox regression model. Planned sample size is 100 patients from 50 sites worldwide.

Secondary endpoints are overall survival, objective response rate (independent and investigator assessed), investigator-assessed PFS, and safety. Exploratory analyses will examine duration of response to time to tumor progression (independent and investigator assessed) and pharmacodynamic relationship between cyclin D1 overexpression and activity. The pharmacokinetic drug interaction component of the study will use a nonrandomized one-sequence, two-treatment design in which the first period is a lead-in to the randomized study. All patients will receive oral desipramine 50mg, a P450 2D6 probe substrate, one week prior to treatment (first period) and approximately 30 minutes prior to the first dose (second period) of temsirolimus to quantify the potential of temsirolimus to alter the disposition of desipramine.

The study is expected to be completed in approximately 3.5 years, with the last follow-up visit of the last patient.


1. Hess G, Herbrecht R, Romaguera J, et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9.