Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas

Ajay Major, Justin Kline, Theodore G Karrison, Paul A S Fishkin, Amy S Kimball, Adam M Petrich, Sreenivasa Nattam, Krishna Rao, Bethany G Sleckman, Kenneth Cohen, Koen van Besien, Aaron P Rapoport, Sonali M Smith, Ajay Major, Justin Kline, Theodore G Karrison, Paul A S Fishkin, Amy S Kimball, Adam M Petrich, Sreenivasa Nattam, Krishna Rao, Bethany G Sleckman, Kenneth Cohen, Koen van Besien, Aaron P Rapoport, Sonali M Smith

Abstract

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).

Figures

Figure 1.
Figure 1.
Waterfall plot for best response for evaluable patients in the phase II study by histology (n=74). Of the 93 patients in the phase II study, 8 patients did not complete 2 cycles of temsirolimus/lenalidomide (TEM/LEN) for pre-specified response assessment, 10 patients did not have reported response data, and 1 patient had Waldenström macroglobulinemia. DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; cHL: classical Hodgkin lymphoma; T-NHL: non-Hodgkin lymphoma; MZL: marginal zone leukemia; MCL: mantle cell lymphoma.
Figure 2.
Figure 2.
Swimmer’s plot for patients in the diffuse large B-cell lymphoma (n=39) and classical Hodgkin lymphoma (n=20) cohorts. The plot includes treatment duration, duration of follow-up, best responses, time of progression, reason for treatment discontinuation, and time of subsequent transplantation. DLBCL: diffuse large B-cell lymphoma.
Figure 3.
Figure 3.
Kaplan-Meier curves for progression-free survival, overall survival and duration of response in the diffuse large B-cell lymphoma (n=39) and exploratory cohorts (n=39). The duration of response curves are based on 10 and 25 responders, respectively. DLBCL: diffuse large B-cell lymphoma.
Figure 4.
Figure 4.
Kaplan-Meier curves for progression-free survival, overall survival and duration of response for the classical Hodgkin lymphoma patients (n=20) in the exploratory cohort. The duration of response curve is based on 16 responders.

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