According to the results of a phase 1/2 study, combination therapy with the mTOR inhibitor temsirolimus and the immunomodulatory agent lenalidomide (TEM/LEN) was feasible and demonstrated activity in heavily pretreated lymphomas, including relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL).

The open-label, multicenter, phase 1/2 study (ClinicalTrials.gov identifier: NCT01076543) accrued patients with R/R Hodgkin and non-Hodgkin lymphomas between 2010 and 2015 for evaluation of TEM/LEN combination therapy. Dosing was established in the phase I study, and primary endpoints of the phase 2 study were rates of complete response (CR) and overall response (ORR).

The phase 1 component of the study included 18 patients (13 male and 5 female), with a median age of 62 years (range, 41-80). Of those, 15 were evaluable for dose-limiting toxicity (DLT). At dose level 1 (TEM 25 mg/LEN 15 mg), a single DLT occurred (grade [Gr] 4 hypokalemia); while at dose level 3 (TEM 25 mg/LEN 25 mg), 2 DLTs occurred (Gr 3 diarrhea and Gr 3 HSV mucositis). Thus, dose level 2 of TEM 25 mg (intravenous) weekly and LEN 20 mg (oral) on days 1-21 every 28 days was established as the recommended phase II dosage.


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The phase 2 component of the study enrolled 93 patients (62 males and 31 females), who were divided into three cohorts: diffuse large B-cell lymphoma (DLBCL; n=39), follicular lymphoma (FL; n=15), and an exploratory cohort of other lymphoma histologies, including 20 patients with cHL (n=39 total, n=20 with cHL). Overall, the median age of 57 years (range, 23-78). Patients were heavily pretreated (median number of prior therapies, 4; range, 1-14), and one-third had relapse after autologous stem cell transplantation (ASCT).

For the DLBCL and exploratory cohorts, the ORRs were 26% (with a CR of 13%) and 64% (with a CR of 18%), respectively. The FL cohort closed prematurely due to slow accrual; the ORR was 47% (with a CR of 33%).

A subgroup analysis was conducted for the patients with cHL within the exploratory cohort; notably, most of these patients had relapsed following both brentuximab vedotin (95%) and ASCT (75%). The patients with cHL had an ORR was 80% (with CR of 35%). Following TEM/LEN therapy, 8 cHL patients (40%) underwent to allogeneic transplantation.

Grade ≥3 hematologic adverse events (AEs) were common and included anemia (n=27), lymphopenia (n=39), neutropenia (n=43), thrombocytopenia (n=40), and

leukocytosis (n=37). Grade 3 or 4 non-hematologic AEs were uncommon; only fatigue occurred in greater than 10% of patients (12%). Grade 5 AEs that were possibly related to TEM/LEN occurred in 3 patients (colonic perforation, myocardial infarction, and sepsis).

“Overall, the combination of TEM/LEN demonstrated encouraging activity in a heavily pretreated group of patients with relapsed and refractory cHL, and could be a platform for future investigations,” the authors concluded in their report.

Reference Major A, Kline J, Karrison TG, et al. Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas. Haematologica. Published online July 29, 2021. doi:10.3324/haematol.2021.278853