Open AccessPhase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas
Author(s) -
Ajay Major,
Justin Kline,
Theodore Karrison,
Paul Fishkin,
Amy Kimball,
Adam M. Petrich,
Sreenivasa Nattam,
Krishna Rao,
Bethany Sleckman,
Kenneth S. Cohen,
Koen van Besien,
Aaron P. Rapoport,
Sonali M. Smith
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.278853
Subject(s) - temsirolimus , medicine , lenalidomide , follicular lymphoma , oncology , lymphoma , transplantation , cohort , phases of clinical research , everolimus , gastroenterology , clinical trial , multiple myeloma , pi3k/akt/mtor pathway , discovery and development of mtor inhibitors , chemistry , apoptosis , biochemistry
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 4 (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of 6 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 AEs were common. Three grade 5 AEs 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.