Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma

• Type of Material: Article
• Authors: R Donald Harvey, Emory University; Bradley Carthon, Emory University; Colleen Lewis, Emory University; Mohammad Hossain, Emory University; Chao Zhang, Emory University; Zhengjia Chen, Emory University; Wayne Harris, Emory University; Olatunji Alese, Emory University; Walid Shaib, Emory University; Mehmet Bilen, Emory University; David H Lawson, Emory University; Christina Wu, Emory University; Conor Steuer, Emory University; Bassel El-Rayes, Emory University; Fadlo Khuri, Emory University; Sagar Lonial, Emory University; Edmund Waller, Emory University; Suresh Ramalingam, Emory University; Taofeek Owonikoko, Emory University
• Language: English
• Date: 2020-07-24
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s), under exclusive licence to Cancer Research UK 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41416-020-0988-2
• Title of Journal or Parent Work: BRITISH JOURNAL OF CANCER
• Volume: 123
• Issue: 8
• Start Page: 1228
• End Page: 1234
• Grant/Funding Information: This work was supported by Celgene Inc. with funding and free supply of lenalidomide and by Novartis Oncology with free supply of everolimus. Additional support in part by NIH/NCI 5K23CA164015 grant award (PI: T.K.O.). Research reported in this publication was also supported, in part, by the Biostatistics and Bioinformatics Shared resource of Winship Cancer Institute of Emory University and National Cancer Institute at the National Institutes of Health under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: MULTICENTER; MULTIPLE-MYELOMA; Life Sciences & Biomedicine; RAPAMYCIN; COMBINATION; MTOR INHIBITOR; MAMMALIAN TARGET; II TRIAL; T-CELLS; Oncology; E3 UBIQUITIN LIGASE; Science & Technology; CANCER
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Background: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. Methods: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. Results: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. Conclusions: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. Clinical Trial Registration: NCT01218555