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- Title
Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma.
- Authors
Harvey, R. Donald; Carthon, Bradley C.; Lewis, Colleen; Hossain, Mohammad S.; Zhang, Chao; Chen, Zhengjia; Harris, Wayne B.; Alese, Olatunji B.; Shaib, Walid; Bilen, Mehmet A.; Lawson, David H.; Wu, Christina; Steuer, Conor E.; El-Rayes, Bassel F.; Khuri, Fadlo R.; Lonial, Sagar; Waller, Edmund K.; Ramalingam, Suresh S.; Owonikoko, Taofeek K.
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers.<bold>Clinical Trial Registration: </bold>NCT01218555.
- Subjects
THERAPEUTIC use of antineoplastic agents; ADENOID cystic carcinoma; CYTOKINES; RESEARCH; DRUG dosage; RESEARCH methodology; ANTINEOPLASTIC agents; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; RESEARCH funding; TUMORS; DRUG toxicity
- Publication
British Journal of Cancer, 2020, Vol 123, Issue 8, p1228
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-0988-2