Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study

Giovanni Lo Re, Davide A. Santeufemia, Francesco Lo Re, Roberto Bortolus, Paolo Doretto, Wally Marus, Lorenzo Buttazzi, Oliviero Lenardon, Alessandra Falda, Rita Piazza, Sandro Sulfaro

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. Methods: Three chronomodulation schedules (5:00–13:00, 13:00–21:00, and 21:00–5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). Results: Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00–13:00, 15 at 13:00–21:00, and 13 at 21:00–5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2–107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1–2), MSKCC score (0–2 vs. ≥ 3), IMDC risk score (0–2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. Conclusion: IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

Original languageEnglish
Article number154984
Number of pages7
JournalCytokine
Volume128
DOIs
Publication statusPublished - Apr 2020

Keywords

  • Chrono-infusion
  • Interleukin-2
  • Metastatic renal cancer
  • Programmated death 1 antibody
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

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