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A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma

  • Clinical Trial Report
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Abstract

Purpose

Preclinical activity of irinotecan has been seen in glioma models, but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, irinotecan liposome injection (nal-IRI) results in prolongation of drug exposure and higher tissue levels of drug due to slower metabolism and the effect of enhanced permeability and retention. The objective of the current study was to assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent high-grade glioma stratified based on UGT1A1 genotyping.

Methods

This phase I study stratified patients with recurrent high-grade glioma into 2 groups by UGT1A1 status: homozygous WT (“WT”) vs heterozygous WT/*28 (“HT”). Patients who were homozygous *28 were ineligible. The design was a standard 3 + 3 phase I design. WT patients were started at 120 mg/m2 intravenously every 3 weeks with dose increases in 60 mg/m2 increments. HT patients were started at 60 mg/m2, with dose increases in 30 mg/m2 increments. The assessment period for dose-limiting toxicity was 1 cycle (21 days).

Results

In the WT cohort (n = 16), the MTD was 120 mg/m2. In the HT cohort (n = 18), the MTD was 150 mg/m2. Dose-limiting toxicity in both cohorts included diarrhea, some with associated dehydration and/or fatigue. PK results were comparable to those seen in other PK studies of nal-IRI; UGT1A1*28 genotype (WT vs. HT) did not affect PK parameters.

Conclusions

Nal-IRI had no unexpected toxicities when given intravenously. Of note, UGT1A1 genotype did not correlate with toxicity or affect PK profile.

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Acknowledgements

The authors would like to thank Ms. Ilona Garner (UCSF) for her expert assistance with manuscript preparation and editing.

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Authors and Affiliations

  1. Division of Neuro-oncology, Department of Neurological Surgery, University of California, San Francisco (UCSF), 505 Parnassus Avenue M779, San Francisco, CA, 94143, USA

    Jennifer L. Clarke, Annette M. Molinaro, Juan R. Cabrera, Ashley A. DeSilva, Jane E. Rabbitt, Susan M. Chang, Nicholas A. Butowski, Jennie W. Taylor & Michael D. Prados

  2. Department of Neurology, University of California, San Francisco, 400 Parnassus Avenue, San Francisco, CA, 94122, USA

    Jennifer L. Clarke & Jennie W. Taylor

  3. Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Joshua Prey

  4. Merrimack Pharmaceuticals, One Kendall Square, 1 Kendall Square B7201, Cambridge, MA, 02139, USA

    Daryl C. Drummond, Jaeyeon Kim, Charles Noble & Jonathan B. Fitzgerald

  5. Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St., San Francisco, CA, 94115, USA

    John W. Park

Authors
  1. Jennifer L. Clarke
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  2. Annette M. Molinaro
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  3. Juan R. Cabrera
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  4. Ashley A. DeSilva
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  5. Jane E. Rabbitt
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  6. Joshua Prey
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  7. Daryl C. Drummond
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  8. Jaeyeon Kim
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  9. Charles Noble
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  10. Jonathan B. Fitzgerald
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  11. Susan M. Chang
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  12. Nicholas A. Butowski
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  13. Jennie W. Taylor
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  14. John W. Park
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  15. Michael D. Prados
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Corresponding author

Correspondence to Jennifer L. Clarke.

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Funding

This clinical trial was funded by the UCSF Brain Tumor Research Center’s Specialized Program of Research Excellence (SPORE) Grant from the NCI: P50 CA097257.

Conflict of interest

Daryl C. Drummond is both an employee and stockholder in Merrimack, and is the inventor of Onivyde (liposomal irinotecan). Jonathan B. Fitzgerald is an employee of Merrimack. Charles Noble is a stockholder in Merrimack.

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Clarke, J.L., Molinaro, A.M., Cabrera, J.R. et al. A phase 1 trial of intravenous liposomal irinotecan in patients with recurrent high-grade glioma. Cancer Chemother Pharmacol 79, 603–610 (2017). https://doi.org/10.1007/s00280-017-3247-3

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  • DOI: https://doi.org/10.1007/s00280-017-3247-3

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