A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors Journal Article

Authors: Tse, A. N.; Klimstra, D. S.; Gonen, M.; Shah, M.; Sheikh, T.; Sikorski, R.; Carvajal, R.; Mui, J.; Tipian, C.; O'reilly, E.; Chung, K.; Maki, R.; Lefkowitz, R.; Brown, K.; Manova-Todorova, K.; Wu, N.; Egorin, M. J.; Kelsen, D.; Schwartz, G. K.
Article Title: A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors
Abstract: Purpose: Both heat shock protein 90 (Hsp90) and checkpoint kinase 1 (Chk1) have emerged as novel therapeutic targets. We conducted a phase I study of irinotecan and the Hsp90 inhibitor 17AAG, which can also down-regulate Chk1, in patients with solid tumors. Experimental Design: During the dose escalation phase, patients received i.v. irinotecan followed by 17AAG once weekly for 2 weeks in a 21-day cycle. At the maximum tolerated dose (MTD), additional patients were enrolled to undergo pre- and post-17AAG tumor biopsies for pharmacodynamic evaluation. The pharmacokinetics of irinotecan, 17AAG, and their metabolites were characterized. Tumor p53 status as determined by immunohistochemistry was correlated with antitumor activity. Results: Twenty-seven patients with a variety of solid tumors were enrolled. Four patients developed dose-limiting toxicity at dose level 4 (100 mg/m2 irinotecan and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The pharmacokinetics of 17AAG and its metabolite were not significantly affected by the coadministration of irinotecan, and vice versa. There was no partial response, although tumor shrinkage was observed in six patients. Five of 10 patients with p53-mutant tumor had stable disease as the best response compared with 2 of 6 patients with p53-wildtype tumor (P = 0.63). Evidence for Hsp90 inhibition by 17AAG, resulting in phospho-Chk1 loss, abrogation of the G2-M cell cycle checkpoint, and cell death could be shown in tumor biopsy samples obtained at the MTD. Conclusions: The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 irinotecan and 300 mg/m 217AAG. © 2008 American Association for Cancer Research.
Keywords: immunohistochemistry; clinical article; controlled study; human tissue; treatment outcome; treatment response; unclassified drug; gene mutation; clinical trial; fatigue; neutropenia; area under the curve; diarrhea; dose response; side effect; solid tumor; unspecified side effect; antineoplastic agent; neoplasm; neoplasms; controlled clinical trial; liver toxicity; multiple cycle treatment; anemia; leukopenia; nausea; neuropathy; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; dehydration; camptothecin; tumor biopsy; antineoplastic activity; drug screening; dose-response relationship, drug; protein p53; irinotecan; abdominal pain; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; lymphocytopenia; lung embolism; blood; drug antagonism; drug combination; drug therapy, combination; thromboembolism; drug derivative; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; cell cycle g2 phase; down regulation; alkaline phosphatase blood level; maximum tolerated dose; phase 1 clinical trial; drug metabolite; checkpoint kinase 1; bilirubin blood level; benzoquinones; lactams, macrocyclic; 17-(allylamino)-17-demethoxygeldanamycin; benzoquinone derivative; macrocyclic lactam
Journal Title: Clinical Cancer Research
Volume: 14
Issue: 20
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2008-10-15
Start Page: 6704
End Page: 6711
Language: English
DOI: 10.1158/1078-0432.ccr-08-1006
PUBMED: 18927314
PROVIDER: scopus
PMCID: PMC3996559
Notes: --- - "Cited By (since 1996): 26" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Gary Schwartz
    384 Schwartz
  2. Mithat Gonen
    912 Gonen
  3. Ki Y Chung
    43 Chung
  4. Archie Tse
    34 Tse
  5. Richard D Carvajal
    147 Carvajal
  6. Robert Maki
    215 Maki
  7. David S Klimstra
    967 Klimstra
  8. Karen T Brown
    178 Brown
  9. Manish Shah
    177 Shah
  10. Nian Wu
    32 Wu
  11. Eileen O'Reilly
    596 O'Reilly
  12. David P Kelsen
    511 Kelsen
  13. Janet Mui
    2 Mui
  14. Tahir N Sheikh
    9 Sheikh
  15. Caroll Cecilia Tipian
    2 Tipian