Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer Journal Article


Authors: Solit, D. B.; Ivy, S. P.; Kopil, C.; Sikorski, R.; Morris, M. J.; Slovin, S. F.; Kelly, W. K.; Delacruz, A.; Curley, T.; Heller, G.; Larson, S.; Schwartz, L.; Egorin, M. J.; Rosen, N.; Scher, H. I.
Article Title: Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer
Abstract: Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily × 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily × 5 schedule; 112 mg/m2 on the daily × 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily × 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies. © 2007 American Association for Cancer Research.
Keywords: protein kinase b; adult; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; unclassified drug; oncoprotein; clinical trial; constipation; disease course; fatigue; neutropenia; hepatitis; raf protein; advanced cancer; diarrhea; dose response; drug safety; drug withdrawal; nonhuman; side effect; solid tumor; antineoplastic agents; follow up; antineoplastic agent; neoplasm; neoplasms; biological marker; metabolism; melanoma; controlled clinical trial; liver toxicity; multiple cycle treatment; pharmacodynamics; phase 2 clinical trial; breast cancer; anemia; leukopenia; lung non small cell cancer; nausea; thrombocytopenia; vomiting; myalgia; pathology; dose-response relationship, drug; bladder cancer; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; dyspnea; fever; prostate cancer; dimethyl sulfoxide; blood sampling; head and neck cancer; disease progression; drug clearance; down regulation; thyroid cancer; seizure; maximum plasma concentration; time to maximum plasma concentration; heat shock protein 70; maximum tolerated dose; phase 1 clinical trial; drug dose titration; drug half life; kidney cancer; heat shock response; benzoquinones; lactams, macrocyclic; plasma concentration-time curve; hsp70 heat-shock proteins; 17-(allylamino)-17-demethoxygeldanamycin; benzoquinone derivative; macrocyclic lactam; heat shock protein; oncogene protein v-akt; 17 allylamino 17 demethoxygeldanamycin; acute abdomen
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 6
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-03-15
Start Page: 1775
End Page: 1782
Language: English
DOI: 10.1158/1078-0432.ccr-06-1863
PUBMED: 17363532
PROVIDER: scopus
PMCID: PMC3203693
DOI/URL:
Notes: --- - "Cited By (since 1996): 102" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Glenn Heller
    291 Heller
  2. Neal Rosen
    356 Rosen
  3. Susan Slovin
    184 Slovin
  4. Michael Morris
    274 Morris
  5. William K Kelly
    108 Kelly
  6. David Solit
    431 Solit
  7. Lawrence H Schwartz
    281 Schwartz
  8. Steven M Larson
    762 Larson
  9. Howard Scher
    816 Scher
  10. Catherine M Kopil
    2 Kopil