Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 4, pp 1089–1097

A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors

  • Gopa Iyer
  • Michael J. Morris
  • Dana Rathkopf
  • Susan F. Slovin
  • Macaulay Steers
  • Steven M. Larson
  • Lawrence H. Schwartz
  • Tracy Curley
  • Anthony DeLaCruz
  • Qing Ye
  • Glenn Heller
  • Merrill J. Egorin
  • S. Percy Ivy
  • Neal Rosen
  • Howard I. Scher
  • David B. Solit
Clinical Trial Report

Abstract

Purpose

To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.

Experimental design

Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m2. 17-AAG was administered over 1–2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m2 in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.

Results

Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m2-17-AAG 650 mg/m2 due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.

Conclusions

The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m2 and 17-AAG 500 mg/m2.

Keywords

17-AAG Geldanamycin Hsp90 Docetaxel Phase I 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Gopa Iyer
    • 1
  • Michael J. Morris
    • 1
  • Dana Rathkopf
    • 1
  • Susan F. Slovin
    • 1
  • Macaulay Steers
    • 1
  • Steven M. Larson
    • 2
  • Lawrence H. Schwartz
    • 3
  • Tracy Curley
    • 1
  • Anthony DeLaCruz
    • 1
  • Qing Ye
    • 4
  • Glenn Heller
    • 5
  • Merrill J. Egorin
    • 7
  • S. Percy Ivy
    • 8
  • Neal Rosen
    • 1
    • 4
  • Howard I. Scher
    • 1
  • David B. Solit
    • 1
    • 6
  1. 1.Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of Nuclear MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of RadiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Department of Molecular Pharmacology and ChemistryMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.Department of BiostatisticsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  6. 6.The Human Oncology and Pathogenesis ProgramMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  7. 7.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh School of MedicinePittsburghUSA
  8. 8.Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and CentersNational Cancer InstituteBethesdaUSA

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