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Phase I and Pharmacodynamic Study of 17-(Allylamino)-17-Demethoxygeldanamycin in Adult Patients with Refractory Advanced Cancers

Authors' Affiliations: ¹ Division of Hematology/Oncology, Department of Medicine and ² Department of Pharmacology, University of Pittsburgh School of Medicine; ³ Molecular Therapeutics/Drug Discovery Program and ⁴ Biostatistics Department, University of Pittsburgh Graduate School of Public Health and Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁵ Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Ramesh K. Ramanathan, University of Pittsburgh Medical Center Cancer Pavilion, #562, 5150 Centre Avenue, Pittsburgh, PA 15232. Phone: 412-648-6507; Fax: 412-648-6579; E-mail: ramanathanrk{at}upmc.edu.

Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week.

Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m² and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m². Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins.

Results: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m², DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m² developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2.

Conclusions: The recommended phase II doses of 17AAG are 175 to 200 mg/m² when given twice a week and consistently cause elevations in PBMC HSP70.

Commentary

Targeting the Molecular Chaperone Heat Shock Protein 90 Provides a Multifaceted Effect on Diverse Cell Signaling Pathways of Cancer Cells

Wanping Xu and Len Neckers
Clin. Cancer Res. 2007 13: 1625-1629. [Full Text] [PDF]

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