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Cancer Chemotherapy and Pharmacology

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01-05-2013 | Original Article

Open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of intravenously administered CNF1010 (17-(allylamino)-17-demethoxygeldanamycin [17-AAG]) in patients with solid tumors

Authors: M. W. Saif, C. Erlichman, T. Dragovich, D. Mendelson, D. Toft, F. Burrows, C. Storgard, D. Von Hoff

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2013

Abstract

Background

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG.

Methods

Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m²/day) and three-to-six-patient (≥25 mg/m²/day) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed.

Results

Thirty-five patients were treated at doses ranging from 6 to 225 mg/m². A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m²; shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m²; extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m²) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m², with a dose-proportional increase in C _max and AUC_0–inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses >83 mg/m².

Conclusion

The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.

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Title: Open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of intravenously administered CNF1010 (17-(allylamino)-17-demethoxygeldanamycin [17-AAG]) in patients with solid tumors
Authors: M. W. Saif
C. Erlichman
T. Dragovich
D. Mendelson
D. Toft
F. Burrows
C. Storgard
D. Von Hoff
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2134-9

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Abstract

Background

Methods

Results

Conclusion

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