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First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile.
- Source :
-
Investigational new drugs [Invest New Drugs] 2018 Apr; Vol. 36 (2), pp. 230-239. Date of Electronic Publication: 2017 Aug 12. - Publication Year :
- 2018
-
Abstract
- Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T <subscript>1/2</subscript> ) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m <superscript>2</superscript> /day), with no dose limiting toxicities.
- Subjects :
- Adult
Aged
Benzodioxoles administration & dosage
Benzodioxoles adverse effects
Benzodioxoles blood
Dose-Response Relationship, Drug
Female
Humans
Male
Metabolome
Middle Aged
Purines administration & dosage
Purines adverse effects
Purines blood
Treatment Outcome
Young Adult
Benzodioxoles pharmacokinetics
Metabolomics
Molecular Chaperones metabolism
Purines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 36
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 28808818
- Full Text :
- https://doi.org/10.1007/s10637-017-0495-3