Details

Autor(en) / Beteiligte

• Speranza, Giovanna
• Anderson, Larry
• Chen, Alice P.
• Do, Khanh
• Eugeni, Michelle
• Weil, Marcie
• Rubinstein, Larry
• Majerova, Eva
• Collins, Jerry
• Horneffer, Yvonne
• Juwara, Lamin
• Zlott, Jennifer
• Bishop, Rachel
• Conley, Barbara A.
• Streicher, Howard
• Tomaszewski, Joseph
• Doroshow, James H.
• Kummar, Shivaani

Titel

First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile

Ist Teil von

• Investigational new drugs, 2018-04, Vol.36 (2), p.230-239

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2018

Link zum Volltext

Quelle

SpringerLink Journals

Beschreibungen/Notizen

• Summary 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 1/2 ) 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 2 /day), with no dose limiting toxicities.