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|Ref Type||Journal Article|
|Authors||Speranza G, Anderson L, Chen AP, Do K, Eugeni M, Weil M, Rubinstein L, Majerova E, Collins J, Horneffer Y, Juwara L, Zlott J, Bishop R, Conley BA, Streicher H, Tomaszewski J, Doroshow JH, Kummar S|
|Title||First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile.|
|Journal||Investigational new drugs|
|Date||2017 Aug 12|
|Abstract Text||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 (T1/2) 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/m2/day), with no dose limiting toxicities.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|PU-H71||NSC 750424|PUH71|PU H71||HSP90 Inhibitor 35||PU-H71 selectively inhibits Heat shock protein 90 (Hsp90), resulting in increased proteosomal degradation of oncogenic client proteins and potentially leading to decreased tumor growth (PMID: 28808818, PMID: 32156599).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||PU-H71||Phase I||Actionable||In a Phase I trial, treatment with PU-H71 was generally well-tolerated, and resulted in stable disease as best response in 35% (6/14) patients with advanced solid tumors (PMID: 28808818; NCT01581541).||28808818|