First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.
OBJECTIVE
This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors.


METHODS
Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed.


RESULTS
Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions.


CONCLUSIONS
Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days.
Authors' Affiliations: Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom; and 4SC AG, Planegg-Martinsried, Germany.
André T
AT
Brunetto
Joo Ern
JE
Ang
Rohit
R
Lal
David
D
Olmos
L Rhoda
LR
Molife
Rebecca
R
Kristeleit
Ann
A
Parker
Isabel
I
Casamayor
Muyibat
M
Olaleye
Anna
A
Mais
Bernhard
B
Hauns
Vera
V
Strobel
Bernd
B
Hentsch
Johann S
JS
de Bono
D000107:Acetylation; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; C550599:resminostat