First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors

Abstract

Purpose: 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.

Experimental design: 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.

Figure 1a

Box plots of HDAC enzyme inhibition at 5 hours post-dose in PBMC after single dose of resminostat on C1D1; dose levels 100 mg to 600 mg: N=3 each, 800 mg dose level: N=6. The lower and upper boundaries of each box define the 25th and 75th percentiles; the horizontal line in each box indicates the median; and the bars define the lowest and highest values, excluding outliers.

Figure 1b

Box plots of median fold increase in histone H4 acetylation in PBMC after single dose of resminostat on C1D1; maximum fold increase of histone acetylation was chosen for each patient. Dose levels 100 mg to 600 mg: N=3 each, 800 mg dose level: N=6. The lower and upper boundaries of each box define the 25th and 75th percentiles; the horizontal line in each box indicates the median; and the bars define the lowest and highest values, excluding outliers.

Figure 2

A 42 year old female patient with mediastinal thymoma (Masaoka stage IV, extensive pleural based deposit pointed to by arrow) who received 3 previous lines of systemic therapy remained on study for 19 cycles with evidence of tumor shrinkage (SD by RECIST). In CT-based assessments, target lesions at baseline (panel A) included a large tumor at the right lung base involving the diaphragmatic pleural surface and a right pulmonary horizontal fissure nodule which reduced in size after 4 treatment cycles (panel B). In addition, the conglomerate of nodular lesions in the right lung decreased in size with a reduction in the degree of pulmonary infiltrates (non-target lesions within encircled regions).