A first in human phase I study of JNJ26481585, a novel oral histone deacetylase inhibitor (HDACi), in patients with advanced solid tumours: early evidence of anti-tumour activity


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AT Brunetto1, R Kristeleit1, D Tan1, T Yap1, S Alam1, S Dolly1, D Olmos1, P Fong1, R Molife1, T Harris1, L Van Besterveldt2, N Fourneau2, P Hellemans2, J De-Bono1, B Venugopal3, J Evans3

1 Royal Marsden Hospital, London, UK, 2Johnson & Johnson Pharmaceuticals, Beerse, Belgium, 3The Beatson Institute, Glasgow, UK

Abstract

Background

JNJ26481585 is a novel orally active pan-HDACi which showed potent anti-tumour activity in a wide range of pre-clinical models.

Method

JNJ26481585 was administered orally, once daily in 3-weekly cycles to patients (pts) with advanced refractory solid tumours in a 2-stage accelerated titration design Phase I trial. Primary objectives were to determine safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of JNJ26481585. Secondary objectives investigated food effect on PK, anti-tumour activity and pharmacodynamic effects in surrogate and tumour tissue.

Results

15 patients have been enrolled and treated with JNJ-26481585 (QD) at 4 dose levels (DL): 2mg (N=2), 4mg (N=2), 8mg (N=8), 12mg (N=3); and expansion is ongoing at 8mg. Dose limiting toxicity (DLT) at 12mg: G2 non-sustained ventricular tachycardia (VT) and G3 fatigue; DLT at 8mg: G1 non-sustained polymorphic VT. Other G2 toxicities observed at 8 and 12mg included palpitations with QT prolongation, anorexia, fatigue, vomiting, dysgeusia and INR increase (patient on warfarin). The 2-4 mg DL were well tolerated. Exposure to JNJ26481585 increased proportionally over the 2 to 12mg dose range, with a constant metabolite/parent ratio (3.5 for Cmax; 7 for AUC). After food intake: Cmax tended to be lower but AUC was not significantly affected. Two partial responses in melanoma (12mg), one clinical response in melanoma (8mg) and one prolonged stable disease in NSCLC (4mg) have been observed. Biomarker assessment is ongoing and will be updated at presentation.

Conclusion

Promising anti-tumour activity has been observed in melanoma with 2 PR and one clinical response. Ongoing expansion at 8mg and intermittent schedules are under evaluation to improve long-term tolerability. The adverse event profile observed with JNJ-26481585 in this study is comparable with other hydroxamate HDACi.