Abstract

Abstract 2955

Introduction:

Deacetylase (DAC) inhibitors show promise as anti-neoplastic agents, the approved drugs are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have suboptimal activity or unacceptable toxicities. AR-42 is a class I/II DAC-I designed at OSU that demonstrates a 20,000-fold improvement in DAC inhibitory potency relative to the parent molecule (IC50=16 nM) with greater antiproliferative effects than Vorinostat in vitro and in vivo (Kulp et al, Clin Cancer Res, 2006 and Lucas et al, PLoS One, 2010).

Methods:

OSU 09102 (NCI 9119) is a first-in-man single agent, cohorts-of-3 phase I dose escalation study in adult patients with relapsed CLL, lymphoma (NHL), or multiple myeloma (MM) with normal kidney and liver function. Patients received AR-42 orally M-W-F in cycles of 28 days (3 weeks of 3-times-per-week dosing followed by a 7-day break). Moderate cell count suppression was allowed with an absolute neutrophil cutoff of 1000/μL, platelets 3 50,000/μL and hemoglobin 3 10 g/dL. In the first stage of dose escalation, each dose level increased by 100% until the first grade 2, drug-related toxicity was observed. Subsequent dose increases will be approximately 33% increase with accrual in cohorts of 3 patients. For pharmacokinetic analysis, plasma was obtained at 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 4, 8, 10, 24, and 48 hours after dosing on day 1 and day 19 (only up to 24 h), and then kept at –80°C until analysis.

Results:

We enrolled 3 patients at 20 mg (MM, MM, NHL), 3 patients at 40 mg (MM) with a transition to a slower dose escalation due to a grade 2 thrombocytopenia. Three more patients were enrolled at 40 mg (MM, MM, T-cell NHL), then 7 patients at 50 mg (MM × 4, follicular × 1, T-cell NHL × 2). One myeloma patient was enrolled at 70 mg. In the 40 mg cohort, related toxicities include 2 grade 3 and 2 grade 2 thrombocytopenia, 1 grade 3 neutropenia, 1 grade 2 vomiting, and 2 grade 1 QTc prolongation. In the 50 mg cohort 1 grade 4 and 3 grade 3 thrombocytopenia, 2 grade 3 neutropenia, 4 grade 2 fatigue, 2 grade 2 muscle spasm, 1 grade 2 blurred vision/dizziness, 3 grade 1 QTc prolongation, and 3 grade 1 nausea. Accrual was temporarily halted for a safety analysis Mar-2012 focused on the 50 mg cohort toxicities – one grade 4 thrombocytopenia considered a DLT, one patient found dead on cycle 2 day 10 without prior evidence of QTc prolongation, and one patient with reproducible dizziness and blurry vision. AR-42 was detected 15 mins after dose in 12 of 17 patients, suggesting rapid absorption. The time to reach the peak concentration in plasma (Tmax) varied from 1.5 hours to 4 hours. The Cmax (see chart) and AUC of AR-42 was not increased proportionally with doses, suggesting that the PK of AR-42 is not linear in the 20–50 mg range.

Conclusion:

The Cmax achieved at the 40 mg and 50 mg dose levels is adequate for HDAC inhibition in vitro and minor clinical responses were observed in myeloma and T-cell lymphoma as a single agent in the 40 mg cohort (see monoclonal proteins chart), hence 40 mg TIW 3-weeks-on and 1-week-off was declared the MTD. Complete pharmacokinetic, toxicity, and results from brief fatigue inventory will be presented at the meeting. AR-42 does not have the severe fatigue and gastrointestinal side effects of other broad DAC inhibitors and may be suitable for combination phase Ib trials in T-cell lymphoma and myeloma.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.