First-in-man trial of 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO) as a continuous intravenous infusion (CIVI), in patients (pt) with advanced solid tumours.
2016; Lippincott Williams & Wilkins; Volume: 34; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2016.34.15_suppl.e14025
ISSN1527-7755
AutoresBen Tran, Anne Hamilton, Lisa G. Horvath, Michael Lam, Peter Savas, Peter Grimison, James R. Whittle, James Kuo, Nicole Signal, David J. Edmonds, Philip J. Hogg, Danny Rischin, Jayesh Desai,
Tópico(s)Drug-Induced Ocular Toxicity
Resumoe14025 Background: PENAO is an organic arsenical with anti-mitochondrial activity mediated by covalent inhibition of adenine nucleotide translocase (ANT). In vitro studies identified potential activity of continuous drug exposure at 1-10µM PENAO (or equivalent arsenic (As) atoms), most evident in central nervous system (CNS) tumours. Renal inflammation was the only significant toxicity in rodents, and murine half life (t½) was 37 minutes. Methods: Eligibility criteria included age ≥ 18, advanced solid tumour, PS ≤ 1, GFR ≥ 75mL/min, normal cardiac function, adequate haematological and biochemical function, and informed consent. Central IV lines and CADD pumps were used. Dose levels initially increased infusion duration (4-21 days), then daily dose, in a 21-day cycle, with weekly pump cassette changes. Standard cycle 1 dose limiting toxicities (DLT) definitions were used in a “3&3” phase I design. Pt were reviewed weekly, with regular monitoring of toxicity and efficacy. Pharmacokinetic (PK) assays of serum and urine As were performed. Results: 27 pt were accrued to 8 dose levels. All pt discontinued treatment due to progressive disease. 1 DLT (fatigue) was observed at 9mg/m2/day. Another pt had rash and transient liver dysfunction immediately after discontinuation of the drug at 6mg/m2/day. No significant organ toxicity was observed. One pt with anaplastic astrocytoma had stable disease at 6mg/m2/day over 10 cycles (30 weeks). PK unexpectedly indicated t½ of 3-4 days in humans. The study was discontinued before a recommended phase II dose was defined, as study drug supply was close to expiration, and the PK findings warranted exploration of more convenient dosing schedules. Conclusions: PENAO can be given safely as an uninterrupted CIVI at 6mg/m2/day. 1 DLT (fatigue) was seen in 1 of 2 pts treated at 9mg/m2/day. The sponsor aims to explore the drug further in a phase 1B trial of an intermittent dosing schedule, in patients with CNS tumours. Clinical trial information: ACTRN12612000908831.
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