A phase 1 trial of 4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid (PENAO) in patients with advanced solid tumours

A phase 1 trial of 4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid (PENAO) in patients with advanced solid tumours.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1007/s00280-020-04225-7
Journal or Publication Title: Cancer Chemotherapy and Pharmacology
Volume: 87
Number: 5
Page Range: pp. 613-620
Date: 2021
Divisions: ACRF Centenary Cancer Research Centre
Depositing User: General Admin
Identification Number: 10.1007/s00280-020-04225-7
ISSN: 0344-5704
Date Deposited: 10 Jun 2021 06:10

Purpose: This phase I study was conducted to evaluate the safety and Maximum Tolerated Dose of PENAO (4-(N-(S-penicillaminylacetyl)amino)-phenylarsonous acid), a second-generation organic arsenical with anti-mitochondrial activity, when given as a continuous intravenous infusion (CIVI), in patients with advanced solid tumours.

Methods: Eligibility criteria for this trial included age ≥ 18 years, advanced solid tumour, ECOG Performance Status ≤ 1 and adequate organ function. PENAO was administered by CIVI, with dose levels initially increased by infusion duration in a 21-day cycle at a fixed daily dose and then increased daily dose. Standard dose-limiting toxicity (DLT) definitions were used in a "3 + 3" design. Patients had regular monitoring of toxicity and efficacy. Pharmacokinetic assays of serum and urine As were performed.

Results: Twenty-six patients were treated across 8 dose levels. The only dose-limiting toxicity (DLT) observed was fatigue, that occurred in one patient treated at the highest dose level of 9 mg/m2/day. No significant organ toxicity or objective responses were observed, although there were two patients with stable disease lasting up to 7 months. Pharmacokinetic analysis unexpectedly indicated a half-life of 9-19 days, invalidating the CIVI dosing resulting in discontinuation of the study before the RP2D was defined.

Conclusions: PENAO was administered by CIVI at dose levels up to 9 mg/m2/day with only one DLT noted. Pharmacokinetic studies invalidated the rationale for continuous dosing and led to discontinuation of the trial without defining a RP2D. Future clinical development of PENAO will use intermittent dosing schedule, alone and in combination with rapamycin.

Sarkar, Sunit
Tran, Ben
Horvath, Lisa
Lam, Michael
Savas, Peter
Grimison, Peter
Whittle, James R.
Kuo, James C.
Signal, Nicole
Edmonds, David
Hogg, Philip
Rischin, Danny
Desai, Jayesh
Hamilton, Anne
Last Modified: 10 Jun 2021 06:10
URI: https://eprints.centenary.org.au/id/eprint/1038

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