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

Autor: Michael Lam, Philip J. Hogg, David Edmonds, Lisa G. Horvath, Jayesh Desai, Peter Grimison, Anne Hamilton, Peter Savas, Sunit Sarkar, Danny Rischin, James R. Whittle, Ben Tran, Nicole Signal, James C Kuo
Rok vydání: 2021
Předmět:
Zdroj: Cancer Chemotherapy and Pharmacology. 87:613-620
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-020-04225-7
Popis: 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. 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. 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. 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.
Databáze: OpenAIRE
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