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Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas.

ABSTRACT: PURPOSE:Batracylin (daniquidone), an ATP-insensitive topoisomerase I/II inhibitor, demonstrated wide interspecies variation in preclinical models consistent with formation of a toxic metabolite, N-acetyl-batracylin, following metabolism by N-acetyl-transferase 2 (NAT2). To minimize exposure to this toxic metabolite, this first-in-human study was conducted in patients with advanced refractory solid tumors or lymphomas demonstrated to have a slow NAT2 acetylator genotype. The objectives were to determine the safety, maximum tolerated dose (MTD), and pharmacokinetics of batracylin and its metabolites. METHODS:Based on the MTD for rats, the most sensitive species, the starting dose was 5 mg/day for 7 days in 28-day cycles. Dose escalation followed accelerated titration design 4B, with restaging performed every 2 cycles. RESULTS:Thirty-one patients were enrolled. Treatment was well tolerated; one patient experienced grade 3 toxicity (lymphopenia). Dose escalation was stopped at 400 mg/day due to grade 1 and 2 hemorrhagic cystitis. No objective responses were observed, but prolonged disease stabilization was observed in 2 patients, one with peritoneal mesothelioma (8 cycles) and another with adrenocortical cancer (18 cycles). Across an 80-fold range of doses, the ratios of systemic exposures for batracylin and N-acetyl batracylin were near 1. CONCLUSIONS:Pharmacogenetically selected patients reached a dose that was 20-fold higher than the MTD in rats and 70 % of the MTD in mice. This genotype-guided strategy was successful in safely delivering batracylin to patients. However, due to unexpected cystitis, not preventable by hydration, and in the absence of a stronger signal for antitumor activity, further development of batracylin has been stopped.

SUBMITTER: Kummar S

PROVIDER: S-EPMC7534863 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas.

Kummar Shivaani S Gutierrez Martin E ME Anderson Lawrence W LW Klecker Raymond W RW Chen Alice A Murgo Anthony J AJ Doroshow James H JH Collins Jerry M JM

Cancer chemotherapy and pharmacology 20130803 4

<h4>Purpose</h4>Batracylin (daniquidone), an ATP-insensitive topoisomerase I/II inhibitor, demonstrated wide interspecies variation in preclinical models consistent with formation of a toxic metabolite, N-acetyl-batracylin, following metabolism by N-acetyl-transferase 2 (NAT2). To minimize exposure to this toxic metabolite, this first-in-human study was conducted in patients with advanced refractory solid tumors or lymphomas demonstrated to have a slow NAT2 acetylator genotype. The objectives we ...[more]

PMID: 23912694

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Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas.

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Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas.

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