title: Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gutierrez
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Anderson
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Klecker
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Collins
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018579:Patient Selection; D010597:Pharmacogenetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013045:Species Specificity; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C057924:batracylin; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
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