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

Our plain-English summary of Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas, by S. Kummar, M.E. Gutierrez, L.W. Anderson, et al (Cancer Chemotherapy and Pharmacology, 2013).

The study

• Authors: S. Kummar, M.E. Gutierrez, L.W. Anderson, R.W. Klecker, A. Chen, A.J. Murgo, J.H. Doroshow, J.M. Collins
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2013;72(4):917-23
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article reported a first-in-human phase 1 trial of batracylin, an experimental anticancer drug. It was not a study of asbestos exposure. Animal studies had linked the drug's toxicity to a breakdown product, N-acetyl-batracylin, so only patients with a 'slow acetylator' NAT2 genotype were enrolled. Thirty-one patients with advanced solid tumors or lymphomas that had not responded to standard therapy were enrolled from February 2007 to July 2010. One of them had peritoneal mesothelioma. Patients took the drug by mouth once a day for 7 days in 28-day cycles, at doses from 5 to 400 mg. No objective tumor responses were observed. Two patients had prolonged disease stabilization: the patient with peritoneal mesothelioma (8 cycles) and a patient with adrenocortical cancer (18 cycles). At 400 mg, three patients developed bladder inflammation (cystitis). At 280 mg, extra fluids did not protect two further patients. Blood levels of the drug and its breakdown product were very similar. The authors concluded that the genotype-guided approach delivered the drug safely, but development was stopped because of the cystitis and the lack of a substantial signal of antitumor activity. Patients with the fast acetylator genotype were not studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open-label, single-arm phase 1 (first-in-human) drug trial with genotype-based patient selection
• Who was studied: 31 patients with advanced solid tumors or low-grade lymphoid malignancies that were refractory to standard therapy, all with a slow acetylator NAT2 genotype, enrolled February 2007 to July 2010. One patient had peritoneal mesothelioma.
• Exposure: The experimental drug batracylin, taken by mouth daily for 7 days in 28-day cycles, at doses escalated from 5 mg to 400 mg per day. No asbestos exposure was studied.
• Main results:
  • No objective tumor responses were observed in the 31 patients.
  • Two patients had prolonged disease stabilization: one with peritoneal mesothelioma received 8 cycles, and one with adrenocortical cancer received 18 cycles.
  • At the 400 mg dose level, two patients developed grade 1 cystitis that resolved without intervention, and one developed grade 2 cystitis requiring IV hydration and interruption of the drug.
  • At the 280 mg dose level, given with added hydration, the two additional patients still developed bladder toxicity and were taken off treatment.
  • In patients, blood exposure to batracylin and to its metabolite N-acetyl-batracylin was very similar.
  • Because hydration did not protect against bladder toxicity, the study was ended.
• The authors' conclusion: The authors concluded that the genotype-guided strategy allowed batracylin doses in patients of about two-thirds of the tolerated dose in mice. Because of the unexpected bladder toxicity and the absence of a substantial signal of antitumor activity, clinical development of batracylin was stopped.
• Limitations the authors state:
  • Patients with the fast acetylator genotype were not studied, so it remains theoretically possible that metabolite levels would not differ by acetylator status.
  • The low mandated starting dose meant 31 patients were needed and the study took longer.
  • No suitable animal model was available to guide attempts to reduce the bladder toxicity.

Topics

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma.

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