The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors

Our plain-English summary of The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors, by B.S. Choi, D.B. Alberti, W.R. Schelman, et al (Cancer Chemotherapy and Pharmacology, 2010).

The study

• Authors: B.S. Choi, D.B. Alberti, W.R. Schelman, J.M. Kolesar, J.P. Thomas, R. Marnocha, J.C. Eickhoff, S.P. Ivy, G. Wilding, K.D. Holen
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2010;66(5):973-80
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: 3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms.

Methods: The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m(2) and 3-AP 85 mg/m(2) per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC.

Results: Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m(2) per day and irinotecan 200 mg/m(2). DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations.

Conclusions: The MTD for this combination was 3-AP 60 mg/m(2) per day on days 1-3 and irinotecan 200 mg/m(2) on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.

In plain English

This was a phase I dose-escalation trial at the University of Wisconsin. It tested the experimental drug 3-AP with the chemotherapy drug irinotecan. Twenty-three adults with advanced solid tumors, for which standard chemotherapy did not exist or was no longer effective, were enrolled between October 2004 and July 2007. Two had mesothelioma; the article did not say where it arose or discuss asbestos. The highest tolerable dose was 3-AP 60 mg/m2 per day on days 1 to 3, with irinotecan 200 mg/m2 on day 1, every 21 days. Common side effects included nausea (70%), diarrhea (61%) and vomiting (57%). Eight patients had grade 3 or 4 neutropenia. Of 20 patients evaluable for response, one with non-small cell lung cancer had a partial response. Fifteen had stable disease, but only one of them, with pancreatic cancer, received more than four cycles. Among 19 genotyped patients, 3 of 4 dose-limiting toxicities occurred in those with the wild-type ABCB1 gene pattern. Citing modest antitumor activity and the substantial irinotecan dose reduction, the authors said further study of this regimen was not being pursued.

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: Phase I dose-escalation clinical trial (standard 3 + 3 design after an early amendment), with pharmacokinetic and ABCB1 genotyping studies
• Who was studied: 23 adults (10 men, 13 women) enrolled at the University of Wisconsin between October 2004 and July 2007. All had metastatic or unresectable solid tumors for which standard chemotherapy did not exist or was no longer effective. Tumor types included 7 pancreatic, 4 lung, 2 cholangiocarcinoma, 2 mesothelioma, 2 ovarian and 6 other cancers. All had received prior chemotherapy.
• Exposure: Not an asbestos exposure study. Patients received irinotecan by 1-hour infusion on day 1 and 3-AP by 2-hour infusion on days 1, 2 and 3 of a 21-day cycle. Doses ranged from irinotecan 100 to 250 mg/m2 and 3-AP 60 or 85 mg/m2 per day across dose levels.
• Main results:
  • The maximum tolerated dose was 3-AP 60 mg/m2 per day on days 1 to 3, with irinotecan 200 mg/m2 on day 1, every 21 days.
  • The most common non-hematologic side effects, of any severity, were nausea (70%), diarrhea (61%), vomiting (57%), abdominal pain or cramping (57%) and fatigue (57%).
  • Grade 3 or 4 neutropenia occurred in eight patients. Only one patient had methemoglobinemia above 15%, at the dose level using 3-AP 85 mg/m2 per day.
  • Of 23 patients, 20 were evaluable for response. One patient with non-small cell lung cancer had a partial response.
  • Fifteen patients had stable disease, but only one of them, with pancreatic cancer, received more than four cycles of therapy.
  • ABCB1 genotype data were available for 19 patients, and 3 of the 4 dose-limiting toxicities in these patients occurred in the wild-type group. Dose-adjusted Cmax and AUC of 3-AP were higher in the wild-type (CC GG CC) than in the all-variant (TT TT TT) haplotype, P = 0.04 and 0.009 respectively.
• The authors' conclusion: The authors concluded that the lower tolerated doses suggest 3-AP and irinotecan are at least additive in toxicity. Given the modest antitumor activity and the substantial dose reduction of irinotecan, they said further study of this regimen was not being pursued.
• Limitations the authors state:
  • The authors attributed the few responses to two things: the patients were heavily pre-treated, and most had tumor types not known to be sensitive to irinotecan.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, Ovarian Cancer, Hypoxia, Non-Small Cell Lung Cancer.

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