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A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study

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Abstract

Background

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.

Methods

Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1–3, days 8–10, and days 15–17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated.

Results

Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route.

Conclusions

Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

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Acknowledgments

This study was supported by the National Institutes of Health, National Cancer Institute under Cooperative Agreements with the Cancer Therapy Evaluation Program (U01 CA62505, City of Hope Medical Center and U01 CA099168, University of Pittsburgh Cancer Institute) and a Cancer Center Support Grant (P30 CA033572, City of Hope Medical Center).

Conflicts of interest

Each author certifies that he or she has no commercial associations (Disclosures: None, e.g., consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. Each author certifies that his or her institution has approved this retrospective investigation and that all investigations were conducted in conformity with ethical principles of research. The corresponding author certifies that all authors provided substantial conceptual or analytic contributions during manuscript preparation, and thus, satisfactorily qualify for authorship under the “Uniform Requirements.” All authors grant approval for publication.

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Authors and Affiliations

  1. City of Hope Medical Center, Building room 4117, 1500 East Duarte Road, 91010, Duarte, CA, USA

    Joseph Chao, Timothy W. Synold, Robert J. Morgan Jr., Jeff Longmate, Dean Lim, Stephen Shibata, Vincent Chung, Edward M. Newman & Yun Yen

  2. Case Western Reserve University, Cleveland, OH, USA

    Charles Kunos

  3. University of Southern California Norris Cancer Center, Los Angeles, CA, USA

    Heinz-Josef Lenz, Mark McNamara & Barbara J. Gitlitz

  4. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Ronald G. Stoller

  5. Penn State Hershey Cancer Institute, Hershey, PA, USA

    Chandra P. Belani

  6. University of California at Davis Cancer Center, Sacramento, CA, USA

    David R. Gandara & Derick H. Lau

  7. Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Suresh S. Ramalingam

  8. OSI Pharmaceuticals, Ardsley, NY, USA

    Angela Davies

  9. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Igor Espinoza-Delgado

Authors
  1. Joseph Chao
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  2. Timothy W. Synold
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  12. David R. Gandara
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  15. Derick H. Lau
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  16. Suresh S. Ramalingam
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  17. Angela Davies
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  18. Igor Espinoza-Delgado
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  19. Edward M. Newman
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  20. Yun Yen
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Corresponding author

Correspondence to Yun Yen.

Additional information

Co-first author: Joseph Chao and Timothy Synold.

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Chao, J., Synold, T.W., Morgan, R.J. et al. A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study. Cancer Chemother Pharmacol 69, 835–843 (2012). https://doi.org/10.1007/s00280-011-1779-5

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  • DOI: https://doi.org/10.1007/s00280-011-1779-5

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