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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1201–1208 | Cite as

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial

  • Thehang Luu
  • Paul Frankel
  • Jan H. Beumer
  • Dean Lim
  • Mihaela Cristea
  • Leonard J. Appleman
  • Heinz J. Lenz
  • David R. Gandara
  • Brian F. Kiesel
  • Richard L. Piekarz
  • Edward M. NewmanEmail author
Original Article
  • 163 Downloads

Abstract

Purpose

The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m2 given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50–100 mg/m2/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.

Methods

Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat.

Results

Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m2/day belinostat with 100 mg/m2/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m2/day belinostat with 100 mg/m2/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer.

Conclusions

The combination of belinostat 2000 mg/m2 days 1–5 and 13-cRA 100 mg/m2 days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.

Keywords

Histone deacetylase (HDAC) inhibitors Retinoids Phase I clinical trial Pharmacokinetics 

Notes

Acknowledgements

The authors thank all of the participating patients and their families, as well as the network of investigators, research nurses, study coordinators, and operation staffs.

Funding

The research reported was supported by the National Cancer Institute of the National Institutes of Health under Award numbers U01CA062505, UM1CA186717 and P30CA033572 to City of Hope; and UM1CA186690 and P30CA047904 to University of Pittsburgh. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

Jan H. Beumer received research support from Spectrum Pharmaceuticals.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Thehang Luu
    • 1
  • Paul Frankel
    • 2
  • Jan H. Beumer
    • 3
  • Dean Lim
    • 1
  • Mihaela Cristea
    • 1
  • Leonard J. Appleman
    • 3
  • Heinz J. Lenz
    • 4
  • David R. Gandara
    • 5
  • Brian F. Kiesel
    • 3
  • Richard L. Piekarz
    • 6
  • Edward M. Newman
    • 7
    Email author
  1. 1.Department of Medical OncologyCity of HopeDuarteUSA
  2. 2.Department of BiostatisticsCity of HopeDuarteUSA
  3. 3.UPMC Hillman Cancer CenterPittsburghUSA
  4. 4.University of Southern California/Norris Comprehensive Cancer CenterLos AngelesUSA
  5. 5.University of California Davis Cancer CenterSacramentoUSA
  6. 6.Cancer Therapy Evaluation ProgramNational Cancer InstituteBethesdaUSA
  7. 7.Beckman Research Institute City of HopeDuarteUSA

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