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Phase I and pharmacokinetic study of the novel anthracycline derivative 5-imino-13-deoxydoxorubicin (GPX-150) in patients with advanced solid tumors

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Summary

Purpose 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin analog modified in two locations to prevent formation of cardiotoxic metabolites and reactive oxygen species. Preclinical studies have demonstrated anti-cancer activity without cardiotoxicity. A phase I study was performed in order to determine the maximum-tolerated dose (MTD) of GPX-150 in patients with metastatic solid tumors. Methods GPX-150 was administered as an intravenous infusion every 21 days for up to 8 cycles. An accelerated dose escalation was used for the first three treatment groups. The dosing groups were (A) 14 mg/m2, (B) 28 mg/m2, (C), 56 mg/m2, (D) 84 mg/m2, (E) 112 mg/m2, (F) 150 mg/m2, (G) 200 mg/m2, and (H) 265 mg/m2. Pharmacokinetic samples were drawn during the first 72 h of cycle 1. Results The MTD was considered to be reached at the highest dosing level of 265 mg/m2 since dose reduction was required in 5 of 6 patients for neutropenia. The most frequent adverse events were neutropenia, anemia, fatigue, and nausea. No patients experienced cardiotoxicity while on the study. The best overall response was stable disease in four (20 %) patients. Pharmacokinetic analysis revealed an AUC of 8.0 (±2.6) μg · h/mL, a clearance of 607 (±210) mL/min/m2 and a t1/2β of 13.8 (±4.6) hours. Conclusions GPX-150 administered every 21 days has an acceptable side effect profile and no cardiotoxicity was observed. Further investigation is needed to determine the efficacy of GPX-150 in anthracycline-sensitive malignancies.

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Funding/Support

This study was sponsored by Gem Pharmaceuticals, LLC, Birmingham, AL and Coronado Biosciences, Inc., Burlington, MA.

Author’s disclosures of potential conflicts of interest

Sarah A. Holstein: none

James C. Bigelow: none

Richard D. Olson: consultant for Gem Pharmaceuticals, LLC

Robert E. Vestal: consultant for Gem Pharmaceuticals, LLC

Gerald M. Walsh: employee of Gem Pharmaceuticals, LLC

Raymond J. Hohl: research funding from Gem Pharmaceuticals, LLC

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY, 14263, USA

    Sarah A. Holstein

  2. Idaho State University, Pocatello, ID, USA

    James C. Bigelow

  3. Gem Pharmaceuticals, LLC, Birmingham, AL, USA

    Richard D. Olson, Robert E. Vestal & Gerald M. Walsh

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

    Raymond J. Hohl

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  1. Sarah A. Holstein
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Correspondence to Sarah A. Holstein.

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Holstein, S.A., Bigelow, J.C., Olson, R.D. et al. Phase I and pharmacokinetic study of the novel anthracycline derivative 5-imino-13-deoxydoxorubicin (GPX-150) in patients with advanced solid tumors. Invest New Drugs 33, 594–602 (2015). https://doi.org/10.1007/s10637-015-0220-z

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