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

Sarah A. Holstein, James C. Bigelow, Richard D. Olson, Robert E. Vestal, Gerald M. Walsh, Raymond Hohl

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)594-602
Number of pages9
JournalInvestigational New Drugs
Volume33
Issue number3
DOIs
StatePublished - Jun 22 2015

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Anthracyclines
Pharmacokinetics
Neoplasms
Maximum Tolerated Dose
Neutropenia
Intravenous Infusions
Doxorubicin
Nausea
Area Under Curve
Fatigue
5-imino-13-deoxydoxorubicin
Anemia
Reactive Oxygen Species
Cardiotoxicity

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Holstein, Sarah A. ; Bigelow, James C. ; Olson, Richard D. ; Vestal, Robert E. ; Walsh, Gerald M. ; Hohl, Raymond. / Phase I and pharmacokinetic study of the novel anthracycline derivative 5-imino-13-deoxydoxorubicin (GPX-150) in patients with advanced solid tumors. In: Investigational New Drugs. 2015 ; Vol. 33, No. 3. pp. 594-602.
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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. / Holstein, Sarah A.; Bigelow, James C.; Olson, Richard D.; Vestal, Robert E.; Walsh, Gerald M.; Hohl, Raymond.

In: Investigational New Drugs, Vol. 33, No. 3, 22.06.2015, p. 594-602.

Research output: Contribution to journalArticle

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T1 - Phase I and pharmacokinetic study of the novel anthracycline derivative 5-imino-13-deoxydoxorubicin (GPX-150) in patients with advanced solid tumors

AU - Holstein, Sarah A.

AU - Bigelow, James C.

AU - Olson, Richard D.

AU - Vestal, Robert E.

AU - Walsh, Gerald M.

AU - Hohl, Raymond

PY - 2015/6/22

Y1 - 2015/6/22

N2 - 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.

AB - 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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