TY - JOUR
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 J.
N1 - Funding Information:
This study was sponsored by Gem Pharmaceuticals, LLC, Birmingham, AL and Coronado Biosciences, Inc., Burlington, MA.
Publisher Copyright:
© 2015 Springer Science+Business Media.
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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U2 - 10.1007/s10637-015-0220-z
DO - 10.1007/s10637-015-0220-z
M3 - Article
C2 - 25698442
AN - SCOPUS:84939942928
SN - 0167-6997
VL - 33
SP - 594
EP - 602
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -
