A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies

Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties tha...

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Veröffentlicht in:Clinical cancer research 2002-07, Vol.8 (7), p.2142-2148
Hauptverfasser: PATNAIK, Amita, ROWINSKY, Eric K, ECKHARDT, S. Gail, VILLALONA, Miguel A, HAMMOND, Lisa A, BRITTEN, Carolyn D, SIU, Lillian L, GOETZ, Andrew, FELTON, Sally A, BURTON, Susan, VALONE, Frank H
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container_end_page 2148
container_issue 7
container_start_page 2142
container_title Clinical cancer research
container_volume 8
creator PATNAIK, Amita
ROWINSKY, Eric K
ECKHARDT, S. Gail
VILLALONA, Miguel A
HAMMOND, Lisa A
BRITTEN, Carolyn D
SIU, Lillian L
GOETZ, Andrew
FELTON, Sally A
BURTON, Susan
VALONE, Frank H
description Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation. None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m 2 /day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation, hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely on this schedule, resulting in a maximum deliverable dose of 3.3 g/m 2 /day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.
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The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation. None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m 2 /day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation, hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely on this schedule, resulting in a maximum deliverable dose of 3.3 g/m 2 /day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. 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There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>12114414</pmid><tpages>7</tpages></addata></record>
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ispartof Clinical cancer research, 2002-07, Vol.8 (7), p.2142-2148
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source MEDLINE; American Association for Cancer Research; Alma/SFX Local Collection; EZB Electronic Journals Library
subjects Adult
Aged
Antineoplastic agents
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Butyrates - administration & dosage
Butyrates - therapeutic use
Cell Differentiation
Chemotherapy
Drug Administration Schedule
Female
Humans
Male
Maximum Tolerated Dose
Medical sciences
Middle Aged
Neoplasms - drug therapy
Neoplasms - metabolism
Pharmacology. Drug treatments
Prodrugs - adverse effects
Prodrugs - therapeutic use
Safety
title A Phase I Study of Pivaloyloxymethyl Butyrate, a Prodrug of the Differentiating Agent Butyric Acid, in Patients with Advanced Solid Malignancies
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