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Cancer Prevention Research

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Research Article

A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers

Jill M. Kolesar, Shannon Andrews, Heather Green, Tom C. Havighurst, Barbara W. Wollmer, Katina DeShong, Douglas E. Laux, Helen Krontiras, Donald D. Muccio, KyungMann Kim, Clinton J. Grubbs, Margaret G. House, Howard L. Parnes, Brandy M. Heckman-Stoddard and Howard H. Bailey
Jill M. Kolesar
College of Pharmacy, University of Kentucky, Lexington, Kentucky.University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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  • For correspondence: jill.kolesar@uky.edu hhb@medicine.wisc.edu
Shannon Andrews
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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Heather Green
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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Tom C. Havighurst
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
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Barbara W. Wollmer
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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  • ORCID record for Barbara W. Wollmer
Katina DeShong
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
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Douglas E. Laux
Department of Internal Medicine, University of Iowa, Iowa City, Iowa.
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Helen Krontiras
Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
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Donald D. Muccio
Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
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KyungMann Kim
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
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Clinton J. Grubbs
Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
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Margaret G. House
Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
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Howard L. Parnes
Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
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Brandy M. Heckman-Stoddard
Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
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Howard H. Bailey
University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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  • For correspondence: jill.kolesar@uky.edu hhb@medicine.wisc.edu
DOI: 10.1158/1940-6207.CAPR-19-0310 Published December 2019
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Abstract

9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.

Footnotes

  • Cancer Prev Res 2019;12:903–11

  • Received June 18, 2019.
  • Revision received August 4, 2019.
  • Accepted August 28, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Prevention Research: 12 (12)
December 2019
Volume 12, Issue 12
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A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers
Jill M. Kolesar, Shannon Andrews, Heather Green, Tom C. Havighurst, Barbara W. Wollmer, Katina DeShong, Douglas E. Laux, Helen Krontiras, Donald D. Muccio, KyungMann Kim, Clinton J. Grubbs, Margaret G. House, Howard L. Parnes, Brandy M. Heckman-Stoddard and Howard H. Bailey
Cancer Prev Res December 1 2019 (12) (12) 903-912; DOI: 10.1158/1940-6207.CAPR-19-0310

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A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers
Jill M. Kolesar, Shannon Andrews, Heather Green, Tom C. Havighurst, Barbara W. Wollmer, Katina DeShong, Douglas E. Laux, Helen Krontiras, Donald D. Muccio, KyungMann Kim, Clinton J. Grubbs, Margaret G. House, Howard L. Parnes, Brandy M. Heckman-Stoddard and Howard H. Bailey
Cancer Prev Res December 1 2019 (12) (12) 903-912; DOI: 10.1158/1940-6207.CAPR-19-0310
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eISSN: 1940-6215
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