Preliminary phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer

Scott Wadler, Edward L. Schwartz, Patrick Anderson, Carolyn D. Runowicz, Linus Chuang, Giuseppe Del Priore, Howard Hochster, Gary Goldberg, Abbie Fields, Gordon Loewen, Hilda Haynes-Lewis

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

PURPOSE 9-cis retinoic add (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic add as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems. METHODS The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRa in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours. RESULTS Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20% or greater to this agent could be ruled out with 95% confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69% between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71% of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28. CONCLUSIONS 9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.

Original languageEnglish (US)
Pages (from-to)165-170
Number of pages6
JournalCancer Journal from Scientific American
Volume5
Issue number3
StatePublished - May 1999

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Uterine Cervical Neoplasms
Pharmacokinetics
Cervix Uteri
Retinoids
Adenosquamous Carcinoma
Carcinoma
Isotretinoin
Phase II Clinical Trials
Retinoic Acid Receptors
Tretinoin
Area Under Curve
alitretinoin
Clinical Studies
Appointments and Schedules
Epithelial Cells
High Pressure Liquid Chromatography
Population
Neoplasms

Keywords

  • 4- oxo-9-cis retinoic acid
  • 9-cis retinoic acid
  • Cervical carcinoma
  • Pharmacokinetics
  • Retinoids

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Preliminary phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer. / Wadler, Scott; Schwartz, Edward L.; Anderson, Patrick; Runowicz, Carolyn D.; Chuang, Linus; Del Priore, Giuseppe; Hochster, Howard; Goldberg, Gary; Fields, Abbie; Loewen, Gordon; Haynes-Lewis, Hilda.

In: Cancer Journal from Scientific American, Vol. 5, No. 3, 05.1999, p. 165-170.

Research output: Contribution to journalArticle

Wadler, S, Schwartz, EL, Anderson, P, Runowicz, CD, Chuang, L, Del Priore, G, Hochster, H, Goldberg, G, Fields, A, Loewen, G & Haynes-Lewis, H 1999, 'Preliminary phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer', Cancer Journal from Scientific American, vol. 5, no. 3, pp. 165-170.
Wadler, Scott ; Schwartz, Edward L. ; Anderson, Patrick ; Runowicz, Carolyn D. ; Chuang, Linus ; Del Priore, Giuseppe ; Hochster, Howard ; Goldberg, Gary ; Fields, Abbie ; Loewen, Gordon ; Haynes-Lewis, Hilda. / Preliminary phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer. In: Cancer Journal from Scientific American. 1999 ; Vol. 5, No. 3. pp. 165-170.
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abstract = "PURPOSE 9-cis retinoic add (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic add as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems. METHODS The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRa in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours. RESULTS Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20{\%} or greater to this agent could be ruled out with 95{\%} confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69{\%} between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71{\%} of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28. CONCLUSIONS 9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.",
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author = "Scott Wadler and Schwartz, {Edward L.} and Patrick Anderson and Runowicz, {Carolyn D.} and Linus Chuang and {Del Priore}, Giuseppe and Howard Hochster and Gary Goldberg and Abbie Fields and Gordon Loewen and Hilda Haynes-Lewis",
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T1 - Preliminary phase II clinical and pharmacokinetic study of 9-cis retinoic acid in advanced cervical cancer

AU - Wadler, Scott

AU - Schwartz, Edward L.

AU - Anderson, Patrick

AU - Runowicz, Carolyn D.

AU - Chuang, Linus

AU - Del Priore, Giuseppe

AU - Hochster, Howard

AU - Goldberg, Gary

AU - Fields, Abbie

AU - Loewen, Gordon

AU - Haynes-Lewis, Hilda

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N2 - PURPOSE 9-cis retinoic add (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic add as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems. METHODS The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRa in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours. RESULTS Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20% or greater to this agent could be ruled out with 95% confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69% between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71% of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28. CONCLUSIONS 9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.

AB - PURPOSE 9-cis retinoic add (ALRT 1057; 9cRA) is a promising new retinoid that binds to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoic acid or all-trans retinoic acid. It has been shown to be at least as active as all-trans retinoic add as a differentiation-inducing and antiproliferative agent in both in vivo and in vitro tumor model systems. METHODS The New York Gynecologic Oncology Group undertook a prospective, multi-institutional phase II clinical and pharmacokinetic trial of 9cRa in patients with advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix. Patients received daily oral doses of 140 mg/m2 of 9cRA. 9cRA and its metabolites were determined by reversed-phase HPLC in plasma samples drawn at 0.5 to 8 hours. RESULTS Sixteen patients with advanced or recurrent carcinoma of the cervix were enrolled. Therapy was well tolerated with no unexpected toxicities. There were no complete or partial responses observed, indicating that a response rate of 20% or greater to this agent could be ruled out with 95% confidence. Pharmacokinetic parameters for 9cRA on day 1 were in agreement with previous studies. The area under the plasma versus time curves for 9cRA declined by 69% between days 1 and 8 with daily 9cRA dosing and remained at this low level in those patients evaluated on day 28. 4-oxo-9-cis retinoic acid (4-oxo-9cRA) was identified as a major plasma metabolite of 9cRA. Plasma levels of 4-oxo-9-cRA were initially 71% of those of 9cRA, but in contrast to 9cRA, there was no decline in plasma levels on days 8 and 28. The ratio of the area under the curve for the 4-oxo metabolite relative to that of the parent compound increased from less than 1 on day 1 to approximately 2.4 on days 8 and 28. Thus, despite early induction of its own metabolism, levels of total retinoid metabolites persisted at pharmacologic levels at day 28. CONCLUSIONS 9cRA with this dose and schedule was inactive in women with advanced carcinoma of the cervix. Despite a decline in plasma levels of 9cRA over time, levels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest that the lack of clinical activity in this patient population may not be attributable exclusively to suboptimal pharmacokinetic parameters.

KW - 4- oxo-9-cis retinoic acid

KW - 9-cis retinoic acid

KW - Cervical carcinoma

KW - Pharmacokinetics

KW - Retinoids

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