TY - JOUR
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, Hilda
PY - 1999/5
Y1 - 1999/5
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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M3 - Article
C2 - 10367173
AN - SCOPUS:0033051723
SN - 1081-4442
VL - 5
SP - 165
EP - 170
JO - Cancer Journal from Scientific American
JF - Cancer Journal from Scientific American
IS - 3
ER -