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

PURPOSE 9-cis retinoic acid (ALRT 1057; 9cRA) is a promising new retinoid that bind s to all known retinoic acid receptors (RAR and RXR), potentially providing it with a broader spectrum of biologic activity than either 13-cis retinoi c acid or all-trans. retinoic acid. It has been shown to be at least as act ive as all-trans retinoic acid as a differentiation-inducing and antiprolif erative agent in both in vivo and in vitro tumor model systems. METHODS The New York Gynecologic Oncology Group undertook a prospective, multi-inst itutional phase II clinical and pharmacokinetic trial of 9cRA in patients w ith advanced or recurrent squamous cell or adenosquamous cell carcinoma of the uterine cervix Patients received daily oral doses of 140 mg/m(2) of 9cR A. 9cRA. and its metabolites were determined by reversed-phase HPLC in plas ma samples drawn at 0.5 to 8 hours. RESULTS Sixteen patients with advanced or recurrent carcinoma of the cervix were en rolled. Therapy was well tolerated with no unexpected toxicities. There wer e no complete or partial responses observed, indicating that a response rat e of 20% or greater to this agent could be ruled outwith 95% confidence. Ph armacokinetic 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 le vel 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 o f 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 a rea 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 to tal retinoid metabolites persisted at pharmacologic levels at day 28, CONCLUSIONS 9cRA with this dose and schedule was inactive in women with advanced carcin oma of the cervix. Despite a decline in plasma levels of 9cRA. over time, l evels of the 4-oxo metabolite tended to persist. While the 4-oxo metabolite is less potent than the parent compound, these data nevertheless suggest t hat the lack of clinical activity in this patient population may not be att ributable exclusively to suboptimal pharmacokinetic parameters.