Purpose: 9-cis retinoic acid (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 acid 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.