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

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 ¼ 8) or placebo (n ¼ 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.

Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers

“…Rexinoid 1 was also a potent stimulator of triglyceride biosynthesis; it increased levels by over 400% using a 200 mg/kg diet dose. Other rexinoids like UAB30 or 2 increased serum triglycerides by less than 100% using the 200 mg/kg diet dose. , In a 28 day human phase I trial (dose escalation), UAB30 did not increase serum triglycerides or cholesterol even when administered chronically at 240 mg/day . Therefore, rexinoids that increase serum triglycerides less than 100% using a 200 mg/kg diet daily dose may not cause significant toxicity in humans.…”

“…15,18 In a 28 day human phase I trial (dose escalation), UAB30 did not increase serum triglycerides or cholesterol even when administered chronically at 240 mg/ day. 12 Therefore, rexinoids that increase serum triglycerides less than 100% using a 200 mg/kg diet daily dose may not cause significant toxicity in humans. Rexinoids 3−6 were evaluated at the 200 mg/kg diet dose for 7 days to determine if oral dosing of these rexinoids increases serum triglyceride levels.…”

“…The zinc clumps were carefully broken up using a mortar and pestle, and the resulting powder was stored in a brown glass container under nitrogen. (12). In a 500 mL, three-neck, round-bottomed flask fitted with a condenser, an addition funnel, and a nitrogen inlet, the above activated zinc dust (15.5 g, 238.4 mmol) was suspended in anhydrous 1,4-dioxane (100 mL) and was heated to 100 °C in an oil bath.…”

“…Previously, we reported the development of a rexinoid called UAB30, which is effective in preventing mammary cancers in rodents while not increasing serum lipids from oral dosing. , In an in vivo mammary cancer prevention model, UAB30 at 200 and 100 mg/kg of diet decreased MNU-initiated cancers by 63 and 29%, respectively, whereas bexarotene orally administered at 150 and 15 mg/kg of diet decreased cancers by 74 and 38%, respectively. ,, Oral dosing of UAB30 in rodents slightly increases serum lipids. Using genomic and proteomic approaches, we demonstrated that unlike bexarotene, UAB30 does not induce the expression of genes in the liver of rodents under the control of the permissive heterodimers that modulate lipid metabolism. , A 28 day oral dosing of UAB30 at multiple doses in normal human volunteers was safely tolerated up to 160 mg daily without any changes in serum lipids or blood chemistry. − Due to its favorable toxicity profile and reasonable potency, UAB30 is currently being evaluated in phase 1b human trials to prevent nonmelanoma skin cancers (NMSCs) in organ transplant patients as well as to prevent other epithelial cancers.…”

Stability of the Retinoid X Receptor-α Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide

“…Our group has designed and studied many rexinoids for the use in cancer treatment and prevention. ,,− UAB30 (Figure B) is a novel rexinoid developed by our group currently in phase II clinical trials. Compared to Targretin, the only clinically used rexinoid approved by the FDA, UAB30 exhibits high efficacy in cancer prevention without inducing hyperlipidemia which is the dose-limiting toxicity of Targretin. ,− UAB110 and UAB111 (Figure B) are two rexinoids belonging to another structural class of UAB rexinoids other than UAB30. Each of these three UAB rexinoids bind the RXRα LBD with nanomolar affinities.…”