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• W796471661 abstract "B82 Background : RTA 402 (CDDO-Me) is a novel synthetic triterpenoid with potent anticancer and anti-inflammatory activity mediated through direct and indirect inhibition of NF-κB and STAT3. The drug suppresses reactive oxygen species-mediated signaling through induction of antioxidant and detoxification systems via Keap1 binding/Nrf2 induction and suppression of pro-inflammatory and anti-apoptotic mediators. Based on broad spectrum preclinical data demonstrating activity against tumors and associated stroma, a Phase 1 dose-finding and pharmacokinetic study was initiated. Methods : The primary objectives of the study were 1) to determine the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended phase II dose of RTA 402 in patients with refractory cancer and 2) to characterize the pharmacokinetics of RTA 402 administered orally once daily for 21 days every 28 days. Secondary objectives were to 1) document any preliminary antitumor activity of RTA 402 in this patient population and 2) determine the in vivo molecular and biological effects of RTA 402 by measuring changes in markers of inflammation and apoptosis in PBMCs, blood plasma, and tumor biopsies. Dose escalation proceeded according to an accelerated titration design until a DLT was reached. Results : RTA 402 was administered to 27 patients at 10 dose levels (5 to 1,300 mg/day). DLT was observed in two patients at 1,300 mg/day who experienced asymptomatic, Grade 3 liver transaminase elevations without concomitant increases in total-bilirubin. Both patients were dose reduced and continued on study. At the higher dose levels (≥ 900 mg/day), occasional fatigue and anorexia were also reported. The median biological half-life of RTA 402 was 31 h (range, 18-67 h), and all patients receiving doses >20 mg/day were continuously exposed to plasma levels of the drug exceeding 1 ng/mL. Evidence of antitumor and biological activity was observed in multiple patients. Of 12 patients evaluable for efficacy, 9 (75%) had stable disease for 2 months or longer, including patients with melanoma (N = 4; stable for 3.4, 4+, 6.3 and 11+ months), renal cell (N = 2; stable for 7 and 8 months), and medullary thyroid cancer (N = 1; stable for 10 months. Four of the patients with stable disease had large increases in neutrophils and platelets. Six patients consented to have biopsies, and suppression of NF-κB and pSTAT3, as well as downstream target genes iNOS, cyclin D1, COX-2, and arginase, was observed after treatment. Relative to baseline, apoptosis as measured by TUNEL positivity was increased up to 3-fold, and the presence of macrophages was increased up to 10-fold. Induction of the Keap1/Nrf2/ARE system was demonstrated in PBMCs by increases in NQO1 and gamma-GCS mRNA. Additionally, circulating plasma cytokine profiles suggest a switch from a Th2 to a Th1 phenotype. Conclusions : Orally administered RTA 402 was well tolerated up to 900 mg/day and with prolonged exposure up to 11 months. Data from initial patients indicate appropriate modulation of targets NF-κB, STAT3, and Keap1/Nrf2 and suggest clinical benefit, with prolonged disease stabilization in several patients with previously progressing disease and high tumor burden. Phase 2 trials in patients with melanoma and pancreatic cancer have begun." @default.
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• W796471661 title "Phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO-Me) in patients with solid tumors and lymphoid malignancies" @default.
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