Interim results of a phase I trial with a novel orally administered synthetic triterpenoid RTA 402 (CDDO-Me) in patients with solid tumors and lymphoid malignancies

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14101 Background: RTA 402 (CDDO-Me) is a novel synthetic triterpenoid with potent anticancer and anti-inflammatory activity through selective modulation of proteins that respond to changes in oxidative stress, including NF-κB, JNK, and STAT3. Based on preclinical data demonstrating effects on tumors and associated stroma, a Phase 1 dose-finding and pharmacokinetic study was initiated. Methods: RTA 402 is administered orally once a day for the first 21 days of a 28-day cycle. Dose escalation is proceeding according to an accelerated titration design until an MTD is reached. Results: RTA 402 has been administered to 11 patients at 7 dose levels (5 to 300 mg/day). Cycle 1 data are available for 8 patients. No significant drug-related toxicity has been reported and dose escalation continues in 100% increments. The median biological half-life of RTA 402 was 49 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 has been observed in initial patients. A patient with medullary thyroid carcinoma treated at 5 mg/day has received eight cycles of therapy and has had stable disease with a 70% reduction of calcitonin levels. A patient with metastatic melanoma has experienced disease stabilization through four cycles and remains on study. A second melanoma patient has also experienced disease stabilization through two cycles and remains on study. Radiographic evidence of regressing lesions has been observed in both melanoma patients. Additionally, significant reductions in circulating VEGF, MMP-9, TNF, IL-8, and IL-10, up to 65%, 91%, 90%, 73%, and 70%, respectively, have been observed in at least half of patient samples. Cytokine suppression has correlated with improvements in reported pain and fatigue. Conclusions: Orally administered RTA 402 appears well tolerated up to 150 mg/day and with prolonged exposure up to 8 months. Data from initial patients indicate biological activity and suggest clinical benefit, with disease stabilization in several patients who had rapidly progressing disease with high tumor burden. Phase 2 trials are planned. No significant financial relationships to disclose.