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Sub-category:
Other Novel Agents
Category:
Developmental Therapeutics: Molecular Therapeutics
Meeting:
2008 ASCO Annual Meeting
Session Type and Session Title:
Oral Presentation, Developmental Therapeutics: Molecular Therapeutics
Abstract No:
3517
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 3517)
Author(s):
D. S. Hong, R. Kurzrock, J. G. Supko, D. P. Lawrence, J. J. Wheler, C. J. Meyer, J. W. Mier, M. Andreeff, G. I. Shapiro, B. J. Dezube
Abstract:
Background: RTA 402 (CDDO-Me) is a first-in-class antioxidant inflammation modulator with potent anticancer and anti- inflammatory activity. The drug suppresses ROS-mediated signaling through suppression of pro-inflammatory transcription factors NF-κB and STAT3 and induction of antioxidant/detoxification transcription factor Nrf2. Methods: The primary objectives of the study were to determine the DLT, MTD and phase II dose of RTA 402 in patients with advanced solid tumors or lymphoid malignancies; and to characterize the pharmacokinetics of RTA 402 given orally once daily for 21 days every 28 days. Dose escalation proceeded via an accelerated titration design. Results: RTA 402 was administered to 34 patients at 10 dose levels (5 to 1,300 mg/day). The MTD is 900 mg/day; DLT at 1,300 mg/day was asymptomatic Grade 3 LFT elevation, which resolved to < Grade 1 upon dose reduction. 50% of all patients and 40% at MTD had no toxicities greater than Grade 1. The median biological half-life of RTA 402 was 33.1 h (range, 18-98 h), with volume of distribution suggesting extensive tissue uptake. Of 18 patients evaluable for efficacy, one Partial Response was observed in a patient with anaplastic thyroid cancer. A further 9 patients had stable disease, 6 of which lasted for 6-12 months (3 melanoma, 2 renal cell, 1 medullary thyroid). Suppression of NF-κB and STAT3, as well as downstream targets iNOS, cyclin D1, COX-2, and arginase, was observed in multiple biopsies at doses as low as 40 mg/day. TUNEL positivity was increased up to 6-fold, and the presence of macrophages was increased up to 10-fold. Consistent with dual NF-κB/STAT3 suppression, leukocytosis was observed in several patients with prolonged stable disease. Induction of Nrf2 was demonstrated in PBMCs by increases in NQO1 and gamma-GCS mRNA. Conclusions: The first-in-class antioxidant inflammation modulator RTA 402 is well tolerated up to 900 mg/day with prolonged exposure up to 12 months. Data indicate appropriate modulation of targets NF-κB, STAT3, and Nrf2 and suggest clinical benefit associated with this novel mechanism, including a PR and prolonged disease stabilization in several patients. Phase II trials have begun.
Abstract Disclosures
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy
and are designated with a caret symbol (^) here and in the print version.
 Associated Presentation(s):
Other Abstracts in this Sub-Category:
Abstracts by D. S. Hong :
Presentations by D. S. Hong :
Educational Book Manuscripts by D. S. Hong :
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