Phase I Study of CDDO in Solid Tumors and Lymphomas

Background:

• CDDO is a novel synthetic triterpenoid which is a potent multifunctional molecule. It induces apoptosis in vitro in malignant cells through both intrinsic and extrinsic pathways, and it controls cellular differentiation, apoptosis, and growth inhibition by serving as a ligand for the transcription factor peroxisome proliferator activator receptor-gamma (PPAR gamma).
• Based on in vitro activity, it holds considerable promise as a novel anti-tumor agent against a wide range of malignancies by concurrently targeting multiple pathways leading to oncogenesis.
• In vivo data demonstrates that the drug is well tolerated in dogs, and has anti-tumor effects, dependent upon dose schedule.

Objectives:

Primary:

• To determine the dose limiting toxicities, toxicity profile, and maximum tolerated dose of CDDO when administered in adult patients with solid tumors and lymphomas.
• To characterize the pharmacokinetics of CDDO.

Secondary:

• To obtain preliminary evidence of anti-tumor activity of CDDO in this population.
• To evaluate the in vivo molecular and biological effects of CDDO by assessing changes in biomarkers of apoptosis and cell cycle arrest.

Eligibility:

• Patients with advance, histological-confirmed malignancies refractory to standard therapy or for which no standard therapy exist.
• Patients should have adequate liver, renal and bone marrow function.

Study Design:

• Accordingly with the accelerated titration design 4B, dose levels will initially be increased at 100% increments, and one new patient per dose level will be treated per 4-week course.
• The accelerated phase ends when one patient experiences DLT during any course of treatment or when two different patients experience grade 2 toxicity during first course of treatment.
• When the first instance of grade 2 toxicity is observed two additional patients must have been treated at that dose, or a higher dose, (during any course) without experiencing moderate or worse toxicity, in order that the accelerated phase continue.
• When the accelerated phase ends, dose-escalation will revert to a more conservative modified Fibonacci scheme with 40% dose-step increments, with at least 3 patients treated per dose level.