Trial of the Combination of Bortezomib and Clofarabine in Adults With Relapsed Solid Tumors

Summary

Participation Requirements

Description

BACKGROUND: The proteasome inhibitor bortezomib and purine nucleoside metabolic inhibitor clofarabine demonstrated greater than additive activity in combination in preclinical xenograft models, justifying the clinical evaluation of this combination for its antitumor activity OBJECTIVES: To establish...

BACKGROUND: The proteasome inhibitor bortezomib and purine nucleoside metabolic inhibitor clofarabine demonstrated greater than additive activity in combination in preclinical xenograft models, justifying the clinical evaluation of this combination for its antitumor activity OBJECTIVES: To establish the safety, tolerability, and maximum tolerated dose (MTD) of bortezomib and clofarabine in patients with refractory solid tumors, lymphomas, or myelodysplastic syndromes (MDS) To determine the molecular effects of the clofarabine-bortezomib combination on biomarkers of cell death and DNA damage in tumor biopsy tissue To explore the mechanism of action of the bortezomib and clofarabine combination by examining markers of DNA damage and apoptosis in tumor cells before and after treatment -To characterize the changes in MDS residual disease burden that occur with bortezomib and clofarabine treatment ELIGIBILITY: Study participants must have histologically confirmed solid tumors or lymphomas or myelodysplastic syndromes that have progressed on standard therapy known to prolong survival or for which no standard treatment options exist Age greater than or equal to 18 No major surgery, radiation, or chemotherapy within 3 weeks prior to entering the study Adequate organ function STUDY DESIGN: This is an open-label Phase I trial The starting dose of clofarabine will be 1 mg/m2 administered intravenously on days 1 through 5 of a 21-day cycle; bortezomib will be administered at 0.8 mg/m2 subcutaneously on days 1 and 4 of a 21-day cycle. Dose escalation will follow a 3+3 design, with dose limiting toxicities defined during cycle 1. Dose escalation will proceed in cohorts comprised of two separate groups of patients (one group of patients with solid tumor/lymphoma and one group of patients with MDS), with at least 1 from each group, until hematologic DLT or the second grade 2 hematologic toxicity is observed, at which point, dose escalation will proceed separately for two cohorts: (1) patients with solid tumors/lymphoma and (2) patients with MDS. Up to 33 patients will be accrued to a PD expansi n cohort at the MTD to further assess pharmacodynamic endpoints in tumor and blood.

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