Phase I trial of the combination of bortezomib and clofarabine in adults with refractory tumors.

PURPOSE: The proteasome inhibitor bortezomib and purine nucleoside analog clofarabine combination had greater than additive activity in the NCI-ALMANAC preclinical screen. We conducted a phase 1 trial (NCT02211755) to evaluate the combination's safety and efficacy in patients. EXPERIMENTAL DESIGN: We administered bortezomib subcutaneously on days 1 and 4, and clofarabine intravenously on days 1-5 of each 21-day cycle. The primary objective was to establish the safety, tolerability, and maximum tolerated dose (MTD) of bortezomib and clofarabine in patients with refractory solid tumors, lymphomas, or MDS. The secondary objective was to determine the effects of the combination on biomarkers of cell death and DNA damage response (DDR) in tumor biopsies. RESULTS: Of 28 patients enrolled, 11 had a best response of stable disease (median 5 cycles; range 2-10 cycles), including 5 patients (4 from the solid tumor cohort, 2 of which were at MTD) with stable disease for ≥ 6 cycles. The MTD for the solid tumor cohort was 1.3 mg/m(2) bortezomib on days 1 and 4, and 1.5 mg/m(2) clofarabine on days 1-5 of each cycle. The MDS cohort closed prior to MTD determination, due to low accrual. The most common study drug related adverse events were hematologic. Two out of 3 patients with evaluable biopsies had increased markers of cell death, and 1 patient also had increased DDR markers after treatment. CONCLUSION: The combination of bortezomib with clofarabine demonstrated limited antitumor effects possibly due to the inability to reach the efficacious doses achieved in preclinical models.