Abstract

Previous studies have demonstrated that both normal B-cells and CLL cells are susceptible to redox stress. The expanded porphyrin, motexafin gadolinium (MGd), is a tumor selective redox active drug that reacts with various intracellular reducing metabolites and protein thiols to generate reactive oxygen species (ROS). Multiple trials in solid tumors have established that this agent is well tolerated and not associated with myelosuppression, although its toxicity profile has not been explored in hematologic malignancies. We therefore initiated a pilot phase I trial of MGd in previously treated CLL and small lymphocytic lymphoma (SLL) to assess the toxicity, pharmacokinetics, and preliminary clinical activity of MGd and to perform pharmacodynamic studies to confirm ROS generation in vivo. MGd was administered 5mg/kg/day IV for 5 days every three weeks until disease progression. MGd uptake was measured in CLL cells by flow cytometry. Effects of MGd treatment on Protein Kinase B (AKT) phosphorylation in vivo were examined, as we have previously demonstrated that this kinase is activated by ROS in CLL cells. Thirteen patients (pts) were enrolled with a median age of 66 years (range 54–80) and a median of 4 prior therapies (range 2–9); 12 pts had fludarabine-refractory disease. Median WBC was 26.9 (range 5.4–152.6); median platelet count was 95,000 (range 33,000–214.000) with 7 pts < 100,000 and 3 pts < 50,000. The most common Grade 1–2 adverse events were transient skin discoloration (13), asthenia (6), bone pain (2), and diarrhea (5). Five pts had possibly drug related Grade 3 toxicity, including neutropenia (2), anemia (2), hypophosphatemia (2), hypocalcemia (1) and cellulitis (1). No pts suffered treatment delay due to toxicity. Evidence of tumor activity was seen in three pts and included decrease in WBC, nodes and/or splenomegaly, although no pts met NCI 96 response criteria. One responding pt during cycle 2 of therapy developed a bowel perforation and was found to have massive tumor necrosis of large cell transformation at the perforation site at surgery. MGd uptake into CLL cells was analyzed 24 hours after dose 1 and 4 in 9 pts. Median fluorescence intensity (MFI) increased 1.1 to 1.4 fold (median 1.2 ± 0.1) over background after dose 1 and 1.5 to 4.0 fold (median 2.2 ± 0.8) after dose 4. AKT phosphorylation increased in serial samples obtained during treatment in a subset of patients, supporting the biologic activity of this agent in vivo. In conclusion, these data suggest that MGd has modest clinical activity in relapsed and refractory CLL when given as a single agent. Drug uptake into tumor cells was confirmed, and evidence of biologic activity was demonstrated by in vivo response and phosphorylation of AKT in a subset of patients. Pharmacodynamic studies suggest that alternative schedules of administration may be used to improve tumor response. Based upon these data, follow-up trials using optimized dosing regimens of MGd are in progress in less heavily treated CLL patients.

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