Novel Cellular Agent Shows Promise in Treating AML

Data published in a recent issue of Blood suggest that valspodar (Amdray), a multidrug resistance modulator being developed by Novartis Pharmaceuticals Corporation, may show promise in treating certain patients with acute myelogenous leukemia (AML) when used in combination with chemotherapy. The data come from a phase II, multicenter study, coordinated by researchers at Stanford University School of Medicine, that involved 37 patients with AML who had not responded to or had relapsed after chemotherapy.

In the study, patients received a combination of mitoxantron, etoposide, and cytarabine (MEC), as well as valspodar. Overall, a complete or partial remission was observed in 43% of the patients (12 achieved a complete remission and 4, a partial remission).

Potent Inhibitor of P-Glycoprotein

One mechanism through which multidrug resistance occurs is overexpression of P-glycoprotein. P-glycoprotein is a protein within the cancer cell membrane that “pumps” out cytotoxic drugs from the cell, thereby preventing these drugs from reaching toxic levels and destroying the cell. Valspodar works as a potent inhibitor of P-glycoprotein, and it does not suppress the immune system or affect the kidneys.

“Multidrug resistance is a significant problem for cancer patients,” said David Parkinson, MD, vice president of clinical research at Novartis. “The results of this study are encouraging in demonstrating the potential role of Amdray in helping to overcome multidrug resistance in patients with AML,” he added. “Novartis currently is completing global, randomized clinical trials of Amdray with chemotherapy in patients with AML. We anticipate the study results to be available by the end of 1999, at which point we can more definitively know the role of Amdray in overcoming multidrug resistance.”

Study Design

The 37 patients with poor-prognosis AML enrolled in the study were divided into two cohorts. All were treated with valspodar plus MEC and received valspodar as a pretreatment loading dose of 2 mg/kg over 4 hours, with a subsequent continuous infusion of 10 mg/kg/d for 120 hours (5 days). Chemotherapy began immediately after the 4-hour loading dose of valspodar was completed, and doses of mitoxantrone and etoposide were reduced to accommodate the known pharmacokinetic interaction between valspodar and these agents.

The six patients in cohort I were treated with mitoxantrone (5 mg/m²/d as an intravenous [IV] bolus on days 1 to 5), etoposide (50 mg/m²/d as a 1-hour infusion on days 1 to 5), and cytarabine (1 g/m²/d as a 1-hour infusion on days 1 to 5). To compensate for the pharmacokinetic interactions that resulted in higher than expected adverse events, the mitoxantrone and etoposide doses were reduced further to 4 and 40 mg/m²/d, respectively, in the 31 patients in cohort II.

To test for P-glycoprotein function, the uptake and efflux of rhodamine-123 was monitored by flow cytometry in leukemic cells gated according to scatter properties and antigen profile. The final study dose determined in cohort II is being investigated further in a phase III, randomized trial conducted by the Eastern Cooperative Oncology Group (ECOG) in the United States.

Study Results

Overall, 12 patients (32%) achieved a complete remission and 4 achieved a partial remission. The regimen that included valspodar did not demonstrate responses in 21 patients. These results were evenly distributed between disease categories and occurred within both cohorts.

In cohort I, one patient achieved a complete response, whereas in cohort II, 11 (36%) of 31 patients had complete responses. One patient in cohort I and three patients in cohort II achieved partial responses.

The study data suggest a possible role for reversal of multidrug resistance in this patient group—a premise which is being evaluated further in ongoing phase III studies.

Tolerability

Thus far, findings from several ongoing studies—including oral and IV formulations—indicate that valspodar is generally well tolerated when administered in conjunction with chemotherapeutic agents. At the doses currently being studied, side effects are transient and reversible. They include dizziness, numbness, tingling of the extremities, nausea, hyperbilirubinemia, and an increase in liver enzymes. In addition, some patients may experience cerebellar dysfunction—manifested by difficulty in walking or impaired coordination—that is rapidly reversible. When valspodar is used in combination with chemotherapeutic drugs in clinical trials, the most clinically significant adverse events are those normally expected from the chemotherapeutic regimen.