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.
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.
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 groupa premise which is being
evaluated further in ongoing phase III studies.
Thus far, findings from several ongoing studiesincluding oral
and IV formulationsindicate 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
dysfunctionmanifested by difficulty in walking or impaired
coordinationthat 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.