Dasatinib Shows Greater Efficacy Than Very High-Dose Imatinib

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Title: Dasatinib Shows Greater Efficacy Than Very High-Dose Imatinib

for Imatinib-Resistant Chronic-Phase Myelogenous Leukemia (CML)

Patients: Presented at ASCO

" Dasatinib Shows Greater Efficacy Than Very High-Dose Imatinib for

Imatinib-Resistant Chronic-Phase Myelogenous Leukemia (CML) Patients:

Presented at ASCO "

By Bruce Sylvester ATLANTA, G.A. -- June 5, 2006 -- Interim data from

a randomized, phase 2 study of dasatinib (140 mg/day) shows higher

response rates versus imatinib (Gleevec) 800 mg/day in patients with

chronic-phase myelogenous leukemia (CML) resistant to imatinib at

doses of 600 mg/day or greater. The data were presented in an oral

session here on June 3[rd at the American Society of Clinical Oncology

2006 Annual Meeting (ASCO).

The FDA approved the 400-mg/day dose of imatinib for CML.

Lead investigator and presenter Neil Shah, MD, PhD, assistant

professor of hematology and oncology, University of California at San

Francisco, San Francisco, California, reported the comparison study on

June 4th.

" Dasatinib is an effective alternative to 800-mg daily imatinib in

patients who do not respond to 400- to 600-mg daily dosing of

imatinib, " he said. " Notably, the percentage of patients showing a

complete cytogenetic response to dasatinib was 21% compared to 8% for

higher-dose imatinib. "

For this multicenter trial, investigators enrolled 150 patients with

chronic-phase CML that was resistant to imatinib. They were randomized

in a 2:1 ratio to dasatinib 140 mg/day (n = 101) or imatinib 800

mg/day (n = 49).

The primary endpoint of the study was major cytogenetic response at 12

weeks, defined both as a complete cytogenic response (no signs of

Philadelphia-chromosome positive cells in the bone marrow) and a

partial cytogenic response of < 35% of Ph+ cells in bone marrow.

Results show that 35% of subjects on dasatinib achieved a major

cytogenetic response (21% complete) compared with 29% of subjects on

high-dose imatinib (8% complete).

In the event of disease progression or intolerable toxicity, the

design of the trial permitted subjects to continue on their initial

drug treatment or crossover to the other drug at week 12. The

researchers reported that 6% of dasatinib-treated patients and 73% of

imatinib-treated patients crossed over to the opposite treatment arm.

At the time of the interim analysis of data, 19 of the patients who

crossed over from imatinib to dasatinib were evaluable. The

researchers reported that 8 of these patients had achieved a major

cytogenetic response (4 were complete responders) and none of the 4

evaluable patients who had switched from dasatinib to imatinib

achieved a major cytogenetic response.

Nonhematologic adverse effects in the dasatinib arm included diarrhea

(26%), fluid retention (25%), nausea (21%), bleeding (17%), and

vomiting (6%). In the imatinib arm these were fluid retention (43%),

nausea (31%), diarrhea (29%), vomiting (22%), and bleeding (8%).

Grade 3 or 4 cytopenia in the dasatinib arm included low absolute

neutrophil white blood cells (58%), platelets (54%), and hemoglobin

(9%). In the imatinib group grade 3 or 4 cytopenia included low

absolute neutrophil white blood cells (38%), platelets (14%), and

hemoglobin (8%).

In a presentation on June 2nd during the ASCO meeting, the Food and

Drug Administration (FDA)'s Oncologic Drugs Advisory Committee (ODEC)

recommended approval of dasatinib for the treatment of adults in all

phases of chronic myeloid leukemia (accelerated, lymphoid blast, and

myeloid blast) with resistance or intolerance to prior therapy,

including Gleevec.

The committee also recommended full approval of dasatinib for the

treatment of adults with Philadelphia chromosome-positive acute

lymphoblastic leukemia with resistance or intolerance to imatinib.

The recommendation will now go to the FDA for final approval.

Previously, the FDA granted a priority review to dasatinib. Based on

the priority review timeline, the FDA's action date for the new drug

application (NDA) is June 28, 2006.

The research was supported by Bristol-Myers Squibb.

[Presentation title: Dasatinib (D) vs High Dose Imatinib (IM) in

Patients (pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML)

Resistant to Imatinib. Results of CA180017 START-R Randomized Trial.

Abstract 6507]