FDA approves lower starting dose for dasatinib for CML

ROCKVILLE, Maryland—FDA has approved new labeling for Bristol-Myers Squibb's Sprycel (dasatinib) to include a lower recommended starting dose of 100 mg once daily, and safety and efficacy data in a greater number of patients with chronic-phase chronic myeloid leukemia resistant or intolerant to prior therapy including imatinib (Gleevec). The product labeling now also includes data from the first randomized trial of Sprycel and imatinib.

Sprycel, which was granted accelerated approval in 2006, is indicated for the treatment of adults with chronic-, accelerated-, or myeloid or lymphoid blast-phase CML with resistance or intolerance to prior therapy including imatinib. FDA also granted regular approval of Sprycel for the treatment of adults with Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy.

The effectiveness of Sprycel is based on hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Resistance to imatinib is often due to mutations of Bcr-Abl, Bcr-Abl overexpression, or activation of new pathways. Sprycel is the first approved oral multiple tyrosine kinase inhibitor that, at nanomolar concentrations, inhibits Bcr-Abl, SRC family, c-KIT, EPHA2, and PDGFRb kinases.

Fewer side effects

"The new, lower once-daily dose reduces the incidence of some side effects while preserving the efficacy of Sprycel for patients with chronic-phase CML no longer responding to currently approved therapies," Hagop Kantarjian, MD, chairman and professor, Leukemia Department, M.D. Anderson Cancer Center, told ONI. "Importantly, the new clinical data now included in the labeling provides further evidence to support the use of Sprycel to treat patients with chronic-phase CML, if their disease is no longer responding to currently available treatment including Gleevec."

The updated labeling was granted priority review and was approved in 6 months based primarily on two studies that enrolled chronic-phase CML patients with resistance or intolerance to imatinib.

Dose-optimization study

The phase III, randomized, open-label study-034 was conducted in patients with chronic-phase CML whose disease was resistant or intolerant to imatinib, to evaluate the efficacy of Sprycel administered once daily compared with twice daily. The primary endpoint was major cytogenetic response in patients with imatinib-resistant chronic-phase CML.

A total of 670 patients (498 imatinib resistant) were randomized to Sprycel 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily.

Those patients who received Sprycel once daily achieved a major cytogenetic response comparable (noninferior) to those who received the drug twice daily. The rate of major cytogenetic response was lower among patients aged 65 years and over. The median duration of treatment was approximately 8 months.

This once-daily dose was associated with a lower frequency of some side effects (severe myelosuppression and fluid retention) (see Table 1).

The starting dose for adults with accelerated-phase, myeloid or lymphoid blast-phase CML or adults with Ph+ ALL resistant or intolerant to prior therapy remains at 70 mg twice daily.

First randomized trial

The phase II study-017 was the first randomized trial of Sprycel and imatinib. It evaluated Sprycel 70 mg twice daily and imatinib 800 mg (400 mg twice daily) in 150 patients with chronic-phase CML resistant to prior imatinib doses of 400 or 600 mg.

At 12 weeks, 36% of the Sprycel patients achieved a major cytogenetic response, the study's primary endpoint (imatinib 29%), and 22% achieved a complete cytogenetic response (imatinib 8%). With longer treatment and follow-up, 52% achieved a major cytogenetic response and 40% achieved a complete cytogenetic response (33% and 16%, respectively, with imatinib). The major cytogenetic response rate with Sprycel was lower among patients aged 65 years and over. The incidence of selected adverse reactions is shown in Table 2.

At the time of analysis, 39 of 49 patients receiving imatinib had crossed over to Sprycel; 15 of 101 Sprycel patients had crossed over to imatinib. Median duration of treatment prior to crossover was 14 months for Sprycel and 3 months for imatinib.