FDA will ask its Oncologic Drugs Advisory Committee whether a lower initial dose of Bristol-Myers Squibb's Sprycel (dasatinib) for chronic-phase chronic myeloid leukemia patients is appropriate.

In a ¹ briefing document for the June 2 panel, FDA suggested that a 50 mg BID dose, rather than the 70 mg dose studied in the primary efficacy trials, may reduce toxicity without sacrificing efficacy.

Bristol is seeking indications for the multi-kinase inhibitor in Gleevec- resistant (Novartis' imatinib) chronic, accelerated or blast phase CML patients and Philadelphia-chromosome-positive acute lymphoblastic lymphoma and lymphoid blast CML patients.

The meeting will be held at the Omni Hotel in Atlanta in conjunction with the American Society of Clinical Oncology annual meeting. [Editor's note: To ² watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

FDA pointed to a Phase I dose escalation study of dasatinib that Bristol conducted in patients with a variety of hematologic malignancies.

"The Phase I study did not determine a maximum tolerated dose; therefore the applicant chose the recommended dose for Phase II based on efficacy observed," the briefing document states. "However, in the Phase I study, efficacy was observed at doses lower than the recommended Phase II dose."

FDA notes that in chronic phase CML patients, "there was no evidence of a linear dose response," with the majority of the major cytogenic responses (MCyR) occurring in patients in the 50 mg BID or 105 mg/day and 70 mg/BID cohorts. Higher and lower cohorts had fewer responses, the agency adds.

"Based on evidence of [complete hematologic response] and MCyR at doses lower than 70 mg, a starting dose of 50 mg BID or lower may be appropriate in chronic phase disease, with dose escalation as needed based on response and toxicity," FDA concludes.

Major toxicities associated with dasatinib seen in clinical trials include bleeding events, myelosuppression, fluid retention, gastrointestinal events, congestive heart failure/left ventricular dysfunction and QT interval prolongation.

In addition to asking the committee to consider the potential to reduce toxicity with a lower starting dose of dasatinib, FDA will also ask the committee "whether sufficient data have been provided to recommend dasatinib for the imatinib tolerant population."

Bristol's application includes data from the Phase I trial and four Phase II trials in a total of 445 Gleevec-resistant or intolerant patients with hematologic malignancies.

The MCyR rate after 12 weeks in studies in chronic phase CML patients was 45%. In the remaining studies, major hematologic response rates after 12 weeks ranged from 30% to 60% (³ Also see "Bristol Sprycel For Gleevec-Resistant Leukemia To Get Committee Review At June ASCO Meeting" - Pink Sheet, 6 April, 2006.).

Bristol will also present data at the advisory committee meeting, as well as at the concurrent ASCO meeting, from a randomized trial (CA 180017) comparing standard-dosed dasatanib with high-dose imatinib in imatinib-resistant patients.

According to FDA's briefing document, "preliminary efficacy results include a MCyR of 45% in the dasatinib arm and 21% in the imatinib arm."

-Andrew Kasper

Sprycel Dose Reduction To Be Considered By Oncology Cmte. During ASCO Road Show

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