Sprycel Dose Reduction To Be Considered By ODAC During ASCO Road Show

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Sprycel Dose Reduction To Be Considered By ODAC During ASCO Road Show

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 during

a June 2 meeting.

In a briefing document for the 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. Sprycel's

priority review user fee date is June 28.

The meeting will be held at the Omni Hotel in Atlanta in conjunction

with the American Society of Clinical Oncology annual meeting.

Bristol conducted a Phase I dose escalation study of dasatinib 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, " the agency 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 prolongation.

In addition to the potential to reduce toxicity via a lower starting

dose, the other issue FDA identified with the application is " 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%.

Bristol will also present data at the advisory committee meeting and

ASCO 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. "