The Agency has accepted durable responses in hematologic malignancies
for approval for both chronic leukemias (accelerated approval) and acute
leukemias (regular approval). The FDA granted Gleevec® (imatinib)
accelerated approval for chronic, accelerated, and blast crisis phases
of CML based on durable major cytogenetic responses and major
Based on the magnitude and duration of responses (Table 1 and 2), has
the sponsor provided sufficient evidence of dasatinib’s effectiveness
for the following: Chronic phase CML?Accelerated phase CML?Myeloid blast CML?Lymphoid blast CML?
For approval – imatinib-resistant populations (except
The major toxicities observed with dasatinib
include the following: gastrointestinal and hematological toxicities,
fluid retention, bleeding, and myelosuppression. Less frequent, but
serious, adverse events include cardiac toxicity and intracranial
bleeding. Based on the phase 2 data, does the risk/ benefit profile
support dasatinib’s approval for the following: Chronic phase CML?
Accelerated phase CML? Myeloid blast CML? Lymphoid blast CML?
For approval – imatinib-intolerant population (except
Imatinib intolerance was defined as either 1) imatinib-related toxicity
leading to imatinib discontinuation, or 2) inability to tolerate
imatinib. The number of intolerant patients enrolled per study (except
for the Chronic phase CML studies) was less than 10%. Based on the data
presented in Table 3, has the sponsor provided evidence of an effect on
a surrogate endpoint (major cytogenetic response) for Chronic phase CML
patients intolerant to Gleevec?Based on the data presented below, has the sponsor provided
sufficient evidence to warrant accelerated approvalin CML patients intolerant to imatinib
in either Accelerated, Myeloid blast, or Lymphoid blast phases
As stated above, the FDA has approved drugs to treat acute leukemias
based on durable complete responses. The sponsor has presented data
(major hematological responses) for Philadelphia-positive acute
lymphoblastic leukemia patients who have experienced disease progression
on imatinib and other therapies. Based on the data presented in the
above tables, has dasatinib demonstrated sufficient evidence to warrant
regular approval in either the imatinib-resistant or intolerant
Philadelphia-positive ALL populations?
Accelerated approval requires a commitment to perform a confirmatory
clinical trial to demonstrate clinical benefit. Please discuss future
study designs to accomplish this goal. These trials could be either
front-line or relapsed disease settings.