Bristol-Myers Squibb Company announced that the US Food and Drug Administration (FDA) has approved new labelling for Sprycel 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 leukaemia (CML) resistant or intolerant to prior therapy including Gleevec.
The product labelling now also includes data from the first randomised trial of Sprycel and Gleevec. Sprycel 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 Gleevec. 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.
"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," said Dr. Hagop Kantarjian, M.D., chairman and professor, Leukaemia Department, MD Anderson Cancer Centre. "Importantly, the new clinical data now included in the labelling 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 labelling was granted priority review and was approved in six months based primarily on two studies that enrolled chronic-phase CML patients with resistance or intolerance to Gleevec.
A lower recommended starting dose of Sprycel100 mg once daily based on a dose-optimisation trial - the first phase III trial in this patient population. This once daily dose was associated with a lower frequency of some side effects (severe myelosuppression and fluid retention).
Cytogenetic responses from the first randomised trial of Sprycel, 70 mg twice daily, and Gleevec 800 mg (400 mg twice daily), study -017. For patients receiving Sprycel, at 12 weeks 36 per cent achieved a major cytogenetic response, the study's primary endpoint (29 per cent with Gleevec), and 22 per cent achieved a complete cytogenetic response (8 per cent with Gleevec). With longer treatment and follow-up, 52 per cent achieved a major cytogenetic response (33 per cent with Gleevec), and 40 per cent of patients achieved a complete cytogenetic response (16 per cent with Gleevec).
The updated Sprycellabelling encompasses safety data for a total of 2,182 patients.
"We believe that this filing and its subsequent approval further demonstrates our commitment and dedication to patients with this disease," said Claude Nicaise, M.D., vice president, Sprycel Global Development, Bristol-Myers Squibb. "Bristol-Myers Squibb is fully committed to further exploring and understanding the appropriate use of Sprycel through a robust clinical development program."
The phase III, randomised, open-label study was conducted in patients with chronic-phase CML, whose disease was resistant or intolerant to Gleevec, to evaluate the efficacy of Sprycel administered once daily compared with twice daily. The primary endpoint was major cytogenetic response in patients with Gleevec-resistant chronic phase CML. A total of 670 patients (498 Gleevec resistant) were randomised to 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 comparable (non-inferior) major cytogenetic response to those who received Sprycel twice daily. The rate of major cytogenetic response was lower among patients aged 65 years and over. The median duration of treatment was approximately eight months. The study supports the new recommended starting dose, 100 mg once daily, for chronic-phase CML.
Incidence of selected adverse reactions (all grades) in the Phase 3 dose- optimisation study in chronic-phase CML patients receiving SPRYCEL100 mg once daily (n=165) or SPRYCEL70 mg twice daily (n=167) included diarrhoea (23 per cent, 25 per cent); fluid retention events (24 per cent, 32 per cent) such as superficial oedema (14 per cent, 16 per cent), pleural effusion (10 per cent, 18 per cent), generalized oedema (2 per cent, 1per cent), congestive heart failure/cardiac dysfunction (0per cent, 4per cent), pericardial effusion (1per cent, 2 per cent), pulmonary oedema (0 per cent, 2 per cent), pulmonary hypertension (0 per cent, 1per cent), and haemorrhage (10 per cent, 14 per cent) including gastrointestinal bleeding (1per cent, 4per cent).
The phase II randomised, open-label study evaluated Sprycel70 mg twice daily and Gleevec 800 mg (400 mg twice daily) in 150 patients with chronic-phase CML resistant to prior Gleevec doses of 400 or 600 mg. For patients receiving Sprycel, at 12 weeks 36 per cent achieved a major cytogenetic response, the study's primary endpoint (29 per cent with Gleevec), and 22 per cent achieved a complete cytogenetic response (8 per cent with Gleevec). With longer treatment and follow-up, 52 per cent achieved a major cytogenetic response (33 per cent with Gleevec), and 40 per cent of patients achieved a complete cytogenetic response (16 per cent with Gleevec). The rate of major cytogenetic response with Sprycel was lower among patients aged 65 years and over.
Major cytogenetic response is defined as complete (0 per cent of Philadelphia chromosome-positive [Ph+] cells in the bone marrow) plus partial (less than or equal to 35 per cent of Ph+ cells in the bone marrow) cytogenetic responses. Complete hematologic response is a measure of how effective a treatment is in returning blood counts to normal and occurs when blood counts appear normal and patients have no signs or symptoms of disease.
On June 28, 2006, the US Food and Drug Administration (FDA) granted accelerated approval of Sprycel, an oral inhibitor of multiple tyrosine kinases, for the treatment of adults in all three phases of CML (chronic-, accelerated-, or myeloid or lymphoid blast-phase) with resistance or intolerance to prior therapy including Gleevec. 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. The FDA also granted full approval of Sprycel for the treatment of adults with Ph+ ALL with resistance or intolerance to prior therapy.
Treatment with Sprycel (dasatinib) is associated with severe CTC Grade 3/4 thrombocytopenia, neutropenia, and anaemia. Dasatinib caused platelet dysfunction in vitro and thrombocytopenia in humans. Severe CNS haemorrhage, including fatalities, occurred in <1per cent of patients. Fluid retention was severe in 8 per cent of patients, including pleural and pericardial effusions reported in 5 per cent and 1 per cent, respectively.
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Nine patients had QTc prolongation as an adverse event. Three patients experienced a QTcF >500 msec. Dasatinib is a CYP3A4 substrate. Drugs that may increase dasatinib concentrations are strong CYP3A4 inhibitors, whereas drugs that may decrease dasatinib concentrations are strong CYP3A4 inducers.
The safety data reflect exposure to Sprycel in 2,182 patients with leukaemia in clinical studies (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). The majority of Sprycel- treated patients experienced adverse reactions at some time. Drug was discontinued for adverse reactions in 9 per cent of patients in chronic phase, 10per cent in accelerated phase, 15per cent in myeloid blast phase CML, and 8per cent in lymphoid blast phase CML or Ph+ ALL.