"Oct. 29, 2012 -- The FDA has approved Teva's Synribo (omacetaxine mepesuccinate) for treating adults with chronic myelogenous leukemia (CML).
The fast-track approval is for people for whom at least two of the most common treatments ha"...
Mechanism of Action
Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.
In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCRABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3–5 hours.
Data from a trial of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.
In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100–500 ng/mL.
Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavincontaining monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.
The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.
Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.
Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Effects of Age and Gender
Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.
Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls.
These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.
Newly Diagnosed Chronic Phase CML
An open-label, multicenter, international, randomized trial was conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those which had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).
Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥ 65 years of age. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian, and 39% were Asian. At baseline, the distribution of Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow up, 85% of patients randomized to SPRYCEL and 81% of patients randomized to imatinib were still on study.
With a minimum of 24 months follow up, 77% of patients randomized to SPRYCEL and 75% of patients randomized to imatinib were still on study and with a minimum of 36 months follow up, 71% and 69% of patients, respectively, were still on study.
Efficacy results are summarized in Table 7.
Table 7: Efficacy Results in Newly Diagnosed Patients
with Chronic Phase CML
|Response rate (95% CI)|
|within 12 months||76.8%
|within 24 months||80.3%||74.2%||-**|
|within 36 months||82.6%||77.3%||-**|
|Major Molecular Responseb|
|p < 0.0001*|
|a Confirmed CCyR is defined as a CCyR noted on two
consecutive occasions at least 28 days apart.
bMajor molecular response (at any time) was defined as BCR-ABL ratios ≤ 0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These are cumulative rates representing minimum follow up for the timeframe specified.
* Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.
** Formal statistical comparison of cCCyR and MMR rates was only performed at the time of the primary endpoint (cCCyR within 12 months).
CI = confidence interval.
After 36 months follow up, median time to confirmed CCyR was 3.1 months in 214 SPRYCEL responders and 5.8 months in 201 imatinib responders. Median time to MMR after 36 months follow up was 8.9 months in 179 SPRYCEL responders and 13.4 months in 146 imatinib responders.
At 36 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 13 patients (5%) on the imatinib arm progressed to either accelerated phase or blast crisis.
The rate of MMR at any time in each risk group determined by Hasford score was higher in the SPRYCEL group compared with the imatinib group (low risk: 81% and 64%; intermediate risk: 64% and 56%; high risk: 61% and 42%, respectively).
BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.
Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.
Imatinib Resistant or Intolerant CML or Ph+ ALL
The efficacy and safety of SPRYCEL were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥ 10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.
Results described below are based on a minimum of 2 years follow up after the start of SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinibresistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and > 600 mg/day in 40% of the patients.
The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).
Chronic Phase CML
Dose-Optimization Trial: A randomized, open-label trial was conducted in patients with chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the SPRYCEL 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was 22 months.
Efficacy was achieved across all SPRYCEL treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [-6.8%–10.6%]).
Efficacy results are presented in Table 8 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily. Additional efficacy results in this patient population are described after the table. Results for all patients with chronic phase CML, regardless of dosage (a starting dosage of 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily), were consistent with those for patients treated with 100 mg once daily.
Table 8: Efficacy of SPRYCEL in Imatinib Resistant or
Intolerant Chronic Phase CML (minimum of 24 months follow up)
|100 mg Once Daily
|CHRa% (95% CI)||92% (86-95)|
|MCyRb% (95% CI)||63% (56-71)|
|CCyR% (95% CI)||50% (42-58)|
|aCHR (response confirmed after 4 weeks): WBC ≤
institutional ULN, platelets < 450,000/mm³ , no blasts or
promyelocytes in peripheral blood, < 5% myelocytes plus metamyelocytes in
peripheral blood, basophils in peripheral blood < 20%, and no extramedullary
bMCyR combines both complete (0% Ph+ metaphases) and partial ( > 0%–35%) responses.
In the SPRYCEL 100 mg once daily group, median time to MCyR was 2.9 months (95% CI: [2.8–3.0]) with a minimum of 24 months follow up. Based on the Kaplan-Meier estimates, 93% (95% CI: [88%–98%]) of patients who had achieved an MCyR maintained that response for 18 months. In the 100 mg once daily group, MMR in all patients assessed for MMR was achieved in 43% within 5 years. The estimated rate of progression-free survival and overall survival at 2 years in all patients treated with 100 mg once daily was 80% (95% CI: [73%–87%]) and 91% (95% CI: [86%–96%]), respectively. Based on data six years after the last patient was enrolled in the trial, 64% were known to be alive at 5 years, 22% were known to have died prior to 5 years and 14% had an unknown 5-year survival status.
By 5 years, transformation to either accelerated or blast phase occurred in eight patients on treatment.
Advanced Phase CML and Ph+ ALL
Dose-Optimization Trial: One randomized open-label trial was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the SPRYCEL 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint.
The efficacy and safety of SPRYCEL were also investigated in patients with Ph+ ALL in one randomized trial (starting dosage 140 mg once daily or 70 mg twice daily) and one single-arm trial (starting dosage 70 mg twice daily). The primary efficacy endpoint was MaHR. A total of 130 patients were enrolled in these studies. The median duration of therapy was 3 months.
Response rates are presented in Table 9.
Table 9: Efficacy of SPRYCEL in Imatinib Resistant or
Intolerant Advanced Phase CML and Ph+ ALL
|140 mg Once Daily|
|MaHRa (95% CI)||66% (59-74)||28% (18-40)||42% (26-61)||38% (23-54)|
|CHRa, (95% CI)||47% (40-56)||17% (10-28)||21% (9-39)||33% (19-49)|
|NELa (95% CI)||19% (13-26)||11% (5-20)||21% (9-39)||5% (1-17)|
|MCyRa (95% CI)||39% (31-47)||28% (18-40)||52% (34-69)||70% (54-83)|
|CCyRb (95% CI)||32% (25-40)||17% (10-28)||39% (23-58)||50% (34-66)|
|a Hematologic response criteria (all responses confirmed
after 4 weeks): Major hematologic response: (MaHR) = complete hematologic
response (CHR) + no evidence of leukemia (NEL).
CHR: WBC ≤ institutional ULN, ANC ≥ 1000/mm³ , platelets ≥ 100,000/mm³ , no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤ 5%, < 5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood < 20%, and no extramedullary involvement.
NEL: same criteria as for CHR but ANC ≥ 500/mm³ and < 1000/mm³ , or platelets ≥ 20,000/mm³ and ≤ 100,000/mm³ .
b MCyR combines both complete (0% Ph+ metaphases) and partial ( > 0%–35%) responses.
CI = confidence interval ULN = upper limit of normal range.
In the SPRYCEL 140 mg once daily group, the median time to MaHR was 1.9 months for patients with accelerated phase CML, 1.9 months for patients with myeloid blast phase CML, and 1.8 months for patients with lymphoid blast phase CML.
In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once daily, the median duration of MaHR was 4.6 months. The medians of progression-free survival for patients with Ph+ ALL treated with SPRYCEL 140 mg once daily and 70 mg twice daily were 4.0 months and 3.5 months, respectively.
Last reviewed on RxList: 7/1/2013
This monograph has been modified to include the generic and brand name in many instances.
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