Summary Basis of Decision for Sprycel

3.3.1 Pharmacodynamics

Dasatinib is a potent tyrosine kinase inhibitor with potency at sub-nanomolar concentrations for BCR-ABL, c-KIT, EPH, PDGFβ receptor, and SRC kinases. The inhibitory effect of dasatinib has been demonstrated in both in vitro and in vivo systems for CML cell lines and some solid tumour cell lines. The potency of dasatinib for inhibiting all the CML cell lines was higher than that of imatinib.

3.3.2 Pharmacokinetics

Absorption

Dasatinib was rapidly absorbed following oral administration in patients with leukemia. The maximum plasma concentrations occurred at 0.5-3 hours post-dose. The mean half-life of dasatinib was approximately 5-6 hours.

Distribution

Dasatinib had a large apparent volume of distribution suggesting that the drug is extensively distributed into the extravascular space.

Metabolism

Dasatinib was extensively metabolized in humans. The cytochrome P450 enzyme, CYP3A4, was the major enzyme responsible for the metabolism of dasatinib.  

Excretion

Dasatinib, mostly in the form of metabolites, was primarily excreted in the feces.

Drug Interactions

Clinical drug interaction studies were conducted with a CYP3A4 substrate (simvastatin) and a CYP3A4 inducer (rifampin). Additional interaction studies with an aluminum hydroxide/magnesium hydroxide-containing antacid (e.g., Maalox) and the H2-blocker famotidine were also conducted.

Co-administration of dasatinib with CYP3A4 substrate, simvastatin, increased the exposures to simvastatin and simvastatin acid by approximately 20-40% compared with simvastatin alone. The effect of the CYP3A4 substrate on the dasatinib exposure was not studied. There was an increased chance of borderline QTc prolongation following the concomitant use of both products in healthy subjects.

Plasma levels of dasatinib and two of its metabolites were significantly reduced by the CYP3A4 inducer, rifampin. It is also noted that more patients experienced borderline QTc prolongation with the combined treatment compared to those that received dasatinib alone, despite the fact that rifampin and dasatinib were administered 12 hours apart. The increased combined effect cannot be explained because no adverse QTc effect was known for rifampin; and rifampin greatly reduced the drug exposure parameters, C_max and AUC of dasatinib and the two active metabolites in the plasma.

Significant reductions of dasatinib exposure, 61% and 55%, were reported 10-12 hours following administration of famotidine and Maalox, respectively. The logical explanation for the reduced exposure of dasatinib is probably due to its pH-dependent solubility.

Famotidine and Maalox are known to increase the GI fluid pH. As a result, dasatinib was less soluble when the GI fluid pH was increased and presumably was less absorbed.

3.3.3 Clinical Efficacy

The clinical efficacy of Sprycel was evaluated for the treatment of adults with chronic, accelerated, or blast phase CML. The effectiveness was based on the rates of hematologic and cytogenetic responses. The primary efficacy endpoints were either hematologic or cytogenetic responses depending on the stage of the disease, i.e., in the advanced stages (accelerated or blast phase) the primary endpoint was the hematologic response whereas in the chronic phase studies it was the cytogenetic response.

Duration of follow-up is limited. There were no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Based on the results of the Phase I dose escalating study, a starting dose of 70 mg BID (twice a day) was chosen. There was no linear dose-response relationship and responses were achieved at levels both above and below 70 mg BID. Further studies confirming the starting dose of 70 mg BID should be conducted.

Chronic Phase CML

Two Phase II studies were conducted with patients with chronic phase CML. Study CA180017 was a randomized, non-comparative study with patients who were resistant to imatinib ≤600 mg per day. No imatinib-intolerant patients were enrolled in this study. Patients were randomized in a 2:1 ratio to receive either Sprycel 70 mg BID or imatinib 400 mg BID. The primary efficacy endpoint was the rate of major cytogenetic response (MCyR). At the time of interim analysis, the number of patients in this study was small. The 12-week assessment from the first 36 randomized patients (22 in the Sprycel arm and 14 in the imatinib arm) showed a MCyR in nine patients receiving Sprycel and in three patients receiving imatinib (based on at least 20 metaphases counted). A complete cytogenetic response (CCyR) occurred in six patients receiving Sprycel and in one patient receiving imatinib. Crossover to alternate therapy occurred in two patients of the Sprycel arm and in 11 patients of the imatinib arm. The median duration of treatment was 3.7 months in the Sprycel arm and 2.7 months in the imatinib arm. The interim data have demonstrated that Sprycel induced complete and major hematologic responses in patients with chronic phase CML resistant to imatinib 400 to 600 mg/day, including those who had not achieved cytogenetic response on prior imatinib therapy. A larger number of patients with a longer follow-up is required in order to assess treatment results in these two groups of patients. Final analysis from this randomized pivotal study will be required to confirm the efficacy of dasatinib when follow-up data become available.

Study CA180013 was a single-arm Phase II study involving 186 patients with chronic phase CML, resistant or intolerant to imatinib. Patients received Sprycel 70 mg BID. Dose escalation to 90 mg BID was allowed for patients who showed evidence of progression or lack of response. In addition to imatinib, 42% of the patients had received prior cytotoxic chemotherapy, 70% had received prior interferon, and 9% had received a prior stem cell transplant. The median duration of treatment was 5.6 months. Based on ≥20 metaphases counted, the percentage of patients that demonstrated a MCyR and CCyR were 40% and 31%, respectively.

Accelerated Phase CML

In study CA180005, Sprycel was evaluated in a total of 107 patients with accelerated phase CML, who were resistant or intolerant to imatinib. Prior treatment also included cytotoxic chemotherapy, interferon, or a stem cell transplant. The median duration of treatment was 5.5 months. The major and complete hematologic response (MaHR, CHR) rates were 59% and 33%, respectively. The MCyR and CCyR rates were 24% and 15%, respectively.

Blast Phase CML

In study CA180006, Sprycel was evaluated in a total of 74 patients with myeloid blast phase CML, who were resistant or intolerant to imatinib. Prior treatment also included cytotoxic chemotherapy, interferon, or a stem cell transplant. The median duration of treatment was 3.5 months. The MaHR and CHR rates were 32% and 24%, respectively. The MCyR and CCyR rates were 22% and 18%, respectively.

In study CA180015, a total of 42 CML patients in the lymphoid blast phase who were resistant or intolerant to imatinib were analyzed. Prior treatment also included cytotoxic chemotherapy, interferon, or a stem cell transplant. The median duration of treatment was 2.8 months. The MaHR and CHR rates were 31% and 26%, respectively. The MCyR and CCyR rates were 43% and 36%, respectively.

Conclusion

The results of the clinical studies show promising evidence of clinical effectiveness based on the rates of hematologic and cytogenetic responses, however additional efficacy data are required to confirm the clinical benefit of Sprycel.

As part of the post-approval commitments, the sponsor has agreed to provide periodic and final efficacy analysis from all ongoing Phase I/II dasatinib studies included in this submission. Results for the chronic phase CML dose optimization study (Study CA180034) will also be provided.

3.3.4 Clinical Safety

One Phase I study and five Phase II studies provided the safety data for this drug submission. Each of the six studies represented a single stage of the disease, with the exception of the Phase I study which included patients from all stages, and Study CA1800015, which included patients with lymphoid blast phase CML and Ph+ ALL. The integrated safety database consisted of 511 patients. Most patients (289, 57%) received treatment for 3-6 months. Fewer patients (167, 33%) were treated for ≤3 months. The remaining patients were treated for 6-12 months (55, 11%) or longer (1, 0%). The majority of deaths were due to disease progression.

Almost all patients reported at least one treatment-emergent adverse event (AE). Most reactions were mild to moderate. The proportion of severe adverse events (SAEs) increased with increasing disease severity, from 48% in chronic phase patients up to 83% in lymphoid blast phase CML and Ph+ ALL patients. The most frequently reported AEs, regardless of causality or severity, were fluid retention (49%), diarrhea (48%), hemorrhage (41%), pyrexia (40%), headache (39%), musculoskeletal pain (38%), fatigue (35%), rash (34%), nausea (32%), dyspnea (31%), infection (29%), abdominal pain (25%), cough (24%), vomiting (23%), asthenia (22%), and pain (21%).

Laboratory Abnormalities

Most (>85%) of the patients developed some degree of myelosuppression, which was severe in more than half of the patients. Patients with greater disease severity had more moderate and severe abnormalities at baseline, and went on to develop more severe myelosuppression on treatment.

Frequent occurrences of significant hypophosphatemia and hypocalemia were reported. The proportion of patients with grade 3 and 4 abnormalities was significantly higher in patients with myeloid blast or lymphoid blast phase CML.

Information on thyroid function was not available. A request was made to the sponsor to provide relevant data. Information from Periodic Safety Update Reports may mandate monitoring of thyroid function.
 
Adverse Events of Special Interest

Generally, SAEs and AEs were common. Many of these were anticipated as a result of underlying disease, and by the nature of the therapy. Certain events were of special interest either because of unexpected frequency or severity. In addition, some potential AEs were noted after examining the safety data from imatinib (another tyrosine kinase inhibitor), and were therefore actively pursued.

Fluid Retention

Fluid retention, manifested as edema and pleural effusions, was reported to be very common with the use of imatinib. The etiology of this was unclear, but an unexpectedly high incidence of myocardial dysfunction was subsequently observed. The possibility of a link between the two is now being assessed prospectively in an ongoing trial with dasatinib. In the integrated safety database of 511 patients, edema and pleural effusion were common throughout all of the CML disease phases. Pericardial effusion was not rare in any disease phase, with an overall incidence of 4%.

Hemorrhagic Events

Patients with CML commonly have thrombocytopenia. This, along with marrow suppression and impaired clot stability due to dasatinib, made bleeding events common, occurring in approximately a third of all patients. The majority of non-gastrointestinal (GI) and non-intracranial hemorrhages were mild (grade 1 or 2). The dosing of dasatinib was reduced or interrupted infrequently, and no patients discontinued treatment because of hemorrhages. Hemorrhages were more common in patients with advanced disease.

GI hemorrhage is common in patients with advanced leukemia and is usually associated with severe thrombocytopenia. Slightly more than 16% of subjects in the studies reported a GI bleed of any grade. Just over a half of all reported GI bleeds were grade 3 or 4, and most of these patients needed blood transfusion.

Intracranial hemorrhage is known to be associated with advanced leukemia, and is frequently fatal. All the central nervous system (CNS) bleeds reported in the studies were associated with grade 3 or 4 thrombocytopenia.

Cardiovascular Events

The safety pharmacology studies revealed that Sprycel has the potential to cause QTc prolongation. This was also observed in healthy volunteers when dasatinib was administered with CYP3A4 substrates or CYP3A4 inducers. In Phase II clinical studies in patients with leukemia treated with Sprycel, the mean changes from baseline in QTcF interval were 3-6 msec; the upper 95% confidence interval for all mean changes from baseline was <8 msec and the lower 95% confidence interval for all mean changes from baseline was >-2 msec. Three patients (<1%) experienced a QTcF >500 msec.
 
The Product Monograph includes a warning that dasatinib may cause significant QTc prolongation if given to subjects known to have a congenital long QTc interval syndrome, and that co-administration of dasatinib with other drugs known to cause QTc prolongation should be monitored carefully.

Attention was focused on cardiac toxicity presented in a paper that was published last year that suggested imatinib therapy may cause left ventricular (LV) dysfunction. Clinical trials with ABL-BCR tyrosine kinase inhibitors have consistently reported a high incidence of edema, some of which were severe, as well as severe dyspnea. Although these findings are relatively common in patients with CML, it is possible that treated patients may develop LV dysfunction and congestive heart failure (CHF) without previous cardiac history. The occurrence of direct drug-induced cardiotoxicity has not been established at this time. From the integrated safety database of 511 patients, the incidence reports of CHF, pulmonary edema, and cardiomyopathy were pooled together for each of the CML disease phases, as all three AEs may represent a manifestation of LV dysfunction. The total number of these three events for the chronic phase, accelerated phase, myeloid blast phase, and lymphoid blast phase were 13 (6%), 10 (8%), 17 (18%), and 3 (3%), respectively.

The incidence of dyspnea was high throughout all CML disease phases. The total numbers of cases in the chronic phase, accelerated phase, myeloid blast phase, and lymphoid blast phase were 52 (25%), 34 (29%), 33 (34%), and 20 (23%), respectively. The etiology of the dyspnea is not known, but it seems likely that a significant proportion is due to LV dysfunction. Interestingly, the incidence is quite similar across the disease spectrum, suggesting that this may be a drug-related effect. The results of prospective and serial cardiac function tests now being carried out in ongoing studies may be illuminating. Warnings regarding CHF and pulmonary edema are presented in the Product Monograph for dasatinib.

Gastrointestinal and Hepatic Events

GI AEs were common throughout all CML disease phases. The most common events were diarrhea, nausea, and vomiting, with incidences of 48%, 32%, and 23%, respectively, for all disease phases pooled. Together, these three AEs were considered to be severe (grade 3 or 4) in 8% of the pooled population. Non-specific abdominal pain was also frequently reported.

Non-specific elevations of liver enzymes, bilirubin, ratio of prothombin time (INR), and decreases in albumin were reported frequently. No patients developed significant hepatic impairment and most abnormalities were resolved spontaneously with or without a dose interruption. The incidence of hepatic function abnormalities increased with increasing disease severity. None of the patients discontinued dasatinib due to hepatic toxicity. Although causality was not established, the development of liver function abnormalities should be approached with caution. The median duration of follow-up for the full safety set was only three months. These hepatic abnormalities are included in the Product Monograph.

Conclusion

Treatment-emergent AEs were frequent in all disease phases, with the frequency of AEs correlating with disease severity. Overall, the safety and tolerability of Sprycel (dasatinib) is acceptable for the patient group for which it is indicated. Ongoing monitoring is required to clarify the importance of some unexpected treatment-emergent AEs.

Additional safety data is required to confirm the clinical benefit and long-term safety of Sprycel. As part of the post-approval commitments, the sponsor has agreed to provide periodic safety analysis and results from the completion of all ongoing Phase I/II dasatinib studies included in this submission. Clinical and non-clinical studies on left ventricular ejection fractions and potential myocardial toxicity will also be provided. The sponsor will report all serious adverse reactions that occurred in Canada and all serious unexpected adverse reactions that occurred outside of Canada within 15 days to Health Canada and submit a periodic safety update report (PSUR) semi-annually until the conditions of the authorization have changed.