Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine analogues; ATC Code: L01BC08

Mechanism of action

Decitabine (5-aza-2′-deoxycytidine) is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that can result in reactivation of  tumour suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.

AML Clinical experience

The use of Dacogen was studied in an open-label, randomised, multicentre Phase III study (DACO-016) in subjects with newly diagnosed de novo or secondary AML according to the WHO classification. Dacogen (n = 242) was compared to treatment choice (TC, n = 243) which consisted of patient’s choice with physician’s advice of either supportive care alone (n = 28, 11.5%) or 20 mg/m2 cytarabine subcutaneously once daily for 10 consecutive days repeated every 4 weeks (n = 215, 88.5%). Dacogen was administered as a 1-hour intravenous infusion of 20 mg/m2 once daily for 5 consecutive days repeated every 4 weeks.

Subjects who were considered candidates for standard induction chemotherapy were not included in the study as shown by the following baseline characteristics. The median age for the intent-to-treat (ITT) population was 73 years (range 64 to 91 years). Thirty-six percent of subjects had poor-risk cytogenetics at baseline. The remainder of the subjects had intermediate-risk cytogenetics. Patients with favourable cytogenetics were not included in the study. Twenty-five percent of subjects had an ECOG performance status ≥2. Eighty-one percent of subjects had significant comorbidities (e.g., infection, cardiac impairment, pulmonary impairment).
The number of patients treated with Dacogen by racial group was White 209 (86.4%) and Asian 33 (13.6%).

The primary endpoint of the study was overall survival. The secondary endpoint was complete remission rate that was assessed by independent expert review. Progression-free survival and Event-free survival were tertiary endpoints.

The median overall survival in the intent-to-treat ITT population was 7.7 months in subjects treated with Dacogen compared to 5.0 months for subjects in the TC arm (hazard ratio 0.85; 95% CI: 0.69, 1.04, p = 0.1079). The difference did not reach statistical significance, however, there was a trend for improvement in survival with a 15% reduction in the risk of death for subjects in the Dacogen arm (Figure 1). When censored for potentially disease modifying subsequent therapy (i.e., induction chemotherapy or hypomethylating agent) the analysis for overall survival showed a 20% reduction in the risk of death for subjects in the Dacogen arm [HR = 0.80, (95% CI: 0.64, 0.99), p-value = 0.0437)].




Figure 1. Overall Survival (Intent-to-Treat ITT Population)
100
N     Death (%)        Median          95% CI
DACOGEN         242     197 (81)         7.7           (6.2, 9.2)
Total TC        243     199 (82)         5.0           (4.3, 6.3)
80

HR (95% CI):         0.85 (0.69, 1.04)
Percent of Subjects Alive



Logrank p-value:        0.1079
60


40



20



0
0   6                 12              18                 24                30                  36 Time (Months)
No. of Subjects at Risk
DACOGEN         242                        137               65              28                 12                 1                  0 Total TC        243                        107               55              19                  7                 4                  0 

In an analysis with an additional 1 year of mature survival data, the effect of Dacogen on overall survival demonstrated a clinical improvement compared to the TC arm (7.7 months vs. 5.0 months, respectively, hazard ratio = 0.82, 95% CI: 0.68, 0.99, nominal p-value = 0.0373, Figure 2) 



Figure 2. Analysis of Mature Overall Survival Data (Intent-to-Treat ITT Population) 100
N     Death (%)      Median        95% CI
DACOGEN         242     219 (90)       7.7         (6.2, 9.2)
Total TC        243     227 (93)       5.0         (4.3, 6.3)
80

HR (95% CI):     0.82 (0.68, 0.99)
Percent of Subjects Alive



Logrank p-value:    0.0373
60


40



20



0
0   6         12        18         24            30           36            42           48 Time (Months)
No. of Subjects at Risk
DACOGEN         242                         137       78        50          28           11            2            0            0 Total TC        243                         107       68        35          20           10            4            2            0 

Based on the initial analysis in the Intent-to-Treat ITT population, a statistically significant difference in complete remission rate (CR + CRp) was achieved in favour of subjects in the Dacogen arm, 17.8% (43/242) compared to the TC arm, 7.8% (19/243); treatment difference 9.9% (95% CI: 4.07; 15.83),p = 0.0011. The median time to best response and median duration of best response in patients who achieved a CR or CRp were 4.3 months and 8.3 months, respectively. Progression-free survival was significantly longer for subjects in the Dacogen arm, 3.7 months (95% CI: 2.7, 4.6) compared with subjects in the TC arm, 2.1 months (95% CI: 1.9, 3.1); hazard ratio 0.75 (95% CI: 0.62, 0.91), p = 0.0031. These results as well as other endpoints are shown in Table 6.

Table 6 : Other efficacy endpoints for Study DACO-016 (ITTpopulation).

Outcomes            DACOGEN                  TC (combined                  p-value group ) n=242 n= 243


CR + CRP                   43 (17.8%)                 19 (7.8%)               0.0011 
OR = 2.5

(1.40, 4.78)b
CR                         38 (15.7%)                 18 (7.4%)                 - 
EFSa                            3.5                       2.1                 0.0025 
(2.5, 4.1)b               (1.9, 2.8)b

HR = 0.75
(0.62, 0.90)b

PFSa                            3.7                       2.1                 0.0031 
(2.7, 4.6)b               (1.9, 3.1)b

HR = 0.75
(0.62, 0.91)b


CR = complete remission; CRp = complete remission with incomplete platelet recovery, EFS = event-free survival, PFS = progression-free survival, OR = odds ratio, HR = hazard ratio
- = Not evaluable a Reported as median months
 b 95% confidence intervals


Overall survival and complete remission rates in pre-specified disease-related sub-groups (i.e., cytogenetic risk, Eastern Cooperative Oncology Group [ECOG] score, age, type of AML, and baseline bone marrow blast count) were consistent with results for the overall study population.
The use of Dacogen as initial therapy was also evaluated in an open-label, single-arm, Phase II study (DACO- 017) in 55 subjects > 60 years with AML according to the WHO classification. The primary endpoint was complete remission (CR) rate that was assessed by independent expert review. The secondary endpoint of the study was overall survival. Dacogen was administered as a 1-hour intravenous infusion of 20 mg/m2 once daily for 5 consecutive days repeated every 4 weeks. In the Intent-to-Treat ITT analysis, a CR rate of 23.6% (95% CI: 13.2, 37) was observed in 13/55 subjects treated with Dacogen. The median time to CR was 4.1 months, and the median duration of CR was 18.2 months. The median overall survival in the Intent-to-Treat ITT population was 7.6 months (95% CI: 5.7, 11.5).
The efficacy and safety of Dacogen has not been evaluated in patients with acute promyelocytic leukaemia or CNS leukaemia.


MDS Clinical experience

A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and
Intermediate-1 prognostic scores. Eighty-nine patients were randomized to Dacogen therapy plus supportive care (only 83 received Dacogen), and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included.
Of the 170 patients included in the study, independent review (adjudicated diagnosis) found that 12 patients (9 in the Dacogen arm and 3 in the SC arm) had the diagnosis of AML at baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar between the 2 groups, as shown in Table 7.

Table 7 Baseline Demographics and Other Patient Characteristics (ITT) Demographic or Other Patient Dacogen                       Supportive Characteristic               N = 89                        Care
N= 81

Age (years)

Mean (±SD)                      69±10                              67±10 

Median (IQR)                    70 (65-76)                         70 (62-74) 
(Range: min-max)                (31-85)                            (30-82) 
Sex n (%)

Male                            59 (66)                            57 (70) 

Female                          30 (34)                            24 (30) 


Race n (%)

White                           83 (93)                            76 (94) 
Black                           4 (4)                              2 (2) 
Other                           2 (2)                              3 (4) 
Weeks Since MDS Diagnosis

Mean (±SD)                      86±131                             77±119 


Median (IQR)                    29 (10-87)                         35 (7-98) 

(Range: min-max)                (2-667)                            (2-865) 

Previous MDS Therapy n (%)

Yes                             27 (30)                            19 (23) 
No                              62 (70)                            62 (77) 
RBC Transfusion Status n
(%)

Independent                     23 (26)                            27 (33) 
Dependent                       66 (74)                            54 (67) 
Platelet Transfusion Status n
(%)

Independent                     69 (78)                            62 (77) 
Dependent                       20 (22)                            19 (23) 
IPSS Classification n (%)

Intermediate–1                  28 (31)                            24 (30) 
Intermediate–2                  38 (43)                            36 (44) 
High Risk                       23 (26)                            21 (26) 
FAB Classification n (%)

RA                              12 (13)                            12 (15) 
RARS                            7 (8)                              4 (5) RAEB                            47 (53)                            43 (53) 
RAEB-t                          17 (19)                            14 (17) 
CMML                            6 (7)                              8 (10) 


Patients randomized to the Dacogen arm received Dacogen intravenously infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The study endpoints were overall response rate (complete response + partial response) and time to AML or death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were required to be RBC and platelet transfusion independent during the time of response. Response criteria are given in Table 8: 

Table 8 Response Criteria for Phase 3 the controlled Trial in MDS*
Complete                       Bone                        On repeat aspirates: Response                       Marrow                      • < 5% myeloblasts (CR)                                                       • No dysplastic changes ≥ 8 weeks                      Peripheral                  In all samples during Blood                       response:
• Hgb > 11 g/dL (no transfusions or erythropoietin
• ANC ≥ 1500/μL (no growth factor)
• Platelets ≥ 100,000/ μL (no thrombopoietic agent)
• No blasts and no dysplasia
Partial                        Bone                        On repeat aspirates: Response                       Marrow                      • ≥ 50% decrease in blasts (PR)                                                       over
≥ 8 weeks                                                  pretreatment values OR
• Improvement to a less advanced
MDS FAB classification
Peripheral                  Same as for CR
Blood
* Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

The overall response rate (CR+PR) in the ITT population was 17% in Dacogen-treated patients and 0% in the SC group (p<0.001). (See Table 9) The overall response rate was 21% (12/56) in Dacogen-treated patients considered evaluable for response (i.e.,those patients with pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The median duration of response (range) for patients who responded to Dacogen was 288 days (116- 388) and median time to response (range) was 93 days (55-272). All but one of the Dacogen- treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13%  of Dacogen-treated patients who had hematologic improvement, defined. as a response less than PR lasting at least 8 weeks, compared to 7% of SC patients. Dacogen treatment did not significantly delay the median time to AML or death versus supportive care.

Table 9     Analysis of Response (ITT)
Parameter                            Dacogen                          Supportive N=89                               Care
N=81
Overall Response Rate                       15 (17%)**                            0 (0%) (CR+PR)†
Complete Response (CR)                          8 (9%)                             0 (0%) Partial Response (PR)                      7 (8%)                             0 (0%) Duration of Response
Median time to (CR+PR)                      93 (55-272)                             NA response - Days (range)
Median Duration of (CR+PR)                 288 (116-388)                            NA response - Days (range)

**p-value <0.001 from two-sided Fisher’s Exact Test comparing Dacogen vs. Supportive Care †In the statistical analysis plan, a p-value of ≤ 0.024 was required to achieve statistical significance.
All patients with a CR or PR were RBC and platelet transfusion independent in the absence of growth factors.
Responses occurred in patients with an adjudicated baseline diagnosis of AML.


Single-arm Studies
Three open-label, single-arm, multicenter studies were conducted to evaluate the safety and efficacy of Dacogen in MDS patients with any of the FAB subtypes. In one study conducted inNorth America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received Dacogen 20mg/m as an intravenous infusion over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The results were consistent with the results of the controlled trial and are summarized in Table 10.

Table 10   Baseline Demographics and Other Patient Characteristics (ITT) Demographic or Other Patient                Dacogen
Characteristic                              N = 99

Age (years)

Mean (±SD)                                          71±9
Median (Range: min-max)                             72 (34-87)

S n (%)



Male                                              71 (72)
Female                                            28 (28)


Race n (%)


White                                             86 (87)


Black                                             6 (6)

Asian                                             4 (4)

Other                                             3 (3)
Days From MDS Diagnosis to First Dose

Mean (±SD)                                        444±626

Median (Range: min-max)                           154 (7-3079)
Previous MDS Therapy n (%)

Yes                                               27 (27)

No                                                72 (73)
RBC Transfusion Status n (%)

Independent                                       33 (33)

Dependent                                         66 (67)
Platelet Transfusion Status n (%)

Independent                                       84 (85)

Dependent                                         15 (15)
IPSS Classification n (%)

Low Risk                                          1 (1)

Intermediate–1                                    52 (53)
Demographic or Other Patient

               Characteristic
Intermediate–2                                    23 (23)

High Risk                                         23 (23)
FAB Classification n (%)

RA                                                20 (20)

RARS                                              17 (17)
RAEB                                              45 (45)

RAEB-t                                            6 (6)
CMML                                              11 (11)



Table 11    Analysis of Response (ITT)*
Parameter                                        Dacogen
N=99
Overall Response Rate (CR+PR)                     16 (16%)
Complete Response (CR)                            15 (15%)
Partial Response (PR)                             1 (1%)

Duration of Response
Median time to (CR+PR) response - Days            162 (50-267)
(range)
Median Duration of (CR+PR) response -             443 (72-722+)
Days (range)


+ indicates censored observation
* Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

Pharmacokinetic Properties

5.2 Pharmacokinetic Properties
The population pharmacokinetic (PK) parameters of decitabine were pooled from 3 clinical studies in 45 patients with AML or myelodysplastic syndrome (MDS) utilizing the 5-Day regimen In each study,
decitabine PK was evaluated on the fifth day of the first treatment cycle.

Distribution

The pharmacokinetics of decitabine following intravenous administration as a 1-hour infusion were described by a linear two-compartment model, characterized by rapid elimination of the drug from the central compartment and by relatively slow distribution from the peripheral compartment. For a typical patient 
(weight 70 kg/body surface area 1.73 m2) the decitabine pharmacokinetic parameters are listed in Table 12 below.

Table 12 Summary of population PK analysis for a typical patient receiving daily 1-hour infusions of Dacogen
20 mg/m2 over 5 days every 4 weeks

Parametera                    Predicted Value        95% CI
Cmax (ng/mL)                        107             88.5 – 129
AUCcum (ng.h/mL)                     580             480 – 695 t1/2 (min)                          68.2            54.2 – 79.6
Vdss (L)                             116            84.1 – 153
CL (L/h)                             298             249 – 359
 a
The total dose per cycle was 100 mg/m2

Decitabine exhibits linear PK and following the intravenous infusion, steady-state concentrations are reached within 0.5 hour. Based on model simulation, PK parameters were independent of time (i.e., did not change from cycle to cycle) and no accumulation was observed with this dosing regimen. Plasma protein binding of decitabine is negligible (<1%). Decitabine Vdss in cancer patients is large indicating distribution into peripheral tissues. There was no evidence of dependencies on age, creatinine clearance, total bilirubin, or disease.

Biotransformation

Intracellularly, decitabine is activated through sequential phosphorylation via phosphokinase activities to the corresponding triphosphate, which is then incorporated by the DNA polymerase. In vitro metabolism data and the human mass balance study results indicated that the cytochrome P450 system is not involved in the metabolism of decitabine. The primary route of metabolism is likely through deamination by cytidine deaminase in the liver, kidney, intestinal epithelium and blood. Results from the human mass-balance study showed that unchanged decitabine in plasma accounted for approximately 2.4% of total radioactivity in plasma. The major circulating metabolites are not believed to be pharmacologically active. The presence of these metabolites in urine together with the high total body clearance and low urinary excretion of unchanged decitabine in the urine (~4% of the dose) indicate that decitabine is appreciably metabolised in vivo. In vitro studies show that decitabine does not inhibit nor induce CYP 450 enzymes up to more than 20-fold of the therapeutic maximum observed plasma concentration (Cmax). Thus; CYP-mediated metabolic drug interactions are not anticipated, and decitabine is unlikely to interact with agents metabolised through these pathways. In addition, in vitro data show that decitabine is a poor P-gp substrate.
Elimination

Mean plasma clearance following intravenous administration in cancer subjects was >200 L/h with moderate inter-subject variability (Coefficient of variation [CV] is approximately 50%). Excretion of unchanged drug appears to play only a minor role in the elimination of decitabine.

Results from a mass balance study with radioactive 14C-decitabine in cancer patients showed that 90% of the administered dose of decitabine (4% unchanged drug) is excreted in the urine.

Additional information on special populations
The effects of renal or hepatic impairment, gender, age or race on the pharmacokinetics of decitabine have not been formally studied. Information on special populations was derived from pharmacokinetic data from the 3 studies noted above, and from one Phase I study in MDS subjects (N=14; 15 mg/m2 X 3-hours q8h X 3 days).

Elderly
Population pharmacokinetic analysis showed that decitabine pharmacokinetics is not dependent on age (range studied 40 to 87 years; median 70 years).
Gender
Population pharmacokinetics analysis of decitabine did not show any clinically relevant difference between men and women.
Race
Most of the patients studied were Caucasian. However, the population pharmacokinetic analysis of decitabine indicated that race had no apparent effect on the exposure to decitabine.
Hepatic impairment
The PK of decitabine have not been formally studied in patients with hepatic impairment. Results from a human mass-balance study and in vitro experiments mentioned above indicated that the CYP enzymes are unlikely to be involved in the metabolism of decitabine. In addition, the limited data from the population PK analysis indicated no significant PK parameter dependencies on total bilirubin concentration despite a wide range of total bilirubin levels. Thus, decitabine exposure is not likely to be affected in patients with impaired hepatic function.
Renal impairment
The PK of decitabine have not been formally studied in patients with renal insufficiency. The population PK analysis on the limited decitabine data indicated no significant PK parameter dependencies on normalised creatinine clearance, an indicator of renal function. Thus, decitabine exposure is not likely to be affected in patients with impaired renal function.