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Dacogen (Decitabine) - Description and Clinical Pharmacology

 
 



RECENT MAJOR CHANGES

  DESCRIPTION

Dacogen (decitabine) for Injection contains decitabine (5-aza-2'-deoxycitidine), an analogue of the natural nucleoside 2'-deoxycytidine. Decitabine is a fine, white to almost white powder with the molecular formula of C8H12N4O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1 H)-one and it has the following structural formula:

Decitabine is slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly soluble in water and soluble in dimethylsulfoxide (DMSO).

Dacogen (decitabine) for Injection is a white to almost white sterile lyophilized powder supplied in a clear colorless glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide.

  CLINICAL PHARMACOLOGY

  Mechanism of Action

Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

  Pharmacodynamics

Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been no studies of decitabine-induced hypomethylation and pharmacokinetic parameters.

  Pharmacokinetics

Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour intravenously (treatment Option 2), Fourteen patients received 15 mg/m2 infused over 3 hours (treatment Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC per cycle following treatment Option 1.

Table 3 Mean (CV% or 95% CI) Pharmacokinetic Parameters of Decitabine
Dose Cmax
(ng/mL)
AUC0-∞
(ng•h/mL)
T1/2(h) CL
(L/h/m2)
AUCCumulative*** (ng•h/mL)
* N=14, **N=11, ***N=35 Cumulative AUC per cycle
15 mg/m2 3-hr infusion every 8 hours for 3 days (Option 1)* 73.8
(66)
163
(62)
0.62
(49)
125
(53)
1332
(1010-1730)
20 mg/m2 1-hr infusion daily for 5 days (Option 2)** 147
(49)
115
(43)
0.54
(43)
210
(47)
570
(470-700)

The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.

  NONCLINICAL TOXICOLOGY

  Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenicity studies with decitabine have not been conducted.

The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.

The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased.

  CLINICAL STUDIES

  Controlled Trial

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 4.

Table 4 Baseline Demographics and Other Patient Characteristics (ITT)

Demographic or Other Patient Characteristic

Dacogen
N = 89
Supportive Care
N= 81
Age (years)
Mean (±SD)
Median (IQR)
(Range: min-max)

69±10
70 (65-76)
(31-85)

67±10
70 (62-74)
(30-82)
Gender n (%)
Male
Female

59 (66)
30 (34)

57 (70)
24 (30)
Race n (%)
White
Black
Other

83 (93)
4 (4)
2 (2)

76 (94)
2 (2)
3 (4)
Weeks Since MDS Diagnosis
Mean (±SD)
Median (IQR)
(Range: min-max)

86±131
29 (10-87)
(2-667)

77±119
35 (7-98)
(2-865)
Previous MDS Therapy n (%)
Yes
No

27 (30)
62 (70)

19 (23)
62 (77)
RBC Transfusion Status n (%)
Independent
Dependent

23 (26)
66 (74)

27 (33)
54 (67)
Platelet Transfusion Status n (%)
Independent
Dependent

69 (78)
20 (22)

62 (77)
19 (23)
IPSS Classification n (%)
Intermediate-1
Intermediate-2
High Risk

28 (31)
38 (43)
23 (26)

24 (30)
36 (44)
21 (26)
FAB Classification n (%)
RA
RARS
RAEB
RAEB-t
CMML

12 (13)
7 (8)
47 (53)
17 (19)
6 (7)

12 (15)
4 (5)
43 (53)
14 (17)
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 5:

Table 5 Response Criteria for Phase 3 Trial*
* Cheson BD, Bennett JM, et al. Report of an International Working Group to Standardize Response Criteria for MDS. Blood. 2000; 96:3671-3674.

Complete
Response (CR)
≥ 8 weeks
Bone Marrow On repeat aspirates:
• < 5% myeloblasts
• No dysplastic changes
Peripheral Blood In all samples during 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
Response (PR)
≥ 8 weeks
Bone Marrow On repeat aspirates:
• ≥ 50% decrease in blasts over pretreatment values
OR
• Improvement to a less advanced MDS FAB classification
Peripheral Blood Same as for CR

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 6) 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 6  Analysis of Response (ITT)

Parameter

Dacogen
N=89

Supportive Care
N=81
**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.
Overall Response Rate (CR+PR)+ Complete Response (CR)
Partial Response (PR)
15 (17%)**
8 (9%)
7 (8%)
0 (0%)
0 (0%)
0 (0%)
Duration of Response
Median time to (CR+PR) response - Days (range)
Median Duration of (CR+PR) response - Days (range)

93 (55-272)

288 (116-388)

NA

NA

  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 in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received Dacogen by intravenous infusion at a dose of 20 mg/m2 IV 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 summarized in Table 8.

Table 7 Baseline Demographics and Other Patient Characteristics (ITT)

Demographic or Other Patient Characteristic

Dacogen
N = 99
Age (years)
Mean (±SD)
Median (Range: min-max)

71±9
72 (34-87)
Gender n (%)
Male
Female

71 (72)
28 (28)
Race n (%)
White
Black
Asian
Other

86 (87)
6 (6)
4 (4)
3 (3)
Days From MDS Diagnosis to First Dose
Mean (±SD)
Median (Range: min-max)

444±626
154 (7-3079)
Previous MDS Therapy n (%)
Yes
No

27 (27)
72 (73)
RBC Transfusion Status n (%)
Independent
Dependent

33 (33)
66 (67)
Platelet Transfusion Status n (%)
Independent
Dependent

84 (85)
15 (15)
IPSS Classification n (%)
Low Risk
Intermediate-1
Intermediate-2
High Risk

1 (1)
52 (53)
23 (23)
23 (23)
FAB Classification n (%)
RA
RARS
RAEB
RAEB-t
CMML

20 (20)
17 (17)
45 (45)
6 (6)
11 (11)
Table 8 Analysis of Response (ITT)

Parameter

Dacogen
N=99
+ 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.
Overall Response Rate (CR+PR)
Complete Response (CR)
Partial Response (PR)
16 (16%)
15 (15%)
1 (1%)
Duration of Response
Median time to (CR+PR) response - Days (range)
Median Duration of (CR+PR) response - Days (range)

162 (50-267)
443 (72-722+)

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