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Dacogen

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Dacogen

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 decitabineinduced 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)

(h)
CL
(L/h/m²)
AUC Cumulative***
(ng •h/mL)
15 mg/m² 3-hr infusion every 8 hours for 3 days (Option1)* 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)
* N=14, **N=11, ***N=35 Cumulative AUC per cycle

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.

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 (decitabine injection) therapy plus supportive care (only 83 received Dacogen (decitabine injection) ), 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 (decitabine injection) 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) 69±10 67±10
  Median (IQR) 70 (65-76) 70 (62-74)
  (Range: min-max) (31-85) (30-82)
Gender 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
  (%) 69 (78) 62 (77)
  Independent 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 (decitabine injection) arm received Dacogen (decitabine injection) 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*

Complete Response (CR) ≥ 8 weeks Bone Marrow On repeat aspirates:
  • < 5% myeloblasts
  • No dysplastic change
Peripheral Blood In all samples during response:
  • Hgb > 11 g/dL (no transfusions or erythropoietin
  • ANC ≥ 1500/μL (no growth factor)
  • Platelets ≥ 00,000/ μL (no thrombopoietic agent)
  • No blasts and no dysplasi
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
* 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 (decitabine injection) -treated patients and 0% in the SC group (p < 0.001). (See Table 6) The overall response rate was 21% (12/56) in Dacogen (decitabine injection) -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 (decitabine injection) was 288 days (116-388) and median time to response (range) was 93 days (55-272). All but one of the Dacogen (decitabine injection) -treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of Dacogen (decitabine injection) -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 (decitabine injection) 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
Overall Response Rate (CR+PR)† 15 (17%)** 0 (0%)
  Complete Response (CR) 8 (9%) 0 (0%)
  Partial Response (PR) 7 (8%) 0 (0%)
Duration of Response
  Median time to (CR+PR) response - Days (range) 93 (55-272) NA
  Median Duration of (CR+PR) response - Days (range) 288 (116-388) NA
**p-value < 0.001 from two-sided Fisher's Exact Test comparing Dacogen (decitabine injection) 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 (decitabine injection) 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 (decitabine injection) 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) 71±9
  Median (Range: min-max) 72 (34-87)
Gender 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 444±626
  Mean (±SD) 154 (7-3079)
  Median (Range: min-max)  
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)
  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 8 : Analysis of Response (ITT)*

Parameter Dacogen
N=99
Overall Response Rate (CR+PR) 16 (16%)
  Complete Response (CR) Exact Test comparing 15 (15%)
  Partial Response (PR) 1 (1%)
Duration of Response
  Median time to (CR+PR) response - Days (range) 162 (50-267)
  Median Duration of (CR+PR) response -Days (range) 443 (72-722+)
+ 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.

Last reviewed on RxList: 4/1/2010
This monograph has been modified to include the generic and brand name in many instances.

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