Decitabine (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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.

12.3 Pharmacokinetics

Pharmacokinetic (PK) 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 clearance (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)

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)

* 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.

Specific Populations

Patients with Renal Impairment

There are no data on the use of Decitabine for Injection in patients with renal impairment.

Patients with Hepatic Impairment

There are no data on the use of Decitabine for Injection in patients with hepatic impairment.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, 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.

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 white blood cell 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.

14 CLINICAL STUDIES

14.1 Controlled Trial in Myelodysplastic Syndrome

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 Decitabine for Injection therapy plus supportive care (only 83 received Decitabine for 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 Decitabine for 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

Decitabine for Injection 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 (%) IndependentDependent

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 Decitabine for Injection arm received Decitabine for 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 the Controlled Trial in MDS *
*
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 Decitabine for Injection -treated patients and 0% in the SC group (p<0.001). (See Table 6) The overall response rate was 21% (12/56) in Decitabine for 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 Decitabine for Injection was 288 days (116 to 388) and median time to response (range) was 93 days (55 to 272). All but one of the Decitabine for Injection -treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 13% of Decitabine for 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. Decitabine for Injection treatment did not significantly delay the median time to AML or death versus supportive care.

Table 6 Analysis of Response (ITT)

Parameter

Decitabine for Injection N=89

Supportive Care N=81

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

**p-value <0.001 from two-sided Fisher’s Exact Test comparing Decitabine For 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.

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