Dacogen

Dacogen Mechanism of Action

Manufacturer:

Janssen

Distributor:

Zuellig Pharma
Full Prescribing Info
Action
Pharmacotherapeutic Group: Antineoplastic and Immunomodulating Agent, Pyrimidine Analogues. ATC Code: L01BC08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Decitabine (5-aza-2'-deoxycytidine) is a cytosine nucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that can result in reactivation of tumor suppressor genes, induction of cellular differentiation or cellular senescence followed by programmed cell death.
Clinical Studies: Clinical studies in MDS: Phase 2 Study (DACO-020): 5-Day Dosing Regimen: An open-label, single arm, multicenter study (DACO-20) was conducted to evaluate the efficacy of DACOGEN in MDS patients with any of the FAB subtypes. In this study, 99 patients with IPSS Intermediate-1, Intermediate-2, or high risk prognostic scores received DACOGEN by the 5-Day dosing regimen of 20 mg/m2 intravenous infusion over 1-hour daily, on Days 1 to 5 every 4 weeks (1 cycle). The results were consistent with the results of the Phase 3 study and summarized in Table 1. (See Table 1.)

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Phase 3 Study (D-0007): 3-Day Dosing Regimen: A randomized, open-label multicenter, controlled study (D-0007) evaluated DACOGEN in 170 subjects with MDS meeting FAB classification criteria and IPSS High Risk, Intermediate-2, and Intermediate-1 prognostic scores. DACOGEN was administered as the 3-Day dosing regimen of 15 mg/m2, by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 consecutive days of every 6-weeks cycle.
In the Phase 3 clinical study, CRs and PRs were seen across all IPSS subgroups. However, a greater beneficial effect was evident in the subgroups of patients classified as Int-2 and High Risk, see Table 2.

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Clinical studies in AML: The use of DACOGEN was studied in an open-label, randomized, multicenter Phase 3 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. 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. 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 population was 7.7 months in subjects treated with DACOGEN compared to 5.0 months for subjects in the TC arm (hazard ratio [HR] 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). (See Figure 1.)

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In an analysis with an additional 1 year of mature survival data, the effect of DACOGEN on overall survival demonstrated a clinically meaningful improvement compared to the TC arm (7.7 months versus 5.0 months, respectively, HR=0.82; 95% CI: 0.68, 0.99, nominal p-value=0.0373, Figure 2). (See Figure 2.)

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Based on the initial analysis in the intent-to-treat population, a statistically significant difference in complete remission rate (CR+CRp) was achieved in favor 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); HR=0.75; 95% CI: 0.62; 0.91, p=0.0031. These results as well as other endpoints are shown in Table 3. (See Table 3.)

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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 2 study (DACO-017) in 55 subjects >60 years with AML according to the WHO classification. The primary endpoint was CR rate 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 ITT analysis, a CR rate of 23.6% (95% CI: 13.2% to 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 population was 7.6 months (95% CI: 5.7, 11.5).
Pharmacokinetics: The population pharmacokinetic (PK) parameters of decitabine were pooled from 3 clinical studies [DACO-017 (n=11), DACO-020 (n=11) and DACO-016 (n=23)] utilizing the 5-Day regimen (20 mg/m2 x 1-hour x 5 days every 4 weeks) and 1 study, DACO-018 (n=12), utilizing the 3-Day regimen (15 mg/m2 x 3-hours every 8 hours x 3 days every 6 weeks) in MDS or AML patients. In the 5-Day regimen, decitabine PK was evaluated on the fifth day of the first treatment cycle. Total dose per cycle was 100 mg/m2. In the 3-Day regimen, decitabine PK was evaluated after the first dose of each dosing day of the first treatment cycle. Total dose per cycle was 135 mg/m2.
Distribution: The pharmacokinetics of decitabine following intravenous administration as a 1-hour (5-Day regimen) or 3-hour (3-Day regimen) infusion was 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 PK parameters are listed in Table 4 as follows. (See Table 4.)

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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 of the drug into peripheral tissues. There was no evidence of dependencies on age, creatinine clearance, total bilirubin, or disease.
Metabolism: Intracellularly, decitabine is activated through sequential phosphorylation via phosphokinase activities to the corresponding triphosphate, which is then incorporated by the DNA polymerase. In light of in vitro metabolism data, 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 drug in the urine (~4% of the dose) indicate that decitabine is appreciably metabolized in vivo. 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.
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 4 studies noted previously.
Elderly: Population pharmacokinetic analysis showed that decitabine PK are not dependent on age (range studied 40 to 87 years; median 70 years).
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 previously 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 normalized creatinine clearance, an indicator of renal function. Thus, decitabine exposure is not likely to be affected in patients with impaired renal function.
Other Populations: Gender: Population PK analysis of decitabine did not show any clinically relevant different between men and women.
Race: Most of the patients studied were Caucasian. However, the population PK analysis of decitabine indicated that race had no apparent effect on the exposure to decitabine.
Toxicology: Non-Clinical Information: Formal carcinogenicity studies have not been performed with decitabine. Evidence from the literature indicates that decitabine has carcinogenic potential. The available data from in vitro and in vivo studies provide sufficient evidence that decitabine has genotoxic potential. Data from the literature also indicate that decitabine has adverse effects on all aspects of the reproductive cycle, including fertility, embryo-fetal development and post-natal development. Multi-cycle repeat-dose toxicity studies in rats and rabbits indicated that the primary toxicity was myelosuppression, including effects on bone marrow, which was reversible on cessation of treatment. Gastrointestinal toxicity was also observed and in males, testicular atrophy which did not reverse over the scheduled recovery periods. Decitabine administration to neonatal/juvenile rats showed a comparable general toxicity profile as in older rats. Neurobehavioral development and reproductive capacity were unaffected when neonatal/juvenile rats were treated at dose levels inducing myelosuppression.
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