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 3). The overall response rate was 21% (12/56) in
Dacogen-treated patients considered evaluable for response (ie, 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 4th 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. (See Table 3).
|
Table 3. Analysis of Response (ITT). |
|
Parameter |
Dacogen (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
Medium time to (CR + PR) response
Day (range)
Median Duration of (CR + PR)
response
Days (range) |
93 (55-272)
288 (116-388) |
NA
NA |
|
** p-value <0.001 from 2-sided Fisher's
Exact Test comparing Dacogen versus Supportive Care.
+ In the co-primary endpoint model, 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. |
Phase 2 Studies: Two additional open-label, single-arm, multicenter studies in
Europe were conducted to evaluate the safety and efficacy of Dacogen in MDS patients with
any of the FAB subtypes. Dacogen was IV infused at a dose of 15 mg/m2 over a 4-hr period,
every 8 hrs, on days 1, 2 and 3 of week 1 every 6 weeks (1 cycle). The results of the Phase 2
studies were consistent with the results of the Phase 3 trial with overall response rates of 26% (N=66) and 24% (N=98).
Pharmacokinetics: No information is available on the pharmacokinetics of decitabine
at the indicated dosage of 15 mg/m2. Patients with advanced solid tumors received a 72-hr
infusion of decitabine at 20-30 mg/m2/day. Decitabine pharmacokinetics were characterized by
a biphasic disposition. The total body clearance (mean±SD) was 124±19 L/hr/m2, and the terminal
phase elimination half-life was 0.51±0.31 hr. Plasma protein-binding of decitabine is negligible (<1%).
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.
Special Populations: The effects of renal or hepatic impairment, gender, age or race
on the pharmacokinetics of decitabine have not been studied.
INDICATIONS: Myelodysplastic syndromes (MDS) including refractory
anemia &/or w/ ringed sideroblasts, w/ excess blasts, w/ excess blasts in transformation & chronic myelomonocytic leukemia.
DOSAGE: Treatment cycle: 15 mg/m2 by continuous IV infusion over
3 hr repeated 8 hrly for 3 days. Repeat cycle every 6 wk up to a min of 4 cycles. If
hematologic recovery from a previous treatment cycle requires >6 wk, reduce dose of
the next cycle to 11 mg/m2 8 hrly & delay dosing by 2 or 4 wk.
OVERDOSAGE: There is no known antidote for overdosage with Dacogen.
Higher doses are associated with increased myelosuppression including prolonged
neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.
CONTRAINDICATIONS: Pregnancy.
PRECAUTIONS: Monitor FBC & platelet count. Renal or hepatic dysfunction. Lactation.
ADVERSE REACTIONS: Neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia.
PRESENTATION/PACKING: Vial 50 mg x 1's.
US FDA Preg Cat, ♀ : D
Launching Date : July 2008
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