Dacogen (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

14.1 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 DacogenN = 89 Supportive CareN = 81
Age (years)
Mean (±SD) Median (IQR) (Range: min-max) 69±1070 (65-76)(31-85) 67±1070 (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±13129 (10-87)(2-667) 77±11935 (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 MDS 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 valuesOR
  • 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 DacogenN=89 Supportive CareN=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.
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

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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