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Vidaza

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Vidaza

CLINICAL PHARMACOLOGY

Mechanism Of Action

VIDAZA is a pyrimidine nucleoside analog of cytidine. VIDAZA is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

Pharmacokinetics

The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m² subcutaneous (SC) dose and a single 75 mg/m² intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour. The bioavailability of SC azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve. Mean volume of distribution following IV dosing is 76 ± 26 L. Mean apparent SC clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. The AUC and Cmax of SC administration of azacitidine in 21 patients with cancer were approximately dose proportional within the 25 to 100 mg/m² dose range. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.

Published studies indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for < 1% of administered radioactivity over 3 days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%. The mean elimination half-lives of total radioactivity (azacitidine and its metabolites) were similar after IV and SC administrations, about 4 hours.

Specific Populations

In patients with cancer the pharmacokinetics of azacitidine in 6 patients with normal renal function (CLcr > 80 mL/min) and 6 patients with severe renal impairment (CLcr < 30 mL/min) were compared following daily SC dosing (Days 1 through 5) at 75 mg/m²/day. Severe renal impairment increased azacitidine exposure by approximately 70% after single and 41% after multiple subcutaneous administrations. This increase in exposure was not correlated with an increase in adverse events. The exposure was similar to exposure in patients with normal renal function receiving 100 mg/m² . Therefore, a Cycle 1 dose modification is not recommended.

The effects of hepatic impairment, gender, age, or race on the pharmacokinetics of azacitidine have not been studied.

Drug-Drug Interactions

No formal clinical drug interaction studies with azacitidine have been conducted.

An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. Whether azacitidine metabolism may be affected by known microsomal enzyme inhibitors or inducers has not been studied.

An in vitro study with cultured human hepatocytes indicated that azacitidine at concentrations up to 100 μM (IV Cmax = 10.6 μM) does not cause any inhibition of CYP2B6 and CYP2C8. The potential of azacitidine to inhibit other cytochrome P450 (CYP) enzymes is not known.

In vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 μM to 100 μM does not induce CYP 1A2, 2C19, or 3A4/5.

Clinical Studies

Myelodysplastic Syndromes (MDS)

Study 1 was a randomized, open-label, controlled trial carried out in 53 U.S. sites compared the safety and efficacy of subcutaneous VIDAZA plus supportive care with supportive care alone (“observation”) in patients with any of the five FAB subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). RA and RARS patients were included if they met one or more of the following criteria: required packed RBC transfusions; had platelet counts ≤ 50.0 x 109/L; required platelet transfusions; or were neutropenic (ANC < 1.0 x 109/L) with infections requiring treatment with antibiotics. Patients with acute myelogenous leukemia (AML) were not intended to be included. Supportive care allowed in this study included blood transfusion products, antibiotics, antiemetics, analgesics and antipyretics. The use of hematopoeitic growth factors was prohibited. Baseline patient and disease characteristics are summarized in Table 3; the 2 groups were similar.

VIDAZA was administered at a subcutaneous dose of 75 mg/m²daily for 7 days every 4 weeks. The dose was increased to 100 mg/m² if no beneficial effect was seen after 2 treatment cycles. The dose was decreased and/or delayed based on hematologic response or evidence of renal toxicity. Patients in the observation arm were allowed by protocol to cross over to VIDAZA if they had increases in bone marrow blasts, decreases in hemoglobin, increases in red cell transfusion requirements, or decreases in platelets, or if they required a platelet transfusion or developed a clinical infection requiring treatment with antibiotics. For purposes of assessing efficacy, the primary endpoint was response rate (as defined in Table 4).

Of the 191 patients included in the study, independent review (adjudicated diagnosis) found that 19 had the diagnosis of AML at baseline. These patients were excluded from the primary analysis of response rate, although they were included in an intent-to-treat (ITT) analysis of all patients randomized. Approximately 55% of the patients randomized to observation crossed over to receive VIDAZA treatment.

Table 3: Baseline Demographics and Disease Characteristics

  VIDAZA
(N=99)
Observation
(N=92)
Gender (n%)
  Male 72 (72.7) 60 (65.2)
  Female 27 (27.3) 32 (34.8)
Race (n%)
  White 93 (93.9) 85 (92.4)
  Black 1 (1.0) 1 (1.1)
  Hispanic 3 (3.0) 5 (5.4)
  Asian/Oriental 2 (2.0) 1 (1.1)
Age (years)
  N 99 91
  Mean ± SD 67.3 ± 10.39 68.0 ± 10.23
  Range 31 - 92 35 - 88
Adjudicated MDS diagnosis at study entry (n%)
  RA 21 (21.2) 18 (19.6)
  RARS 6 (6.1) 5 (5.4)
  RAEB 38 (38.4) 39 (42.4)
  RAEB-T 16 (16.2) 14 (15.2)
  CMMoL 8 (8.1) 7 (7.6)
  AML 10 (10.1) 9 (9.8)
Transfusion product used in 3 months before study entry (n%)
  Any transfusion product 70 (70.7) 59 (64.1)
  Blood cells, packed human 66 (66.7) 55 (59.8)
  Platelets, human blood 15 (15.2) 12 (13.0)
  Hetastarch 0(0.0) 1(1.1)
  Plasma protein fraction 1(1.0) 0(0.0)
  Other 2(2.0) 2(2.2)

Table 4: Response Criteria

    RA RARS RAEB RAEB-T CMMoL
Complete Response (CR), duration ≥ 4 weeks Marrow < 5% blasts
Peripheral Blood Normal CBC if abnormal at baseline Absence of blasts in the peripheral circulation
Partial Response (PR), duration ≥ 4 weeks Marrow No marrow requirements ≥ 50% decrease in blasts Improvement of marrow dyspoiesis
Peripheral Blood ≥ 50% restoration in the deficit from normal levels of baseline white cells, hemoglobin and platelets if abnormal at baseline
No blasts in the peripheral circulation
For CMMoL, if WBC is elevated at baseline, a ≥ 75% reduction in the excess count over the upper limit of normal

The overall response rate (CR + PR) of 15.7% in VIDAZA-treated patients without AML (16.2% for all VIDAZA randomized patients including AML) was statistically significantly higher than the response rate of 0% in the observation group (p < 0.0001) (Table 5). The majority of patients who achieved either CR or PR had either 2 or 3 cell line abnormalities at baseline (79%; 11/14) and had elevated bone marrow blasts or were transfusion dependent at baseline. Patients responding to VIDAZA had a decrease in bone marrow blasts percentage, or an increase in platelets, hemoglobin or WBC. Greater than 90% of the responders initially demonstrated these changes by the 5th treatment cycle. All patients who had been transfusion dependent became transfusion independent during PR or CR. The mean and median duration of clinical response of PR or better was estimated as 512 and 330 days, respectively; 75% of the responding patients were still in PR or better at completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML.

Table 5: Response Rates

  VIDAZA (N=89) Observation Before Crossover
(N=83)
 
Response n (%) n (%) P value
  Overall (CR+PR) 14 (15.7) 0 ( 0.0) ( < 0.0001)
    Complete (CR) 5 ( 5.6) 0 ( 0.0) -0.06
    Partial (PR) 9 (10.1) 0 ( 0.0) --

Patients in the observation group who crossed over to receive VIDAZA treatment (47 patients) had a response rate of 12.8%.

Study 2, a multi-center, open-label, single-arm study of 72 patients with RAEB, RAEB-T, CMMoL, or AML was also carried out. Treatment with subcutaneous VIDAZA resulted in a response rate (CR + PR) of 13.9%, using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 810 and 430 days, respectively; 80% of the responding patients were still in PR or better at the time of completion of study involvement. In Study 3, another open-label, single-arm study of 48 patients with RAEB, RAEB-T, or AML, treatment with intravenous VIDAZA resulted in a response rate of 18.8%, again using criteria similar to those described above. The mean and median duration of clinical response of PR or better was estimated as 389 and 281 days, respectively; 67% of the responding patients were still in PR or better at the time of completion of treatment. Response occurred in all MDS subtypes as well as in patients with adjudicated baseline diagnosis of AML in both of these studies. VIDAZA dosage regimens in these 2 studies were similar to the regimen used in the controlled study.

Benefit was seen in patients who did not meet the criteria for PR or better, but were considered “improved.” About 24% of VIDAZA-treated patients were considered improved, and about 2/3 of those lost transfusion dependence. In the observation group, only 5/83 patients met criteria for improvement; none lost transfusion dependence. In all 3 studies, about 19% of patients met criteria for improvement with a median duration of 195 days.

Study 4 was an international, multicenter, open-label, randomized trial in MDS patients with RAEB, RAEB-T or modified CMMoL according to FAB classification and Intermediate-2 and High risk according to IPSS classification. Of the 358 patients enrolled in the study, 179 were randomized to receive azacitidine plus best supportive care (BSC) and 179 were randomized to receive conventional care regimens (CCR) plus BSC (105 to BSC alone, 49 to low dose cytarabine and 25 to chemotherapy with cytarabine and anthracycline). The primary efficacy endpoint was overall survival.

The azacitidine and CCR groups were comparable for baseline parameters. The median age of patients was 69 years (range was 38-88 years), 98% were Caucasian, and 70% were male. At baseline, 95% of the patients were higher risk by FAB classification: RAEB (58%), RAEB-T (34%), and CMMoL (3%). By IPSS classification, 87% were higher risk: Int-2 (41%), High (47%). At baseline, 32% of patients met WHO criteria for AML.

Azacitidine was administered subcutaneously at a dose of 75 mg/m² daily for 7 consecutive days every 28 days (which constituted one cycle of therapy). Patients continued treatment until disease progression, relapse after response, or unacceptable toxicity. Azacitidine patients were treated for a median of 9 cycles (range 1 to 39), BSC only patients for a median of 7 cycles (range 1 to 26), low dose cytarabine patients for a median of 4.5 cycles (range 1 to 15), and chemotherapy with cytarabine and anthracycline patients for a median of 1 cycle (range 1 to 3, i.e. induction plus 1 or 2 consolidation cycles).

In the Intent-to-Treat analysis, patients treated with azacitidine demonstrated a statistically significant difference in overall survival as compared to patients treated with CCR (median survival of 24.5 months vs. 15.0 months; stratified log-rank p=0.0001). The hazard ratio describing this treatment effect was 0.58 (95% CI: 0.43, 0.77).

Kaplan-Meier Curve of Time to Death from Any Cause: (Intent-to-Treat Population)

Kaplan-Meier Curve of Time to Death from Any Cause - Illustration

Key: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval; HR = Hazard Ratio

Azacitidine treatment led to a reduced need for red blood cell transfusions (see Table 6). In patients treated with azacitidine who were RBC transfusion dependent at baseline and became transfusion independent, the median duration of RBC transfusion independence was 13.0 months.

Table 6: Effect of Azacitidine on RBC Transfusions in MDS Patients

Efficacy Parameter Azacitidine plus BSC
(n= 179)
Conventional Care Regimens
(n= 179)
Number and percent of patients who were transfusion dependent at baseline who became transfusion independent on treatment1 50/111 (45.0%) 13/114 (11.4%)
(95% CI: 35.6%, 54.8%) (95% CI: 6.2%, 18.7%)
Number and percent of patients who were transfusion-independent at baseline who became transfusion-dependent on treatment 10/68 (14.7%) 28/65 (43.1%)
(95% CI: 7.3%, 25.4%) (95% CI: 30.9%, 56.0%)
1A patient was considered RBC transfusion independent during the treatment period if the patient had no RBC transfusions during any 56 consecutive days or more during the treatment period. Otherwise, the patient was considered transfusion dependent.

Last reviewed on RxList: 1/23/2014
This monograph has been modified to include the generic and brand name in many instances.

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