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Doxil

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Doxil




CLINICAL PHARMACOLOGY

Mechanism Of Action

The active ingredient of DOXIL is doxorubicin HCl. The mechanism of action of doxorubicin HCl is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

Pharmacokinetics

The pharmacokinetic parameters for total doxorubicin following a single dose of DOXIL infused over 30 minutes are presented in Table 8.

Table 8: Pharmacokinetic Parameters of Total Doxorubicin from DOXIL in Patients With AIDS-Related Kaposi’s Sarcoma

Parameter (units) Dose
10 mg/m² 20 mg/m²
Peak Plasma Concentration (μg/mL) 4.12 ± 0.215 8.34 ± 0.49
Plasma Clearance (L/h/m²) 0.056 ± 0.01 0.041 ± 0.004
Steady State Volume of Distribution (L/m²) 2.83 ± 0.145 2.72 ± 0.120
AUC (μg/mL•h) 277 ± 32.9 590 ± 58.7
First Phase (λ1) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4
Second Phase (λ1) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8
N=23
Mean ± Standard Error

DOXIL displayed linear pharmacokinetics over the range of 10 to 20 mg/m². Relative to DOXIL doses at or below 20 mg/m², the pharmacokinetics of total doxorubicin following a 50 mg/m² DOXIL dose are nonlinear. At this dose, the elimination half-life of DOXIL is longer and the clearance lower compared to a 20 mg/m² dose.

Distribution

Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation.

In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m²), the small steady state volume of distribution of liposomal doxorubicin suggests that DOXIL is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of DOXIL has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

Metabolism

Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m² DOXIL.

Elimination

The plasma clearance of total doxorubicin from DOXIL was 0.041 L/h/m² at a dose of 20 mg/m² . Following administration of doxorubicin HCl, the plasma clearance of doxorubicin is 24 to 35 L/h/m² .

Clinical Studies

Ovarian Cancer

DOXIL was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel-and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received DOXIL at 50 mg/m² every 3 or 4 weeks for 3-6+ cycles in the absence of dose-limiting toxicity or disease progression.

The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%).

The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel-and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression.

The response rates for the individual single arm trials are given in Table 9 below.

Table 9: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Trials

  Trial 1 (U.S.)
N=27
Trial 2 (U.S.)
N=82
Trial 3 (non-U.S.)
N=36
Response Rate 22.2% 17.1% 0%
95% Confidence Interval 8.6% - 42.3% 9.7% - 27.0% 0.0% - 9.7%

In a pooled analysis of Trials 1-3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks.

In Trial 4, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either DOXIL 50 mg/m² every 4 weeks (n=239) or topotecan 1.5 mg/m² daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 cm in size). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate.

Of the 474 patients, the median age at diagnosis was 60 years (range 25 to 87), 90% were FIGO stage III and IV; 46% were platinum sensitive; and 45% had bulky disease.

There was no statistically significant difference in TTP between the two arms. Results are provided in Table 10.

Table 10: Results of Efficacy Analyses1

  Protocol Defined ITT Population
DOXIL
(n=239)
Topotecan
(n=235)
TTP (Protocol Specified Primary Endpoint)
Median (Months)2 4.1 4.2
p-value3 0.62
Hazard Ratio4 0.96
95% CI for Hazard Ratio (0.76, 1.20)
Overall Survival
Median (Months) 2 14.4 13.7
p-value5 0.05
Hazard Ratio4 0.82
95% CI for Hazard Ratio (0.68, 1.00)
Response Rate
Overall Response n (%) 47 (19.7) 40 (17.0)
Complete Response n (%) 9 (3.8) 11 (4.7)
Partial Response n (%) 38 (15.9) 29 (12.3)
Median Duration of Response (Months) 2 6.9 5.9
1Analysis based on investigators' strata for protocol defined ITT population.
2Kaplan-Meier estimates.
3p-value is based on the stratified log-rank test.
4Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for DOXIL.
5p-value not adjusted for multiple comparisons.

AIDS-Related Kaposi’s Sarcoma

DOXIL was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m² every 3 weeks, until disease progression or unacceptable toxicity (Trial 5).

Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin HCl.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of DOXIL was 154 mg/m² (range 20 to 620 mg/m²). Among the 77 patients, mean age was 38 years (range 24 to 54); 87% were Caucasian, 5% Hispanic, 4% Black, and 4% Asian/Other/Unknown; median CD4 count was 10 cells/mm³; ACTG staging criteria were 78% poor risk for tumor burden, 96% poor risk for immune system, and 58% poor risk for systemic illness at baseline; and mean Karnofsky status score was 74%. All patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonar y lesions, and 14% had lesions of the stomach/intestine.

Two analyses of tumor response were used: one based on investigator assessment of changes in lesions based on modified ACTG criteria (partial response defined as no new lesions, sites of disease, or worsening edema; flattening of ≥ 50% of previously raised lesions or area of indicator lesions decreasing by ≥ 50%; and response lasting at least 21 days with no prior progression), and one based on changes in up to five prospectively indentified representative indicator lesions (partial response defined as flattening of ≥ 50% of previously raised indicator lesions, or > 50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression).

Of the 77 patients, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment; analyses of tumor responses are shown in Table 11.

Table 11: Response in Patients with Refractory1 AIDS-Related Kaposi’s Sarcoma

Investigator Assessment All Evaluable Patients
(n=34)
Evaluable Patients Who Received Prior Doxorubicin
(n=20)
Response2
  Partial (PR) 27% 30%
  Stable 29% 40%
  Progression 44% 30%
Duration of PR (Days)
  Median 73 89
  Range 42+ -210+ 42+ -210+
Time to PR (Days)
  Median 43 53
  Range 15 - 133 15 - 109
Indicator Lesion Assessment All Evaluable Patients (n=42) Evaluable Patients Who Received Prior Doxorubicin (n=23)
Response2
  Partial (PR) 48% 52%
  Stable 26% 30%
  Progression 26% 17%
Duration of PR (Days)
  Median 71 79
  Range 22+ -210+ 35 -210+
Time to PR (Days)
  Median 22 48
  Range 15 - 109 15 - 109
1Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy.
2There were no complete responses in this population.

Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent DOXIL and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses.

Multiple Myeloma

The efficacy of DOXIL in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either DOXIL (30 mg/m²) administered IV on day 4 following bortezomib (1.3 mg/m² IV on days 1, 4 , 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1-18).

The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).

Table 12 : Summary of Baseline Patient and Disease Characteristics

Patient Characteristics DOXIL + bortezomib
n=324
bortezomib
n=322
Median age in years (range) 61 (28, 85) 62 (34, 88)
% Male/female 58 / 42 54 / 46
% Caucasian/Black/other 90 / 6/ 4 94 / 4 / 2%
Disease Characteristics
% with IgG/IgA/Light chain 57 / 27 / 12 62 / 24 /11
% β 2-microglobulin group
   ≤ 2.5 mg/L 14 14
   > 2.5 mg/L and ≤ 5.5 mg/L 56 55
   > 5.5 mg/L 30 31
Serum M-protein (g/dL): Median (Range) 2.5 (0-10.0) 2.7 (0-10.0)
Urine M-protein (mg/24 hours): Median (Range) 107 (0-24883) 66 (0-39657)
Median Months Since Diagnosis 35.2 37.5
% Prior Therapy
  One 34 34
  More than one 66 66
Prior Systemic Therapies for Multiple Myeloma
  Corticosteroid (%) 99 > 99
  Anthracyclines 68 67
  Alkylating agent (%) 92 90
  Thalidomide/lenalidomide (%) 40 43
  Stem cell transplantation (%) 57 54

The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the DOXIL + bortezomib combination. Survival continued to be followed after the interim analysis and survival data are not mature at this time. Efficacy results are as shown in Table 13 and Figure 1.

Table 13: Efficacy of DOXIL in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma

Endpoint DOXIL + bortezomib
n=324
Bortezomib
n=322
Time to Progression1
Progression or death due to progression(n) 99 150
  Censored (n) 225 172
  Median in days (months) 282 (9.3) 197 (6.5)
  95% CI 250;338 170;217
  Hazard ratio2(95% CI) 0.55 (0.43, 0.71)
  p-value3 < 0.001
Response (n)4 303 310
  % Complete Response (CR) 5 3
  %Partial Response (PR) 43 40
  %CR + PR 48 43
  p-value5 0.25
Median Duration of Response (months) (95% CI) 10.2 (10.2;12.9) 7.0 (5.9;8.3)
1Kaplan Meier estimate.
2Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio < 1 indicates an advantage for DOXIL+bortezomib.
3Stratified log-rank test.
4RR as per EBMT criteria.
5Cochran-Mantel-Haenszel test adjusted for the stratification factors.

Figure 1:Time to Progression Kaplan-Meier Curve

Time to Progression Kaplan-Meier Curve -  Illustration

Last reviewed on RxList: 3/10/2015
This monograph has been modified to include the generic and brand name in many instances.

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