"The U.S. Food and Drug Administration today approved the first generic version of the cancer drug Doxil (doxorubicin hydrochloride liposome injection).
Doxorubicin hydrochloride liposome injection is currently on the FDA’s drug sh"...
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.
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
|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|
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.
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%.
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.
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 .
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.)
|Trial 2 (U.S.)
|Trial 3 (non-U.S.)
|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
|Protocol Defined ITT Population|
|TTP (Protocol Specified Primary Endpoint)|
|95% CI for Hazard Ratio||(0.76, 1.20)|
|Median (Months) 2||14.4||13.7|
|95% CI for Hazard Ratio||(0.68, 1.00)|
|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.
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
|Evaluable Patients Who Received Prior Doxorubicin
|Duration of PR (Days)|
|Range||42+ -210+||42+ -210+|
|Time to PR (Days)|
|Range||15 - 133||15 - 109|
|Indicator Lesion Assessment||All Evaluable Patients (n=42)||Evaluable Patients Who Received Prior Doxorubicin (n=23)|
|Duration of PR (Days)|
|Range||22+ -210+||35 -210+|
|Time to PR (Days)|
|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.
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
|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%|
|% 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|
|More than one||66||66|
|Prior Systemic Therapies for Multiple Myeloma|
|Corticosteroid (%)||99||> 99|
|Alkylating agent (%)||92||90|
|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
|Time to Progression1|
|Progression or death due to progression(n)||99||150|
|Median in days (months)||282 (9.3)||197 (6.5)|
|Hazard ratio2(95% CI)||0.55 (0.43, 0.71)|
|% Complete Response (CR)||5||3|
|%Partial Response (PR)||43||40|
|%CR + PR||48||43|
|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
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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