Doxorubicin Hydrochloride Liposome (Page 6 of 7)

14.2 AIDS-Related Kaposi’s Sarcoma

Doxorubicin hydrochloride liposome injection 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 hydrochloride.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of doxorubicin hydrochloride liposome injection 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% pulmonary 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

1

Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy.

2

There were no complete responses in this population.

Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection 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.

14.3 Multiple Myeloma

The efficacy of doxorubicin hydrochloride liposome injection 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 doxorubicin hydrochloride liposome injection (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

Doxorubicin hydrochloride liposomeinjection + bortezomibn=324

bortezomibn=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

% β2 -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 doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1.

Table 13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma

Endpoint

Doxorubicin hydrochloride liposome injection + 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)

10.2

7.0

(95% CI)

(10.2; 12.9)

(5.9; 8.3)

1

Kaplan Meier estimate.

2

Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio < 1 indicates an advantage for doxorubicin hydrochloride liposome injection +bortezomib.

3

Stratified log-rank test.

4

RR as per EBMT criteria.

5

Cochran-Mantel-Haenszel test adjusted for the stratification factors.

Figure 1 -- Time to Progressopm Kaplan-Meier Curve
(click image for full-size original)

Figure 1- Time to Progression Kaplan-Meier Curve

At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for doxorubicin hydrochloride liposome injection + bortezomib vs. bortezomib = 0.96 (95% CI 0.80, 1.14)].

Seventy-eight percent of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.

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