PROMACTA (Page 8 of 9)

14.2 Chronic Hepatitis C-associated Thrombocytopenia

The efficacy and safety of PROMACTA for the treatment of thrombocytopenia in adult patients with chronic hepatitis C were evaluated in two randomized, double-blind, placebo-controlled trials. The ENABLE1 study (NCT00516321) utilized peginterferon alfa-2a (PEGASYS®) plus ribavirin for antiviral treatment and the ENABLE2 study (NCT00529568) utilized peginterferon alfa-2b (PEGINTRON®) plus ribavirin. In both trials, patients with a platelet count of less than 75 x 109 /L were enrolled and stratified by platelet count, screening HCV RNA, and HCV genotype. Patients were excluded if they had evidence of decompensated liver disease with Child-Pugh score greater than 6 (Class B and C), history of ascites, or hepatic encephalopathy. The median age of the patients in both trials was 52 years, 63% were male, and 74% were Caucasian. Sixty-nine percent of patients had HCV genotypes 1, 4, 6, with the remainder genotypes 2 and 3. Approximately 30% of patients had been previously treated with interferon and ribavirin. The majority of patients (90%) had bridging fibrosis and cirrhosis, as indicated by noninvasive testing. A similar proportion (95%) of patients in both treatment groups had Child-Pugh Class A (score 5 to 6) at baseline. A similar proportion of patients (2%) in both treatment groups had baseline international normalized ratio (INR) greater than 1.7. Median baseline platelet counts (approximately 60 x 109 /L) were similar in both treatment groups. The trials consisted of 2 phases – a pre-antiviral treatment phase and an antiviral treatment phase. In the pre-antiviral treatment phase, patients received open-label PROMACTA to increase the platelet count to a threshold of greater than or equal to 90 x 109 /L for ENABLE1 and greater than or equal to 100 x 109 /L for ENABLE2. PROMACTA was administered at an initial dose of 25 mg once daily for 2 weeks and increased in 25-mg increments over 2- to 3-week periods to achieve the optimal platelet count to initiate antiviral therapy. The maximal time patients could receive open-label PROMACTA was 9 weeks. If threshold platelet counts were achieved, patients were randomized (2:1) to the same dose of PROMACTA at the end of the pre-treatment phase or to placebo. PROMACTA was administered in combination with pegylated interferon and ribavirin per their respective prescribing information for up to 48 weeks.

The efficacy of PROMACTA for both trials was evaluated by sustained virologic response (SVR) defined as the percentage of patients with undetectable HCV-RNA at 24 weeks after completion of antiviral treatment. The median time to achieve the target platelet count greater than or equal to 90 x 109 /L was approximately 2 weeks. Ninety-five percent of patients were able to initiate antiviral therapy.

In both trials, a significantly greater proportion of patients treated with PROMACTA achieved SVR (see Table 20). The improvement in the proportion of patients who achieved SVR was consistent across subgroups based on baseline platelet count (less than 50 x 109 /L versus greater than or equal to 50 x 109 /L). In patients with high baseline viral loads (greater than or equal to 800,000), the SVR rate was 18% (82/452) for PROMACTA versus 8% (20/239) for placebo.

Table 20. ENABLE1 and ENABLE2: Sustained Virologic Response (SVR) in Adults With Chronic Hepatitis C
Abbreviation: HCV, hepatitis C virus.a PROMACTA given in combination with peginterferon alfa-2a (180 mcg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,200 mg daily in 2 divided doses orally). b PROMACTA given in combination with peginterferon alfa-2b (1.5 mcg/kg once weekly for 48 weeks for genotypes 1/4/6; 24 weeks for genotype 2 or 3) plus ribavirin (800 to 1,400 mg daily in 2 divided doses orally). c Target platelet count was ≥ 90 x 109 /L for ENABLE1 and ≥ 100 x 109 /L for ENABLE2. d p- value < 0.05 for PROMACTA versus placebo.

ENABLE1a

ENABLE2b

Pre-antiviral Treatment Phase

n = 715

n = 805

% Patients who achieved target platelet counts and initiated antiviral therapyc

95%

94%

Antiviral Treatment Phase

PROMACTA

n = 450

%

Placebo

n = 232

%

PROMACTA

n = 506

%

Placebo

n = 253

%

Overall SVRd

23

14

19

13

HCV Genotype 2,3

35

24

34

25

HCV Genotype 1,4,6

18

10

13

7

The majority of patients treated with PROMACTA (76%) maintained a platelet count greater than or equal to 50 x 109 /L compared with 19% for placebo. A greater proportion of patients on PROMACTA did not require any antiviral dose reduction as compared with placebo (45% versus 27%).

14.3 Severe Aplastic Anemia

First-Line Treatment of Severe Aplastic Anemia

PROMACTA in combination with h-ATG and cyclosporine was investigated in a single-arm, single-center, open-label sequential cohort trial (Study ETB115AUS01T, referred to as Study US01T [NCT01623167]) in patients with severe aplastic anemia who had not received prior immunosuppressive therapy (IST) with any ATG, alemtuzumab, or high dose cyclophosphamide. A total of 153 patients received PROMACTA in Study US01T in three sequential cohorts and an extension of the third cohort. The multiple cohorts received the same PROMACTA starting dose but differed by treatment start day and duration. The starting dose of PROMACTA for patients 12 years and older was 150 mg once daily (a reduced dose of 75 mg was administered for East and Southeast Asians), 75 mg once daily for pediatric patients aged 6 to 11 years (a reduced dose of 37.5 mg was administered for East and Southeast Asians), and 2.5 mg/kg once daily for pediatric patients aged 2 to 5 years (a reduced dose of 1.25 mg/kg was administered for East and Southeast Asians).

  • Cohort 1 (n = 30): PROMACTA on Day 14 to Month 6 (D14-M6) plus h-ATG and cyclosporine
  • Cohort 2 (n = 31): PROMACTA on Day 14 to Month 3 (D14-M3) plus h-ATG and cyclosporine
  • Cohort 3 + Extension cohort [PROMACTA D1-M6 cohort] (n = 92): PROMACTA on Day 1 to Month 6 (D1-M6) plus h-ATG and cyclosporine (with all patients eligible to receive low dose of cyclosporine (maintenance dose) if they achieved a hematologic response at 6 months)

PROMACTA dose reductions were conducted for elevated platelet counts and hepatic impairment. Table 21 includes the dosages of h-ATG and cyclosporine administered in combination with PROMACTA in Study US01T.

Data from the Cohort 3 + Extension cohort support the efficacy of PROMACTA for the first-line treatment of patients with severe aplastic anemia (Table 22). The results presented in this section represent the findings from the Cohort 3 and Extension cohort (n = 92).

Table 21. Dosages of Immunosuppressive Therapy Administered With PROMACTA in Study US01T
a Dose of cyclosporine was adjusted to achieve the above recommended target trough levels; refer to the appropriate cyclosporine prescribing information.b Calculated as the midpoint between the ideal body weight and actual body weight.

Agent

Dose Administered in the Pivotal Trial

Horse antithymocyte globulin (h-ATG)

40 mg/kg/day, based on actual body weight, administered intravenously on Days 1 to 4 of the 6-month treatment period

Cyclosporinea (therapeutic dose for 6 months, from Day 1 to Month 6, adjusted to obtain a target therapeutic trough level between 200 mcg/L and 400 mcg/L)

Patients 12 years and older (total daily dose of 6 mg/kg/day)

3 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1

Patients > 20 years of age with a body mass index > 35 or patients 12 to 20 years of age with a body mass index > 95th percentile:

3 mg/kg, based on adjusted body weightb , orally every 12 hours for 6 months, starting on Day 1

Patients 2 to 11 years of age (total daily dose of 12 mg/kg/day)

6 mg/kg, based on actual body weight, orally every 12 hours for 6 months, starting on Day 1

Patients 2 to 11 years of age with a body mass index > 95th percentile:

6 mg/kg, based on adjusted body weightb , orally every 12 hours for 6 months, starting on Day 1

Cyclosporine(maintenance dose, from Month 6 to Month 24)

For patients who achieve a hematologic response at 6 months

2 mg/kg/day administered orally at a fixed dose for an additional 18 months

In the PROMACTA D1-M6 cohort, the median age was 28 years (range, 5 to 82 years) with 16% and 28% of patients ≥ 65 years of age and < 17 years of age, respectively. Forty-six percent of patients were male and the majority of patients were White (62%). Patients weighing 12 kg or less or patients with ALT or AST > 5x upper limit of normal were excluded from the trial.

The efficacy of PROMACTA in combination with h-ATG and cyclosporine was established on the basis of complete hematological response at 6 months. A complete response was defined as hematological parameters meeting all 3 of the following values on 2 consecutive serial blood count measurements at least one week apart: absolute neutrophil count (ANC) > 1000/mcL, platelet count > 100 x 109 /L and hemoglobin > 10 g/dL. A partial response was defined as blood counts no longer meeting the standard criteria for severe pancytopenia in severe aplastic anemia equivalent to 2 of the following values on 2 consecutive serial blood count measurements at least one week apart: ANC > 500/mcL, platelet count > 20 x 109 /L, or reticulocyte count > 60,000/mcL. Overall response rate is defined as the number of partial responses plus complete responses.

Table 22. Study US01T: Hematologic Response in First-Line Treatment of Patients With Severe Aplastic Anemia
Abbreviation: NE, not estimable.a The number of patients who reached the 6-month assessment or withdrew earlier is the denominator for percentage calculation.b Number of responders at any time.

PROMACTA D1-M6 + h-ATG + cyclosporinen = 92

Month 6, na

Overall response, n (%) [95% CI]

Complete response, n (%) [95% CI]

87 69 (79) [69, 87] 38 (44) [33, 55]

Median duration of overall response, nb

70

Months (95% CI)

24.3 (21.4, NE)

Median duration of complete response, nb

46

Months (95% CI)

24.3 (23.0, NE)

The overall and complete hematological response rates at Year 1 (n = 78) are 56.4% and 38.5% and at Year 2 (n = 62) are 38.7% and 30.6%, respectively.

Pediatric Patients

Thirty-four patients 2 to 16 years of age were enrolled in Study US01T. In the D1-M6 cohort, 7 and 17 out of 25 pediatric patients achieved a complete and overall response, respectively, at 6 months.

Refractory Severe Aplastic Anemia

PROMACTA was studied in a single-arm, single-center, open-label trial (Study ETB115AUS28T, referred to as Study US28T [NCT00922883]) in 43 patients with severe aplastic anemia who had an insufficient response to at least one prior immunosuppressive therapy and who had a platelet count less than or equal to 30 x 109 /L. PROMACTA was administered at an initial dose of 50 mg once daily for 2 weeks and increased over 2-week periods up to a maximum dose of 150 mg once daily. The efficacy of PROMACTA in the study was evaluated by the hematologic response assessed after 12 weeks of treatment. Hematologic response was defined as meeting 1 or more of the following criteria: 1) platelet count increases to 20 x 109 /L above baseline, or stable platelet counts with transfusion independence for a minimum of 8 weeks; 2) hemoglobin increase by greater than 1.5 g/dL, or a reduction in greater than or equal to 4 units of red blood cell (RBC) transfusions for 8 consecutive weeks; 3) ANC increase of 100% or an ANC increase greater than 0.5 x 109 /L. PROMACTA was discontinued after 16 weeks if no hematologic response was observed. Patients who responded continued therapy in an extension phase of the trial.

The treated population had median age of 45 years (range, 17 to 77 years) and 56% were male. At baseline, the median platelet count was 20 x 109 /L, hemoglobin was 8.4 g/dL, ANC was 0.58 x 109 /L, and absolute reticulocyte count was 24.3 x 109 /L. Eighty-six percent of patients were red blood cell (RBC) transfusion dependent and 91% were platelet transfusion dependent. The majority of patients (84%) received at least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline.

Table 23 presents the efficacy results.

Table 23. Study US28T: Hematologic Response in Patients With Refractory Severe Aplastic Anemia
a Includes single- and multi-lineage. b NR = not reached due to few events (relapsed).

Outcome

PROMACTA

n = 43

Response ratea , n (%)

95% CI (%)

17 (40)

(25, 56)

Median of duration of response in months (95% CI)

NRb (3.0, NRb)

In the 17 responders, the platelet transfusion-free period ranged from 8 to 1096 days with a median of 200 days, and the RBC transfusion-free period ranged from 15 to 1082 days with a median of 208 days.

In the extension phase, 8 patients achieved a multi-lineage response; 4 of these patients subsequently tapered off treatment with PROMACTA and maintained the response (median follow up: 8.1 months, range, 7.2 to 10.6 months).

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