Truxima (Page 10 of 12)

14.5 Chronic Lymphocytic Leukemia (CLL)

The safety and effectiveness of rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with rituximab for up to 6 cycles in patients with previously untreated CLL [CLL Study 1 (n=817)] or previously treated CLL [CLL Study 2 (n=552)]. Patients received fludarabine 25 mg/m2 /day and cyclophosphamide 250 mg/m2 /day on days 1, 2 and 3 of each cycle, with or without rituximab. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of rituximab-based therapy.

In CLL Study11, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0-1, 74% were male, and 100% were White. In CLL Study 2, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0-1, 67% were male and 98% were White.

The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (CLL Study 1) or an independent review committee (CLL Study 2). The investigator assessed results in CLL Study 2 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 8.

Table 8 Efficacy Results in CLL Studies 1 and 2
CLL Study 1*(Previously untreated) CLL Study 2*(Previously treated)
R-FCN = 408 FCN = 409 R-FCN = 276 FCN = 276
*
As defined in 1996 National Cancer Institute Working Group guidelines.
Median PFS (months) 39.8 31.5 26.7 21.7
Hazard ratio (95% CI) 0.56 (0.43, 0.71) 0.76 (0.6, 0.96)
P value (Log-Rank test) < 0.01 0.02
Response rate(95% CI) 86%(82, 89) 73%(68, 77) 54%(48, 60) 45%(37, 51)

Across both studies, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older and 100 rituximab-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 9.

Table 9 Efficacy Results in CLL Studies 1 and 2 in Subgroups Defined by Age *
CLL Study 1 CLL Study 2
Age subgroup Number of Patients Hazard Ratio for PFS (95% CI) Number of Patients Hazard Ratio for PFS (95% CI)
*
From exploratory analyses.
Age < 65 yrs 572 0.52 (0.39, 0.70) 313 0.61 (0.45, 0.84)
Age ≥ 65 yrs 245 0.62 (0.39, 0.99) 233 0.99 (0.70, 1.40)
Age < 70 yrs 736 0.51 (0.39, 0.67) 438 0.67 (0.51, 0.87)
Age ≥ 70 yrs 81 1.17 (0.51, 2.66) 108 1.22 (0.73, 2.04)

14.6 Rheumatoid Arthritis (RA)

Reducing the Signs and Symptoms: Initial and Re-Treatment Courses

The efficacy and safety of rituximab were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints.

In RA Study 1 (NCT00468546), patients were randomized to receive either rituximab 2 x 1000 mg + MTX or placebo + MTX for 24 weeks. Further courses of rituximab 2 x 1000 mg + MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of rituximab. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 10.

In RA Study 2 (NCT00266227), all patients received the first course of rituximab 2 x 1000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 x 1000 mg + MTX or placebo + MTX, the majority between Weeks 2428. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 10.

Table 10 ACR Responses in RA Study 1 and RA Study 2 (Percent of Patients) (Modified Intent-to-Treat Population)
Inadequate Response to TNF Antagonists
RA Study 124 Week Placebo-Controlled(Week 24)RA Study 2Placebo-Controlled Retreatment(Week 24 and Week 48)
ResponsePlacebo + MTXn = 201Rituximab+ MTXn = 298Treatment Difference(Rituximab Placebo)*(95% CI)ResponsePlacebo + MTX Retreatmentn = 157Rituximab+ MTX Retreatmentn = 318Treatment Difference (Rituximab Placebo), , *(95% CI)
*
For RA Study 1, weighted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive > 20 IU/mL, negative < 20 IU/mL) at baseline; For RA Study 2, weighted difference stratified by RF status at baseline and 20% improvement from baseline in both SJC and TJC at Week 24 (Yes/No).
In RA Study 2, all patients received a first course of rituximab 2 x 1000 mg. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 x 1000 mg + MTX or placebo + MTX at or after Week 24.
Since all patients received a first course of rituximab, no comparison between Placebo + MTX and rituximab + MTX is made at Week 24.
ACR20ACR20
Week 2418%51%33%(26%, 41%)Week 2448%45%NA
Week 4845%54%11%(2%, 20%)
ACR50ACR50
Week 245%27%21%(15%, 27%)Week 2427%21%NA
Week 4826%29%4%(-4%, 13%)
ACR70ACR70
Week 241%12%11%(7%, 15%)Week 2411%8%NA
Week 4813%14%1%(-5%, 8%)

Improvement was also noted for all components of ACR response following treatment with rituximab, as shown in Table 11.

Table 11 Components of ACR Response at Week 24 in RA Study 1 (Modified Intent-to-Treat Population)
Inadequate Response to TNF Antagonists
Parameter(median)Placebo + MTX(n = 201)Rituximab+ MTX(n = 298)
BaselineWk 24BaselineWk 24
*
Visual Analogue Scale: 0 = best, 100 = worst.
Disability Index of the Health Assessment Questionnaire: 0 = best, 3 = worst.
Tender Joint Count31.027.033.013.0
Swollen Joint Count20.019.021.09.5
Physician Global Assessment *71.069.071.036.0
Patient Global Assessment *73.068.071.041.0
Pain *68.068.067.038.5
Disability Index (HAQ)2.01.91.91.5
CRP (mg/dL)2.42.52.60.9

The time course of ACR 20 response for RA Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the rituximab group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with rituximab. Similar patterns were demonstrated for ACR 50 and 70 responses.

Figure 2 Percent of Patients Achieving ACR 20 Response by Visit *RA Study 1 (Inadequate Response to TNF Antagonists)
*
The same patients may not have responded at each time point.
//medlibrary.org/lib/images-rx/truxima/figure-2-300x267.jpg
(click image for full-size original)

Radiographic Response

In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. Rituximab + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 12.

Table 12 Mean Radiographic Change From Baseline to 104 Weeks in RA Study 1
Inadequate Response to TNF Antagonists
ParameterRituximab 2 × 1000 mg + MTX *Placebo + MTX Treatment Difference(Placebo Rituximab)95% CI
*
Patients received up to 2 years of treatment with rituximab + MTX.
Patients receiving Placebo + MTX. Patients receiving Placebo + MTX could have received retreatment with rituximab + MTX from Week 16 onward.
Based on radiographic scoring following 104 weeks of observation.
Change during First Year
TSS0.661.771.11(0.47, 1.75)
ES0.441.190.75(0.32, 1.19)
JSN Score0.220.580.36(0.10, 0.62)
Change during Second Year
TSS0.481.04
ES0.280.62
JSN Score0.200.42

Following 2 years of treatment with rituximab + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of rituximab + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with rituximab + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the rituximab + MTX treated patients who had no progression in the first year also had no progression in the second year.In RA Study 1 and its open-label extension, 70% of patients initially randomized to rituximab + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 12, progression of structural damage in rituximab + MTX patients was further reduced in the second year of treatment.

Lesser Efficacy of 500 Vs. 1000 mg Treatment Courses for Radiographic Outcomes

RA Study 3 (NCT00299104) is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to rituximab 2 x 500 mg + MTX and rituximab 2 x 1000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both rituximab dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the rituximab 1000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction.

Physical Function Response

RA Study 4 (NCT00299130) is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of rituximab 500 mg, rituximab 1000 mg, or placebo in addition to background MTX.

Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of rituximab-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 13. HAQ-DI results for the rituximab 500 mg treatment group were similar to the rituximab 1000 mg treatment group; however radiographic responses were not assessed (see Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks.

Table 13 Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 in RA Study 4
Placebo + MTXn = 172Rituximab 2 × 1000 mg + MTXn = 170Treatment Difference(Rituximab Placebo)*(95% CI)
*
Adjusted difference stratified by region (US, rest of the world) and rheumatoid factor (RF) status (positive 20 IU/mL, negative < 20 IU/mL) at baseline.
Minimal Clinically Important Difference: MCID for HAQ = 0.22.
Mean Improvement from Baseline0.190.420.23 (0.11, 0.34)
Percent of patients with “Improved” score (Change from Baseline MCID)48%58%11% (0%, 21%)

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