"The U.S. Food and Drug Administration today approved Rituxan (rituximab) to treat certain patients with chronic lymphocytic leukemia (CLL), a slowly progressing blood and bone marrow cancer.
Rituxan, an anti-cancer drug, is intended fo"...
Mechanism of Action
Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. The antigen is expressed on > 90% of B-cell non-Hodgkin's lymphomas (NHL), but the antigen is not found on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissues. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation.
B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production.
Mechanism of Action: The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.
Normal Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the non-lymphoid tissues examined.
Non-Hodgkin's Lymphoma (NHL)
In NHL patients, administration of Rituxan resulted in depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following completion of treatment.
There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range.
In RA patients, treatment with Rituxan induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/μl) within 2 weeks after receiving the first dose of Rituxan. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment.
Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of Rituxan treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with Rituxan in RA patients during repeated Rituxan treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving Rituxan, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with Rituxan are unclear.
Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis
In GPA and MPA patients, peripheral blood CD19 B-cells depleted to less than 10 cells/μl following the first two infusions of Rituxan, and remained at that level in most (84%) patients through Month 6. By Month 12, the majority of patients (81%) showed signs of B-cell return with counts > 10 cells/μL. By Month 18, most patients (87%) had counts > 10 cells/μL.
Non-Hodgkin's Lymphoma (NHL)
Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m² Rituxan weekly by intravenous infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.
The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.
Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab.
Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days).
Following administration of 2 doses of Rituxan in patients with RA, the mean ( ± S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were 157 ( ± 46; 29%) and 183 ( ± 55; 30%) mcg/mL, and 318 ( ± 86; 27%) and 381 ( ± 98; 26%) mcg/mL for the 2 x 500 mg and 2 x 1000 mg doses, respectively.
Based on a population pharmacokinetic analysis of data from 2005 RA patients who received Rituxan, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half-life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis
Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m² rituximab once weekly by intravenous infusion for four weeks, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). Rituximab mean clearance and volume of distribution were 0. 312 L/day (range, 0.115 to 0.728 L/day) and 4.50 L (range, 2.21 to 7.52 L) respectively. Male patients and patients with higher BSA or positive HACA levels have higher clearance. However, further dose adjustment based on gender or HACA status is not necessary.
The pharmacokinetics of rituximab have not been studied in children and adolescents. No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post-coitum days 20 through 50). Rituximab was administered as loading doses on post-coitum (PC) days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells.
A subsequent pre- and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.
Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
The safety and effectiveness of Rituxan in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients.
A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m² of Rituxan given as an intravenous infusion weekly for 4 doses. Patients with tumor masses > 10 cm or with > 5000 lymphocytes/μL in the peripheral blood were excluded from the study.
Results are summarized in Table 4. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry.
In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m² of Rituxan weekly for 8 doses. Results are summarized in Table 4.
In a multicenter, single-arm study, 60 patients received 375 mg/m² of Rituxan weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to Rituxan administered 3.8-35.6 months (median 14.5 months) prior to retreatment with Rituxan. Of these 60 patients, 5 received more than one additional course of Rituxan. Results are summarized in Table 4.
In pooled data from studies 1 and 3, 39 patients with bulky (single lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL received Rituxan 375 mg/m² weekly for 4 doses. Results are summarized in Table 4.
Table 4 : Summary of Rituxan Efficacy Data by
Schedule and Clinical Setting
|Study 1 Weekly x 4
|Study 2 Weekly x 8
|Study 1 and Study 3 Bulky disease, Weekly x 4
|Study 3 Retreatment, Weekly x 4
|Overall Response Rate||48%||57%||36%||38%|
|Complete Response Rate||6%||14%||3%||10%|
|Median Duration of Responseb, c, d (Months) [Range]||11.2
[1.9 to 42.1+]
[2.5 to 36.5+]
[2.8 to 25.0+]
[3.0 to 25.1+]
|a Six of these patients are included in the
first column. Thus, data from 296 intent-to-treat patients are provided in this
b Kaplan-Meier projected with observed range.
c “+” indicates an ongoing response.
d Duration of response: interval from the onset of response to disease progression.
Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
The safety and effectiveness of Rituxan in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients.
A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with Rituxan 375 mg/m² on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death. Twenty-six percent of the study population was > 60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score ≥ 2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 5. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.
Table 5 : Efficacy Results in Study 4
|Median PFS (years)a||2.4||1.4|
|Hazard ratio (95% CI)b||0.44 (0.29, 0.65)|
|a p < 0.0001, two-sided stratified log-rank
b Estimates of Cox regression stratified by center.
An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to Rituxan in combination with chemotherapy. Patients were randomized to Rituxan as single-agent maintenance therapy, 375 mg/m² every 8 weeks for up to 12 doses or to observation. Rituxan was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review.
Of the randomized patients, 40% were ≥ 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0-1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response.
PFS was longer in patients randomized to Rituxan as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.
Figure 1 : Kaplan-Meier Plot of IRC Assessed
A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive Rituxan, 375 mg/m² intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was > 60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score ≥ 2.
There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to Rituxan as compared to those who received no additional treatment.
Diffuse Large B-Cell NHL (DLBCL)
The safety and effectiveness of Rituxan were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with previously untreated diffuse large B-cell NHL received Rituxan in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.
A total of 632 patients age ≥ 60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of Rituxan 375 mg/m² on Days -7 and -3 (prior to Cycle 1) and 48-72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received Rituxan prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive Rituxan or no further therapy.
Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III-IV disease, 56% had IPI scores ≥ 2, 86% had ECOG performance status of < 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 6. These results reflect a statistical approach which allows for an evaluation of Rituxan administered in the induction setting that excludes any potential impact of Rituxan given after the second randomization.
Analysis of results after the second randomization in Study 7 demonstrates that for patients randomized to R-CHOP, additional Rituxan exposure beyond induction was not associated with further improvements in progression-free survival or overall survival.
A total of 399 patients with DLBCL, age ≥ 60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received Rituxan 375 mg/m² on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI ≥ 2, 80% had ECOG performance status scores < 2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 6.
A total of 823 patients with DLBCL, aged 18-60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with Rituxan. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III-IV disease, 100% had IPI scores of ≤ 1, 99% had ECOG performance status of < 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 6.
Table 6 : Efficacy Results in Studies 7, 8, and
|Main outcome||Study 7
|Progression-free survival (years)||Event-free survival (years)||Time to treatment failure (years)|
|Median of main outcome measure||3.1||1.6||2.9||1.1||NEb||NEb|
|Overall survival at 2 yearsc||74%||63%||69%||58%||95%||86%|
|a Significant at p < 0.05, 2-sided.
b NE = Not reliably estimable.
c Kaplan-Meier estimates.
d R-CHOP vs. CHOP.
In Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively.
Ninety-Minute Infusions in Previously Untreated Follicular NHL and DLBCL
In Study 10, a total of 363 patients with previously untreated follicular NHL (n=113) or DLBCL (n=250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m² plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m² plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count < 5000/mm³ before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to Rituxan infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2 [See ADVERSE REACTIONS].
Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes [See DOSAGE AND ADMINISTRATION]. Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8).
The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and 0.0% (95% CI [0.0%, 1.5%]) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion related reactions were observed.
Chronic Lymphocytic Leukemia (CLL)
The safety and effectiveness of Rituxan were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with Rituxan for up to 6 cycles in patients with previously untreated CLL [Study 11 (n=817)] or previously treated CLL [Study 12 (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 Rituxan. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy.
In Study 11, 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 Study 12, 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 (Study 11) or an independent review committee (Study 12). The investigator assessed results in Study 12 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 7.
Table 7 : Efficacy Results in Studies 11 and 12
|Study 11* (Previously untreated)||Study 12* (Previously treated)|
|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)|
|*As defined in 1996 National Cancer Institute Working Group guidelines.|
Across both studies, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older and 100 Rituxan-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 8.
Table 8 : Efficacy Results in Studies 11 and 12
in Subgroups Defined by Agea
|Study 11||Study 12|
|Number of Patients||Hazard Ratio for PFS (95% CI)||Number of Patients||Hazard Ratio for PFS (95% CI)|
|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)|
|a From exploratory analyses.|
Rheumatoid Arthritis (RA)
Reducing the Signs and Symptoms: Initial and Re-Treatment Courses
The efficacy and safety of Rituxan 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, patients were randomized to receive either Rituxan 2 x 1000 mg + MTX or placebo + MTX for 24 weeks. Further courses of Rituxan 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 Rituxan. 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 9.
In RA Study 2, all patients received the first course of Rituxan 2 x 1000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either Rituxan 2 x 1000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. 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 9.
Table 9 : ACR Responses in Study 1 and Study 2
(Percent of Patients) (Modified Intent-to-Treat Population)
|Response||Inadequate Response to TNF Antagonists|
|Study 1 24 Week Placebo-Controlled (Week 24)||Study 2 Placebo-Controlled Retreatment (Week 24 and Week 48)|
|Placebo + MTX
n = 201
|Rituxan + MTX
n = 298
|Treatment Difference (Rituxan – Placebo)c (95% CI)||Response||Placebo + MTX Retreatment
|Rituxan +MTX Retreatment
|Treatment Difference (Rituxan – Placebo)a,b,c (95% CI)|
|Week 24||18%||51%||33% (26%, 41%)||Week 24||48%||45%||NA|
|Week 48||45%||54%||11% (2%, 20%)|
|Week 24||5%||27%||21% (15%, 27%)||Week 24||27%||21%||NA|
|Week 48||26%||29%||4% (-4%, 13%)|
|Week 24||1%||12%||11% (7%, 15%)||Week 24||11%||8%||NA|
|Week 48||13%||14%||1% (-5%, 8%)|
|a In Study 2, all patients received a first
course of Rituxan 2 x 1000 mg. Patients who experienced ongoing disease activity
were randomized to receive a second course of either Rituxan 2 x 1000 mg + MTX
or placebo + MTX at or after Week 24.
b Since all patients received a first course of Rituxan, no comparison between Placebo + MTX and Rituxan + MTX is made at Week 24.
c For 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 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).
Improvement was also noted for all components of ACR response following treatment with Rituxan, as shown in Table 10.
Table 10 : Components of ACR Response at Week
24 in Study 1 (Modified Intent-to-Treat Population)
|Parameter (median)||Inadequate Response to TNF Antagonists|
|Placebo + MTX
(n = 201)
|Rituxan + MTX
|Baseline||Wk 24||Baseline||Wk 24|
|Tender Joint Count||31||27||33||13|
|Swollen Joint Count||20||19||21||9.5|
|Physician Global Assessmenta||71||69||71||36|
|Patient Global Assessmenta||73||68||71||41|
|Disability Index (HAQ)b||2||1.9||1.9||1.5|
|a Visual Analogue Scale: 0 = best, 100
b Disability Index of the Health Assessment Questionnaire: 0 = best, 3 = worst.
The time course of ACR 20 response for 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 Rituxan group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with Rituxan. Similar patterns were demonstrated for ACR 50 and 70 responses.
Figure 2 : Percent of Patients Achieving ACR 20
Response by Visit* Study 1 (Inadequate Response to TNF Antagonists)
*The same patients may not have responded at each time point.
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. Rituxan + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 11.
Table 11 : Mean Radiographic Change From
Baseline to 104 Weeks
|Parameter||Inadequate Response to TNF Antagonists|
|Rituxan 2 x 1000 mg + MTXb||Placebo +MTXc||Treatment Difference (Placebo – Rituxan)||95% CI|
|Change during First Year|
|JSN Score||0.22||0.58||0.36||(0.10, 0.62)|
|Change during Second Yeara|
|a Based on radiographic scoring following 104
weeks of observation.
b Patients received up to 2 years of treatment with Rituxan + MTX.
c Patients receiving Placebo + MTX. Patients receiving Placebo + MTX could have received retreatment with Rituxan + MTX from Week 16 onward.
In RA Study 1 and its open-label extension, 70% of patients initially randomized to Rituxan + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 11, progression of structural damage in Rituxan + MTX patients was further reduced in the second year of treatment.
Following 2 years of treatment with Rituxan + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of Rituxan + 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 Rituxan + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the Rituxan + MTX treated patients who had no progression in the first year also had no progression in the second year.
Lesser Efficacy of 500 Vs. 1000 mg Treatment Courses for Radiographic Outcomes
RA Study 3 is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to Rituxan 2 x 500 mg + MTX and Rituxan 2 x 1000 mg + MTX treatment courses in MTX-na´ve 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 Rituxan dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the Rituxan 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 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 Rituxan 500 mg, Rituxan 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 Rituxan-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 12. HAQ-DI results for the Rituxan 500 mg treatment group were similar to the Rituxan 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 12 : Improvement from Baseline in Health
Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 in Study 4
|Placebo + MTX
n = 172
|Rituxan 2 x 1000 mg +MTX
|Treatment Difference (Rituxan – Placebo)b (95% CI)|
|Mean Improvement from Baseline||0.19||0.42||0.23 (0.11, 0.34)|
|Percent of patients with “Improved” score (Change from Baseline ≥ MCID)a||48%||58%||11% (0%, 21%)|
|a Minimal Clinically Important Difference:
MCID for HAQ = 0.22.
b 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.
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculidities) were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) ≥ 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease.
Patients in both arms received 1000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either Rituxan 375 mg/m² once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to Rituxan infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituxan group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. As shown in Table 13, the study demonstrated non-inferiority of Rituxan to cyclophosphamide for complete remission at 6 months.
Table 13 : Percentage of Patients Who Achieved
Complete Remission at 6 Months (Intent-to-Treat Population)
(n = 98)
|Treatment Difference (Rituxan – Cyclophosphamide)|
|95.1%b CI||(54%, 73%)||(43%, 63%)||(-3%, 24%) a|
|a non-inferiority was demonstrated because the
lower bound was higher than the prespecified non-inferiority margin (-3% > -20%).
b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.
Complete Remission (CR) at 12 and 18 months
In the Rituxan group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months.
Retreatment with Rituxan
Based upon investigator judgment, 15 patients received a second course of Rituxan therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the first course of Rituxan. The limited data preclude any conclusions regarding the efficacy of subsequent courses of Rituxan in patients with GPA and MPA [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 10/21/2013
This monograph has been modified to include the generic and brand name in many instances.
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