Clinical Trial Result Information

Title of Study:
An Open-Label, Randomized, Multi-Center Study Comparing Standard Cyclophosphamide, Vincristine, Prednisolone (CVP) Chemotherapy with Rituximab plus CVP (R-CVP) in Patients with Previously Untreated CD20-Positive Follicular Lymphoma (Stage III-IV)

Fast Facts:

Protocol number:	M39021
Sponsor:	F Hoffman-La Roche
Company division:	Pharmaceutical
Product name:	MabThera/Rituxan
Generic name:	rituximab
Phase of development:	III
Therapeutic area, approved indication:	Non-Hodgkin’s lymphoma
Date of report:	12/22/2003

Clinical study summary:
This prospective, multi-center, open-label, randomized trial evaluated the clinical efficacy and safety of adding rituximab (MabThera) to standard CVP chemotherapy in patients with previously untreated non-Hodgkin’s lymphoma (NHL).

Study center(s) :
Patients were recruited at 47 centers in 11 countries (Australia 7, Belgium 3, Brazil 1, Canada 6, France 2, Israel 1, Poland 3, Portugal 3, Spain 6, Switzerland 2, and United Kingdom 13).

Objectives:
To evaluate the clinical efficacy (time to treatment failure) and safety of repeated doses of MabThera in combination with CVP, in patients with previously untreated CD20-positive follicular NHL (Stage III-IV) as compared with CVP alone.

Methodology:
Eligible patients were randomized to treatment with either standard CVP chemotherapy or R-CVP. If patients achieved a partial or complete response after 4 cycles of treatment, they would continue to receive an additional 4 treatment cycles. Patients who did not show any response after 4 treatment cycles were withdrawn from the treatment phase and the treating clinician decided on an alternative course of action for that patient.

A study visit was performed 28 days after the last treatment cycle to collect follow-up data (including assessment of tumor response). After this time point and unless otherwise clinically indicated, further visits were to be made every 3 months for the first 3 years and then every 6 months thereafter until the disease progressed and the patient received new lymphoma treatment (NLT) or died, for up to 7 years after the last patient completed treatment. An assessment of tumor response was also performed by an independent critical event committee (CEC).

Adverse events were collected up to 28 days after the end of randomized treatment or until NLT was started. Serious adverse events were collected up to 12 months after the last administration of study medication or until NLT was started.

Number of patients (planned/analyzed):
322

Diagnosis and main criteria for inclusion:
Male and female patients 18 years of age; previously untreated, biopsy-proven, CD20-positive follicular NHL (Ann Arbor Stage III-IV).

Test product, dose and mode of administration or test procedure:
MabThera, 375 mg/m²/slow iv infusion

Duration of treatment:
One dose every 3 weeks for 8 cycles.

Reference therapy, dose and mode of administration or reference procedure:
CVP chemotherapy: cyclophosphamide, 750 mg/m²/iv; vincristine 1.4 mg/m² (maximum 2 mg/m²)/iv; prednisolone, 40 mg/m²/po for 5 days every 3 weeks for 8 cycles.

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: Time to treatment failure (events were progressive disease, relapse after response, institution of NLT during or after the randomized treatment phase, stable disease after cycle 4 (SD4), and death from any cause).

Secondary efficacy parameters: (1) Overall survival at 3 and 5 years; (2) overall tumor response rate (complete and partial); (3) duration of response; (4) time to NLT; (5) disease-free survival.

Safety parameters: Adverse events, including infusion-related reactions; clinical laboratory safety parameters.

Statistical methods:
Time to treatment failure was analyzed using a log-rank test stratified by center. Kaplan-Meier estimates for median time to treatment failure and risk ratios (R-CVP vs CVP) with 95% confidence intervals are presented. A similar procedure was used to analyze duration of response, time to NLT, overall survival and disease-free survival.

Response rate was analyzed using a chi-squared test, and prognostic factors were analyzed using Cox regression analysis methodology.

The primary efficacy analysis was based on the population of all 321 randomized patients who received >=1 dose of study drug, and the safety evaluation included all randomized patients who received study drug and had a safety follow-up (n=321).

Summary (efficacy, safety, other results):
Efficacy – At the time of the final analysis, the median follow-up time in the overall population was 18 months. Treatment with R-CVP was associated with a significant prolongation in time to treatment failure compared with CVP (P<.0001, log-rank test). R-CVP was also superior to CVP for overall tumor response rate, duration of response, time to NLT or death, and time to disease progression or death. Because few patients in the CVP group achieved a complete response, conclusions cannot be drawn for disease-free survival. In addition, few patients had died at the time of data cut-off ; hence, a conclusion regarding treatment differences for overall survival cannot be made.

Parameter	Median Time to Event (Months)		Log-Rank p Value	Risk Reduction+
	CVP	R-CVP
Primary
TTF	6.7	25.9	<0.0001	67%
Secondary
Overall Survival	NE	NE	0.1854	41%
ORR (CR, CRu, PR)*	57%	81%	<0.0001**	3.2***
DR	9.8	NE	<0.0001	70%
DFS	NE	NE	0.1807	58%
TNLT	12.3	NE	<0.0001	66%
Exploratory
TTP	14.5	27.0	<0.0001	59%
Robustness of Primary Analysis
TTF ignoring SD4	9.2	27.0	<0.0001	67%
TTF in confirmed FL	7.4	27.0	<0.0001	73%
TTF in PPP	7.5	25.9	<0.0001	67%
TTF according to CEC	3.0	14.7	<0.0001	65%
DFS: disease-free survival; ;DR: duration of response; FL follicular lymphoma; NE: not estimable; PPP: per protocol population; SD4: stable disease after cycle 4; TNLT: time to new lymphoma treatment or death; TTF: time to treatment failure; TTP: time to disease progression or death; *ORR: Overall response rate (complete and partial) calculated from the tumor response as assessed at the end of trial treatment; + Treatment effect: for event-free parameters, estimates were calculated by risk reduction; for tumor response, odds ratio was used. ** chi-square test, *** odds ratio

Analyses of the primary parameter (time to treatment failure) based on investigator’s assessments were supported by analyses based on data from an independent committee (CEC) that reviewed the investigators tumor response. The superior efficacy of R-CVP over CVP was maintained with a longer follow-up time (7 months). The treatment effect was consistent across all patient subgroups

Safety – More patients on R-CVP (85%) than CVP (68%) completed 8 cycles of study treatment; this was mainly due to the better response in the R-CVP group. Exposure to study drugs was comparable between treatment groups for prednisolone and vincristine but was lower for cyclophosphamide in the R-CVP groups, mainly due to dose reductions for neutropenia.

The majority of adverse events were mild to moderate in intensity. A higher proportion of patients on R-CVP (33%) compared with those on CVP (20%) had severe or life-threatening adverse events (only 6 patients [1 CVP, 5 R-CVP] experienced life-threatening adverse events) reported in several body systems. The overall incidence of infections was comparable between treatment groups (32% CVP, 33% R-CVP). More patients treated with R-CVP reported adverse events within the blood and lymphatic body system (13% R-CVP vs 6% CVP); the difference was largely accounted for by a higher incidence of neutropenia with R-CVP.

More patients on R-CVP (71%) than CVP (51%) experienced adverse events within 24 hours of study treatment; the highest incidence was seen in the first treatment cycle. The incidence of severe or life-threatening MabThera-related infusion reactions was estimated to be 9%, which is within the expected range. The proportion of patients that experienced severe adverse events was 16% for CVP and 22% for R-CVP; with the exception of adverse events that are typical of MabThera administration, there were no relevant differences between the treatment groups. Few patients (4% CVP, 3% R-CVP) discontinued treatment for adverse events. Approximately 10% and 6% of patients in the CVP and R-CVP groups, respectively, had died by the time of data cut-off ; most deaths were considered related to disease progression. There were no treatment-related deaths in this study.

There was a higher incidence of severe neutropenia and leukopenia in the R-CVP group. The higher incidence of neutropenia (14% CVP, 24% R-CVP) in the R-CVP group was not associated with a higher incidence of infections.

Conclusions:
The R-CVP regimen is safe and effective in the treatment of patients with previously untreated Stage III-IV follicular NHL. The results from this study demonstrate that the addition of MabThera to CVP chemotherapy significantly improved the clinical outcome of patients with previously untreated Stage III-IV follicular lymphoma. The treatment benefits of R-CVP compared with CVP were seen across all principal efficacy parameters and were consistent across patient subgroups.

The addition of MabThera did not significantly increase the toxicity of the CVP regimen. During the study, no unexpected adverse events were reported and no treatment-related deaths occurred.

R-CVP is an efficacious, short duration, and modestly toxic regimen in patients with untreated Stage III-IV follicular lymphoma.

Publications (references, if available):
Marcus R, Imrie K, Belch A et al, CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105 (4): 1417-1423, (2005)