SYNOPSIS

TRIAL ID: ML16865

Protocol title: Rituximab (Mabthera^â) as single agent and in combination with
interferon-a2a (Roferon-A^â), a phase-III randomized trial in patients with follicular or other CD20+ low-grade (indolent) lymphoma.

LIST OF INVESTIGATORS

Writing committee:

Principal Investigator: Eva Kimby

Center no.: 1

Address: Dept of Haematology, Huddinge University Hospital, S 141 86 Huddinge, Sweden

Telephone no.: +46 8 58 58 00 00

Fax no.: +46 8 774 87 25

Investigator: Hans Hagberg

Center no.: 2

Address: Dept of Oncology, Academic Hospital, S 751 85 Uppsala, Sweden

Telephone no.: +46 18 66 55 29

Fax no.: +46 18 66 55 28

Investigator: Björn Östenstad

Center no.: 50

Address: Dept of Oncology, Ullevål Hospital, N 0407 Oslo, Norway

Telephone no.: +47 22 11 75 31

Fax no.: +47 22 11 93 18

Investigator: Mads Hansen

Center no.: 30

Address: Dept of Haematology, Rigshospitalet, DK 2100 Copenhagen, Denmark

Telephone no.: +45 35 45 35 45

Fax no.: +45 35 45 48 41

TRIAL ID: ML16865

Protocol title: Rituximab (Mabthera^Ò) as single agent and in combination
with interferon-a2a (Roferon-A^Ò), a phase-III randomized trial
in patients with follicular or other CD20+ low-grade
(indolent) lymphoma.

Protocol version Final

Sponsor F. Hoffmann-La Roche, LTD

Project Phase III

Indication Lymphoma

Objectives Primary objective
To compare time to treatment failure (TTF) between the two
treatment groups.

                                                      Secondary objectives
To determine (after total treatment)
1) clinical objective response rate and quality
    (complete and partial remission, molecular
    response rate).
2) response duration
3) time to progression

4) overall survival

Study design Prospective, open label, randomized, multicentre trial.

Planned sample size 313

Total no. of centers 25 - 30

Selection criteria Patients with an established diagnosis of CD20+ low grade
(indolent) lymphoma of follicular (grade 1-3a) and marginal
zone type (WHO criteria). Also small lymphocytic lymphoma
(SLL) without a B-CLL immunophenotype and other indolent
lymphoma, not otherwise specified will be included.

B-CLL, mantle cell lymphoma and lymphoplasmacytic
lymphoma (Waldenström’s disease) are excluded.

CD20+ tumor cells as determined by either lymph node
and / or bone marrow immunohistochemistry and flow
cytometry.

Patients with bulky stage II, stage III or stage IV tumors. No
prior chemotherapy or less than 6 months chlorambucil or
cyclophosphamide treatment (with CR or PR and a response
duration > 9 months). Prior chemotherapy or radiotherapy must
have been finalized > 9 months before enrollment into this
study. Patients age must be > 18 years and the performance
status (WHO) 0-2.

Study medication Patients will randomly be allocated to:

Reference treatment
Rituximab (Mabthera^Ò) is given during 4 weeks (the cycle
length is 4 weeks). Patients obtaining MR, PR or CR after the
first cycle will receive another for a total of two cycles.

Experimental treatment
Interferon-a2a (Roferon^Ò) is given during week 1-5 and
Rituximab (Mabthera^Ò) during week 3-6 (the cycle length is 6
weeks). Patients obtaining MR, PR or CR after the first cycle
will receive another for a total of two cycles.

Main parameters of efficacy Primary: Time to treatment failure

Secondary: Clinical objective response rate, response duration, time to progression, overall survival, molecular response.

Main parameters of safety Adverse events, laboratory parameters.

Study procedure                           Eligible patients will receive one cycle of rituximab or one
cycle of interferon + rituximab. Further study treatment is
guided by the week 10 clinical assessment. Patients in SD or
PD will be withdrawn from further study treatment. All other
patients will receive another cycle of the same treatment, as
given in the first cycle. The following investigations will be
performed:

At baseline: Physical examination, laboratory tests, ECG,
chest X-ray, CT-thorax, CT-abdomen/pelvis and CT-sinus
(if Waldeyer’s ring is involved), lymph node biopsy and bone marrow aspiration and biopsy.

During treatment: Laboratory tests and documentation of side effects.

Restaging: 10 weeks after start of rituximab therapy (first cycle) and 16 weeks after start of the second cycle. Only those investigations will be repeated that were abnormal at study entry and are being used to determine response to the induction therapy. Re-biopsy of bone marrow will be performed for restaging (if initially positive) and at 16 weeks after start of the second cycle in all patients with CR (for molecular response evaluation).

At follow-up: Patients with CR, PR and MR at the week 16
evaluation should be seen every 3^rd month until disease
progression requiring new therapy is noted or for a maximum
of 3 years. At each visit a physical examination, laboratory
tests and documentation of side effects will be performed. In
patients with clinical CR at month 18 in the follow-up period, a molecular response evaluation (peripheral blood test and a bone marrow biopsy) will be performed annually (i.e. months 18, 30, 42, 54 ) until relapse or for a total of 5 years.

Randomization procedure Randomization will be performed centrally at the Southern
Swedish Regional Tumor Registry in Lund.

Statistical considerations Sample size calculation:
The primary endpoint of the study, time to treatment failure
(TTF), was used to assess sample size.
Under the assumptions of:
- A median time to TTF in the rituximab single agent arm of
18 months.
- A median time to TTF in the rituximab+interferon arm of 27
months.
- A recruitment period of > 4 years.
- A follow-up period of 3 years.
Then 313 patients should be sufficient to demonstrate, with
85 % power, a statistically significant difference between the
two treatment arms applying the log-rank test at the level of
5 %. This calculation has been performed using a 20 %
exponential drop out rate, and assumes that 219 events will
have occurred.

Interim analysis
One interim analysis will be performed after 66 (30%) of the 219 events have occurred. (Performed as planned the 26^th of May 2006, by the DSMB.)

Duration of the Study The study duration consists in cycle I (10 weeks), cycle II (16 weeks) as well as an untreated follow-up to 3 years (MR, PR) or 5 years (CR).

Treatment flow-chart ML16865, May 2002

TABLE OF CONTENT PAGE

1. BACKGROUND 9

1.1. Disease Background 9

1.2. Drug Background 9

1.2.1. Interferon-a2a 9

1.2.2. Rituximab 10

1.2.3. Interferon-a2a combined with rituximab 12

1.3. Rationale for Performing the Study 13

2. STUDY OBJECTIVES 13

2.1. Primary Objective 13

2.2. Secondary objectives 14

3. STUDY DURATION AND STUDY EARLY TERMINATION 14

4. NUMBER OF CENTERS 14

5. SELECTION CRITERIA 14

5.1. Total Number of Patients 14

5.2. Inclusion Criteria 15

5.3. Exclusion Criteria 16

6. DISEASE EVALUATION (EFFICACY CRITERIA) 17

6.1. Schedule of Investigations 17

6.2. Molecular Biology Investigations 19

6.3. Definition of Efficacy Criteria 20

6.3.1. Response 20

6.3.2. Response Duration 21

6.3.3. Time to Treatment Failure (TTF) 21

6.3.4. Time to Progression (TTP) 21

6.3.5. Overall survival 22

7. STUDY DESIGN 22

7.1. Design 22

7.2. Randomization Procedure and Assignment to Treatment Group 22

8. STUDY MEDICATION 23

8.1. Drug Names, Formulation, Storage 23

8.2. Packaging and Labeling 23

8.3. Study Treatment 25

8.3.1. Rationale for Dose Selection 25

8.3.2. Dosage Regimen & Dose Adjustment 25

8.3.2.1. Dose Regimen 25

8.3.2.2. Rituximab - Dose modification 26

8.3.2.3. Interferon-a2a -Dose modification 26

8.3.3. Route of Administration 26

8.3.3.1. Rituximab (Mabthera^Ò) - IV (Intravenous) infusion 26

8.3.3.2. Interferon-a2a (Roferon-A^Ò) - SC (subcutaneous) injection 28

8.3.4. Treatment Duration 28

8.3.5. Anticipated Study Drug Toxicities 28

8.3.5.1. Rituximab 28

8.3.5.2. Interferon-a2a 30

8.4. Dispensing and Accountability of Study Medication Supplies 32

8.5. Assessment of Compliance 32

8.6. Concomitant Treatment 32

9. PREMATURE WITHDRAWAL 33

10. WARNINGS AND PRECAUTIONS 33

10.1 Rituximab dispensing information 33

10.2 Storage Information 34

11. SAFETY PARAMETERS 34

11.1. Definition of Toxicity Criteria 34

12. SERIOUS ADVERSE EVENTS 34

13. STATISTICAL CONSIDERATIONS 36

13.1. Sample Size Calculation 36

13.2. Analysis Plan 37

13.2.1. Intent-to-treat Analysis - Assessment of Efficacy 38

13.2.2. Per Protocol Analysis - Assessment of Efficacy 38

13.2.3. Per Protocol Analysis - Assessment of Safety 38

14. Ethics / Quality control 38

15. rules for use of study data / publication 38

16. SIGNATURE 40

17. REFERENCES 41

18. APPENDICES 44

1. BACKGROUND

1.1. Disease Background

Indolent lymphomas are incurable diseases with an overall median survival of 6-9 years from time of diagnosis (Horning 1994, Johnson PW et al 1995). Patients with advanced disease (stage III-IV) are usually not treated until symptoms appear (wait and watch-policy). Initial treatment often consists of an alkylating agent, such as chlorambucil alone or in combination with prednisone with a response rate of 50-60 % (Gallagher et al 1986) and a median response duration of 12-24 months (Rohatiner 1995 ). In a Swedish randomized trial, combination chemotherapy (CHOP) showed better response quality than chlorambucil/prednisone, but without prolonged survival (Kimby et al 1994).

With a nucleoside analogue such as fludarabine or CdA, higher response rates have been reported . When used as primary therapy, complete response (CR) rates of 30-40 %, and median times to disease progression of 20-24 months have been observed (Redman et al, 1992 Solal-Celigny et al 1996). However, due to concerns over long term immunosuppression and bone marrow toxicity, nucleoside analogues are mostly used as second line therapy.

Cyclophosphamide (included in the COP regimen) or for some patients with high tumor burden in the CHOP or CHOP-like regimens is used both initially and at relapse. The effect of the purine analogs in comparison to other chemotherapy regimens and in combination with other cytostatic drugs is currently under investigation (McLaughlin et al 1996, Zinzani et al 1997, Klasa et al 1999). With a combination of fludarabine, mitoxantrone and a corticosteroid, objective response has been observed in 70-90 % of patients with recurrent indolent lymphomas and the CR rate has been 35-45 % (McLaughlin et al 1996, Zinzani et al 1997). The impact on survival, however, is uncertain. High-dose chemotherapy with autologous transplantation is sometimes used at relapse in young patients and if evidence of transformation to an aggressive histology.

Resistance to chemotherapy increases over time with lower response rates and duration of response. The median survival after first relapse is mostly only 4-5 years (Johnson PW et al). In one series median durations of the first 3 remissions were between 1-2 years but only about 6 months in the fourth remission (Gallagher et al 1986). Only 20 % of the patients had a first remission lasting more than 5 years.

1.2. Drug Background

1.2.1. Interferon-a2a

Interferon-a2a (IFN) is a pleiotropic cytokine with antiproliferativ, antiviral and
immunomodulatory effects and has been used for treatment of different tumors. In
patients with relapsed low-grade follicular lymphoma response rates of 30-50 % to
IFN has been reported (Foon et al 1984, Rohatiner et al 1991). In primary disease, responses to single agent IFN were seen in 70 % of the patients in a randomized trial (Brice et al 1997).

In several studies IFN, given either in combination with chemotherapy (Arranz et al 1998, Solal-Celigny et al 1998) or as maintenance after chemotherapy (Hiddemann et al 1998), has been shown to increase response rate and progression-free survival. Also overall survival has been extended in patients with follicular lymphoma.

In a randomized study of 242 previously untreated patients with advanced low-grade follicular lymphoma and a high tumor burden, performed by the Groupe d’Etude des
Lymphomes Folliculaires (GELF), the addition of IFN to a CHOP-like regimen
increased the response rate from 69 to 85 % (p=0.006), median duration of response
from 19 to 34 months (p<0.001) and survival at 5 years from 56 to 71 % (p=0.02)
(Solal-Celigny et al 1998).

In another randomized study including 249 patients, IFN-a similarly increased 5-year
disease-free survival from 19 to 34 % (p=0.001) and overall survival from
approximately 55 to 65 % (n.s.), when added to a CHOP-like regimen. The
objective response rates did not differ (86 %). The last study was updated in 2001
with a current median follow-up time of 12 years. The study continued to show a
benefit in time to treatment failure median 1.9 years vs. 2.9 years, p=0.008 and in
overall survival (median 5.7 years and 7.8 years, p = n s) for the IFN- containing arm
(Smalley et al 2001).

In a third randomized study of 155 patients induction treatment with COP was compared with COP+IFN (Arranz et al 1998). The response rates were 79 and 76 %,
respectively. Duration of responses was significantly longer in patients treated with
IFN but without differences in overall survival (p=0.30) after a median follow-up
period of 3 years.

In contrast to these 3 studies, where IFN was combined with combination
chemotherapy, the addition of IFN to single agent chlorambucil or cyclophosphamide
did not improve either response rates, remission durations or overall survival
in 2 randomized studies (Chisesi et al 1991, Rohatiner et al 2001).

The role of IFN for maintenance of remission after successful initial chemotherapy
has been addressed in at least 8 randomized studies. Taken together, the results of the
trials indicate that the duration of the remissions can be prolonged, whereas overall
survival is not influenced (Hiddemann et al 1998).

In summary, IFN given concurrently with combination chemotherapy increases
response rates and prolongs remission duration but a favorable effect on overall
survival has been seen only in two randomized studies, both with anthracycline
containing chemotherapy.

1.2.2. Rituximab

Most lymphoma cells of B-cell type express the CD20 antigen (Jaffe et al 2001).
Rituximab (Mabthera^â) is a chimeric monoclonal antibody (anti-CD20) approved
1998 for treatment of relapsing follicular lymphoma.

Because of its mouse Fab/human Fc chimeric construction, rituximab binds to human CD20 with high affinity, and the antibody is able to bind to C1q human complement through its Fc receptor and thus might mediates both complement directed (CDC) and antibody directed cell mediated (ADCC) cytotoxicity
(Reff et al 1994, Janakiraman et al 1998,).

It has also been shown that rituximab blocks proliferation and induces apoptosis in
NHL B-cell lines in vitro (Maloney 1996). The significance of effector cells for the effect of rituximab is not well-known. The absolute number of circulating NK cells in patients undergoing therapy with rituximab may be an important factor since in vitro NK cells mediate ADCC of CD20⁺ tumor cells in response to rituximab, and a direct relationship between absolute NK cell count and response to rituximab has been observed in lymphoma patients (Janakiraman 1998). In the Nordic Study, NK cell counts were evaluated before and after Mabthera^Ò +/-IFN (data on file).

In the largest experience of single agent rituximab in relapsing and chemo refractory
indolent lymphomas (the pivotal study, 166 patients), an objective response rate of
48 % was demonstrated, of which 6 % were CRs. The median progression-free
survival for responding patients was around 13 months (McLaughlin et al 1998). With re-defined response criteria the overall response rate was not affected, but CR response rate was higher (Grillo-Lopez et al 2000). The rituximab treatment was well
tolerated with no unexpected toxicities. Transient fevers, chills, mild hypotension
drop and hypoxia, urticaria or other rash were seen mostly with the first rituximab
infusions (McLaughlin et al 1998). The regimen used in this protocol was four weekly infusions of 375 mg/m² rituximab, which has been the approved standard dose. The serum concentration of rituximab was related to ant-tumor response in the pivotal trial (Berinstein et al 1998). Later phase II trials have shown that a prolonged course of rituximab could further enhance the efficacy (Piro et al 1999, Aviles et al 2001). An extended dosing schedule (weekly x 8) resulted in an overall response rate of 57 % (Piro et al 1999). According to the results from another phase II trial, re-treatment with rituximab is also feasible and resulted in an overall response rate of 40 % in 57 evaluable patients with relapsed or refractory indolent NHL, who had responded to at least one prior course of rituximab (Davis et al 2000). Furthermore, the results from this trial indicated that re-treatment with rituximab can achieve response durations exceeding those obtained with prior therapeutic agents.

The favorable safety profile, short duration of treatment, and proven clinical efficacy makes rituximab an attractive first-line treatment option. In a preliminary report
(Hainsworth 2000) the objective response rate in 39 patients with indolent
lymphomas was 75 % with a median time to remission of 2+ months and a remission
duration of 9+ months. An objective response rate (OR) of 73 % in 49
evaluable patients with untreated follicular lymphoma has also been reported
(Colombat et al 2001, Solal-Celigny 2001). All patients in these two studies had
small tumor burden.

One interesting approach to augment the activity of rituximab is the combination
with chemotherapy. This approach is currently being studied with the hopes of
augmenting objective response rates and response durations over single agent
rituximab in patients with indolent lymphoma. With the combination of CHOP and
rituximab no side effects besides those related to the CHOP regimen was reported
(Czuczman et al 1999). With the first combinations of fludarabine in conventional doses and rituximab, myelotoxicity was pronounced why the fludarabine dose had to be reduced (Czuczman 2001).

1.2.3. Interferon-a2a combined with rituximab

Another approach to augment the activity of rituximab is to combine it with IFN.
A small single arm multicentre phase II trial (Davis et al 2000) performed in the USA
combined rituximab (four infusions in conventional doses) with IFN-a2a ( in a dose
of 2.5-5 MIU) three times a week during 4 weeks before, concomitant with and 4
weeks after rituximab treatment, when rituximab still should be circulating in the
serum). The objective response rate in 38 relapsed or refractory low-grade lymphoma
patients was 45 % and the estimated median time to progression was 25.2 months in
responding patients. The trial indicated that the combination was feasible and safe
and that the time to treatment failure might be prolonged.

An Italian group also determined the clinical activity and safety of rituximab+IFN in
64 patients with relapsed low-grade or follicular B-cell lymphoma (Sacchi et al 2001). Four infusions of rituximab (each infusion 375 mg/m²) was given after priming and simultaneous treatment with IFN-a2a (5 MIU three times a week). The objective response rate was 70 % with 33 % CR. Median duration of response was 19 months, after a median follow-up of 22 months. An univariate analysis revealed none of the most common prognostic factors to predict for response to therapy. After treatment10 patients became bcl-2 negative in the bone marrow, but no correlation between molecular and clinical response was found. Fifty-three patients (83 %) had drug related adverse events or adverse events of unknown origin. Twenty-three patients required reduction in the dose and/or short discontinuation of the IFN treatment, either during priming or subsequent treatment due to side effects. The most frequent toxicities were fever, hypotension, neutropenia and thrombocytopenia. Only few (2 %) of the toxic events were grade 4. This report shows that combination
immunotherapy with rituximab+IFN is active and relatively well tolerated.

The Nordic Lymphoma Study Group performed a clinical trial evaluating the efficacy of concomitant administration of rituximab (Mabthera^®) and interferon-a2a (Roferon-A^®) with the hope to improve the response rate in patients who had a suboptimal response to initial rituximab monotherapy (Kimby et al 2000). A total of 127 patients with previously untreated or first relapse indolent lymphoma were recruited from 9/98 to 11/99 of which 126 were treated with four infusions of Mabthera^® monotherapy. All patients had symptomatic advanced stage, CD20+ low-grade lymphoma. After a first cycle of rituximab (Mabthera^®), 375 mg/m² weekly x 4
(IV infusion), response was assessed at weeks 9 and 14.

Patients in CR at week 14 received no further treatment and those with SD or PD
went off study. Patients with PR or minor response (MR) were randomized to a
second cycle of rituximab, 375 mg/m²/weekly during weeks 1-4, or IFN

(Roferon-A^®) 3 MIU/day SC (week 1), 4.5 MIU/day (weeks 2-5) + rituximab (weeks 3-6). At the week 14 evaluation (after the first cycle) the following responses were noted: 14 CR (11 %), 56 PR (45 %) and 13 MR (10 %). After a second cycle the objective response rate in the rituximab single agent group was 78 % (28/36 patients) and 94 % (31/33 patients) in the rituximab+IFN group (p=0,087). The CR rate was higher in the rituximab+IFN group: 16 patients (48 %) vs. 8 patients (22 %) in the rituximab single agent group (p=0.05).

Toxicity was mild and mostly related to the first infusion in both cycles. Reversible
thrombocytopenia and leucopenia (WHO grade 3) were seen in 1 and 6 patients, in
the single agent rituximab group and the rituximab+IFN group respectively. At a
median follow-up of 29 months (12/2001), 10/14 patients who were in CR after one
rituximab cycle were still in remission as were 59 % of patients who received a
second cycle of rituximab and 71 % of patients who received rituximab+IFN. The
median time to treatment failure (calculated from the date of randomization) was 28
months in the rituximab group. The failure-free rate at the same time point in the
combined group was 70 %.

The conclusion from this study was that two cycles of rituximab is an efficient and
well tolerated treatment for patients with symptomatic low-grade, previously
untreated lymphoma or lymphoma in first relapse. By combining rituximab with IFN
the objective response rate seemed to be augmented with a prolonged failure-free
survival.

1.3. Rationale for Performing the Study

The rationale for the present study is to investigate, in a prospective randomized trial
whether or not rituximab combined with interferon-a2a will increase time to
treatment failure when compared to rituximab single agent treatment. In the majority of patients with advanced disease the lymphoma will relapse after conventional
chemotherapy, and both the response rate and the relapse-free survival is steadily
decreasing after subsequent salvage treatments.

Eventually the disease will become resistant to chemotherapy. In addition, a
transformation to aggressive lymphoma occurs with increasing frequency over time.
For this reason, new treatment modalities resulting in increased progression-free and
overall survival are urgently required. Postponing the need for chemotherapy by
using low-toxic, biological treatments such as rituximab and rituximab+IFN upfront,
might be of great value.

2. STUDY OBJECTIVES

2.1. Primary Objective

To investigate the time to treatment failure (TTF). A definition of TTF is given in
section 6.3.3.

2.2. Secondary objectives

To investigate:

· Clinical response rate

· Molecular response rate

· Time to progression

· Response duration

· Overall survival

3. STUDY DURATION AND STUDY EARLY TERMINATION

All patients will receive the first cycle. Patients who obtain CR, PR or MR, at the
first evaluation time point (e.g. 10 weeks after start of rituximab treatment) will
receive a second cycle of the same treatment, for a maximum of two cycles. The
second cycle should be started within two weeks from the date of first evaluation.
Patients with SD or PD at the week 10 evaluation, will be taken off further study
drugs and will be treated according to institutional praxis. Patients who receive the
second cycle will have another clinical assessment 16 weeks from start of rituximab in the second cycle.

Follow-up investigations will be done every 3^rd month until PD requiring new
therapy is noted, or for a maximum of 3 years. Patients in clinical CR after 2 years
will be followed-up annually for molecular response for a total of 5 years.

Criteria for discontinuation of study treatments

In absence of unacceptable toxicity or other cause for discontinuation (see below),
patients will receive study treatment as outlined in section 8.3.2.1. of this protocol.
The following events are deemed sufficient cause to terminate study treatment.

· Severe (grade 4) subjective toxicity

· Events demanding medical intervention not allowed in this protocol

· The patients own whish to terminate study treatment

· If the responsible physician thinks a change of therapy would be in the best
interest of the patient.

4. NUMBER OF CENTERS

The study will be open to patients at 25-30 participating medical centers in Sweden, Norway and Denmark (Appendix 1).

5. SELECTION CRITERIA

5.1. Total Number of Patients

A total of 313 patients will be randomized (section 13.1.).

5.2. Inclusion Criteria

1. An established diagnosis of CD20+ low-grade (indolent) lymphoma according to the WHO criteria (Appendix 2) of follicular (grade 1-3a) and marginal zone type. Also small lymphocytic lymphoma (SLL) without a B-CLL phenotype will be included as well indolent lymphoma not otherwise specified.

2. CD20+ tumor cells as determined by either lymph node and/or bone marrow immunohistochemistry and flow cytometry.

3. Stage II (with bulky disease), III or IV lymphoma according to the Ann Arbor staging system (Appendix 3).

4. Patients with no previous chemotherapy or patients with a maximum of 6 months
chlorambucil or cyclophosphamide treatment can be enrolled. Treated patients
should have attained a CR or PR with a response duration > 9 months.

5. Baseline staging requirements (Appendix 4) within 28 days of study entry.

6. Adequate organ function defined as:

·     Creatinine < 2.5 x UNL (upper normal limit)
·     Total bilirubin < 2.5 x UNL
·     Alkaline phosphatase < 2.5 x UNL
·     SGOT < 2.5 x UNL

7. Age greater than 18 years old, with a life expectancy of 6 months or greater.

8. WHO Performance status of 0-2 (Appendix 5).

9. Patient information and written informed consent according to the rules of the
respective country.

10. Indication for treatment (at least one of these indications must be fullfilled):

· Symptomatic enlarged lymph nodes, spleen or other lymphoma
manifestations.

· Steady, clinically significant progression over at least 6 months of lymphadenopathy or splenomegaly..

· Anemia (Hb < 100 g/L) or thrombocytopenia (platelets < 100 x 10⁹/L), or
clinically significant progressive decrease in Hb or platelet count due to lymphoma.

· General symptoms as weight loss > 10 % in 6 months, night sweats or fever > 38⁰ C not due to infection.

5.3. Exclusion Criteria

1. Prior treatment with more than 6 months systemic single agent alkylator
chemotherapy.

2. Chlorambucil/cyclophosphamide or radiation therapy within 9 months of study entry.

3. Prior treatment with rituximab or interferon.

4. B-CLL, mantle cell lymphoma and lymphoplasmacytic lymphoma
(Waldenström’s disease).

5. Indolent lymphoma transformed into aggressive lymphoma.

6. Indolent lymphoma with bulky tumor requiring urgent therapy.

7. Severe cardiac (i.e. severe heart failure requiring symptomatic treatment), pulmonary, neurologic, psychiatric or metabolic disease.

8. Pregnant women.

9. Men and women of reproductive potential not agreeing to use a safe method of birth control during treatment and for six months after completion of treatment (p-pills or intrauterine device are considered as safe methods).

10. Prior malignancies except: non-melanoma skin tumors, stage 0 (in situ) cervical carcinoma or curative surgical therapy performed more than 5 years ago.

11. Known HIV positivity.

12. Uncontrolled infectious disease.

13. CNS lymphoma.

14. Uncontrolled asthma or allergy, requiring steroid treatment.

15. Serious co-morbid disease or patient who cannot provide informed written consent .

16. Known allergic reactions against foreign proteins.

6. DISEASE EVALUATION (EFFICACY CRITERIA)

6.1. Schedule of Investigations

	Prior to first treatment ¹⁾	Weekly during treatment	Evaluation time points ²⁾	Follow-up investigations³⁾
Informed consent	x
History	x
Physical examination⁴⁾	x	x	x	x
Tumor examinations⁵⁾	x		x	x
Pathology and cytology examinations⁶⁾	x		x
Hematology⁷⁾	x	x	x	x
Blood chemistry⁸⁾	x		x	x
b2 microglobulin	x		x	x
S-electrophoresis (quantification of immunoglobulines)¹³⁾	x		x	x
Serology⁹⁾	x
Urine analysis¹⁰⁾	x
Pregnancy test	x
Serum sample for storage¹¹⁾	x
Body temperature¹²⁾	x	x