AZR, 04 Dec Amendment 2 : 1 October 2003 approved METC Erasmus MC, 05 Nov

HOVON 46 NHL ________________________

Version: 1 October 2003

A randomized phase III study of chimeric anti-CD20 monoclonal antibody (Rituximab) with 2-weekly CHOP chemotherapy (CHOP 14) in elderly patients with intermediate- or high-risk non-Hodgkin’s lymphoma

PROTOCOL

Study Coordinators :

P. Sonneveld P.C. Huijgens

Statistician

:

B. van der Holt

Datamanager

:

M.M.C. Steijaert

Registration

:

HOVON Data Center University Hospital Rotterdam - Daniel P.O.Box 5201 3008 AE

ROTTERDAM

The Netherlands tel.

+31.10.4391568

fax

+31.10.4391028

http://www.hdc.hovon.nl/top First version

:

1 August 2000

Final version

:

19 June 2001

Date of activation

:

28 November 2001

METC approved

:

METC EUR/AZR 202.109/2001/120, 24 July 2001

CKTO approved

:

CKVO 2000-10, 9 July 2001

Amendment 1

:

19 September 2001

approved METC EUR/AZR, 04 Dec. 2001

Amendment 2

:

1 October 2003

approved METC Erasmus MC, 05 Nov. 2003

Page 1 of 46

HOVON 46 NHL ________________________

1


Scheme of study

Intermediate- or high-risk NHL Age ≥ 65 years

Arm A

R

Arm B

Induction cycles I-III CHOP + G-CSF

CHOP + G-CSF + Rituximab at day 3

CHOP + G-CSF


CHOP + G-CSF

CHOP + G-CSF + Rituximab at day 1 Not at least PR

At least PR

At least PR

Induction cycles IV-VIII CHOP + G-CSF


CHOP + G-CSF


CHOP + G-CSF


CHOP + G-CSF

CHOP + G-CSF

CHOP + G-CSF

CHOP + G-CSF

Off protocol treatment

Follow up

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HOVON 46 NHL ________________________

2


Table of contents Page

1

Scheme of study.................................................................................................................................... 2

2

Table of contents................................................................................................................................... 3

3

Synopsis................................................................................................................................................. 5

4

Investigators and study administrative structure.............................................................................. 6 4.1

5

Pathology review ............................................................................................................................6

Introduction............................................................................................................................................ 7 5.1 5.2

Elderly patients with NHL ...............................................................................................................7 Induction therapy: addition of anti-CD20 (Rituximab) ....................................................................9

6

Study objectives .................................................................................................................................. 10

7

Study design ........................................................................................................................................ 10 7.1

8

Study population ................................................................................................................................. 11 8.1

9

Remission induction .....................................................................................................................10

Eligibility for registration ...............................................................................................................11 8.1.1 Inclusion criteria ............................................................................................................11 8.1.2 Exclusion criteria...........................................................................................................11

Treatments ........................................................................................................................................... 12 9.1 9.2 9.3 9.4 9.5

Remission induction treatment.....................................................................................................12 Dose modifications of CHOP .......................................................................................................12 Special management Rituximab administration...........................................................................13 Patients with detectable circulating tumor cells and Rituximab treatment ...................................14 Concomitant medication and treatment .......................................................................................14

10

End of protocol treatment .................................................................................................................. 15

11

Required clinical evaluation............................................................................................................... 15 11.1 Observations prior to start of treatment .......................................................................................15 11.2 Observations after 3 and 8 cycles of CHOP ................................................................................16 11.2.1 Response assessment after cycle 3 and cycle 8..........................................................16 11.3 Observations during follow up......................................................................................................16

12

Toxicities .............................................................................................................................................. 16

13

Reporting serious adverse events..................................................................................................... 17

14

Endpoints ............................................................................................................................................. 19

15

Forms and procedures for collecting data ....................................................................................... 19 15.1 CRF’s and schedule for completion .............................................................................................19

16

Registration and randomization ........................................................................................................ 20

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HOVON 46 NHL ________________________ 17


Statistical considerations................................................................................................................... 21 17.1 Patient number and power considerations...................................................................................21 17.2 Statistical analysis ........................................................................................................................21 17.2.1 Efficacy analysis ...........................................................................................................22 17.2.2 Toxicity analysis............................................................................................................22 17.2.3 Additional analyses .......................................................................................................22 17.3 Interim analyses ...........................................................................................................................22 17.4 Data and safety monitoring board ................................................................................................23

18

Ethics .................................................................................................................................................... 23 18.1 Independent ethics committee or Institutional review board........................................................23 18.2 Ethical conduct of the study .........................................................................................................23 18.3 Patient information and consent...................................................................................................23

19

Trial insurance ..................................................................................................................................... 24

20

Publication policy................................................................................................................................ 24

21

Glossary of abbreviations .................................................................................................................. 25

22

References ........................................................................................................................................... 27

Appendices A.

NHL WHO classification ..................................................................................................................... 29

B.

HOVON Staging and Response Criteria for Non Hodgkin’s Lymphomas ..................................... 30

C.

Ann Arbor staging classification ....................................................................................................... 35

D.

Common toxicity Criteria.................................................................................................................... 36

E.

ZUBROD-ECOG-WHO Performance Status Scale............................................................................ 37

F.

NYHA* scoring list............................................................................................................................... 38

G.

Age-adjusted International Prognostic Index................................................................................... 39

H.

Patiënteninformatie ............................................................................................................................. 40

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HOVON 46 NHL ________________________

3


Synopsis

Study phase

Phase III

Study objectives

Evaluation of the effect of anti-CD20 (Rituximab) combined with 2-weekly CHOP + G-CSF in comparison to 2-weekly CHOP + G-CSF alone

Patient population

Patients with intermediate- or high-risk NHL (MCL, Follicular Lymphoma grade III or DLBCL), CD20-positive, previously untreated, age ≥ 65 years and good WHO performance status (WHO 0-2)

Study design

Prospective, multicenter, randomized

Duration of treatment

Expected duration of treatment is 16 weeks

Number of patients

400 patients registered and randomized

Adverse events

Adverse events will be documented if observed, mentioned during open questioning, or when spontaneously reported

Planned start and end of

Start of recruitment: III 2001

recruitment

End of recruitment: III 2006

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HOVON 46 NHL ________________________

4


Investigators and study administrative structure

Responsibility

Name

Study Coordinators

P. Sonneveld P.C. Huijgens J.W. Baars

Writing Committee

Affiliation/Address

G.W. van Imhoff M.H.H. Kramer M. van Marwijk-Kooy M.H.J. van Oers M.R. Schaafsma H.C. Schouten M.B. van ‘t Veer L.F. Verdonck P.W. Wijermans R. Willemze

A. van Leeuwenhoek Hospital, Amsterdam St. Antonius Hospital, Nieuwegein University Hospital Rotterdam-Dijkzigt University Hospital Free University, Amsterdam University Hospital Groningen General Hospital Eemland, Amersfoort Isala Clinic, Zwolle Academic Medical Center, Amsterdam Medical Spectrum Twente, Enschede University Hospital Maastricht University Hospital Rotterdam-Daniel UMCU, Utrecht Leyenburg Hospital, The Hague LUMC, Leiden

Pathology review

K.H. Lam

University Hospital Rotterdam-Dijkzigt

Statistician

B. van der Holt

HOVON Data Center, Rotterdam

Datamanagement

M.M.C. Steijaert

HOVON Data Center, Rotterdam

Serious Adverse Events (SAE’s) notification

HOVON Data Center

fax: +31.10.4391028

D.H. Biesma J.K. Doorduijn, P. Sonneveld P.C. Huijgens

4.1

Pathology review

A central review of the diagnosis is performed for each case by Dr. K.H. Lam (e-mail: [email protected]), to confirm the diagnosis of B-cell lymphoma, to confirm the CD20 positivity, and to define the subtype according to the WHO lymphoma classification. A review by a second/third hematopathologist will be performed in case of discrepancy with the local pathologist or when judged appropriate. The review analysis will be done without the knowledge of patient outcome. It will comprise: •

a confirmation of the diagnosis of Mantle Cell Lymphoma, Follicular Lymphoma grade III or Diffuse Large B-cell Lymphoma as defined in the WHO classification

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HOVON 46 NHL ________________________


•

a definition of the sub-entity according to the WHO subgroups

•

a confirmation of the diagnosis of B-cell proliferation with an anti-CD20 antibody and an anti-CD79a antibody.

Once a patient is randomized, the local pathologist as well as the central pathologist will be notified by email. The local pathologist will be asked to send the slides (suitable to perform immunohistochemical stainings) to the review pathologist. A copy of the results of the review will be sent to the local pathologist and to the HOVON Data Center. All histological materials are to be sent to: Dr. K.H. Lam, Department of Pathology Josephine Nefkens Institute University Hospital Rotterdam P.O.Box 2040 3000 CA Rotterdam The Netherlands

5

Introduction

5.1

Elderly patients with NHL

The incidence of non-Hodgkin’s lymphoma (NHL) has been increasing in Western Europe and the United States during the past decade (1). The majority of cases are observed in patients over 65 years of age (2). Within this subgroup of patients the incidence of intermediate-/or high-risk NHL is 30-35% (3-6). In a recent multicenter trial in the Netherlands 71% of these patients were diagnosed with diffuse large B-Cell lymphoma (DLBCL) and 12% had Mantle cell lymphoma (MCL) (HOVON25, unpublished results). The vast majority of DLBCL and MCL are phenotypically CD20-positive. Despite the high incidence of DLBCL and MCL in elderly patients, this age group has been poorly represented in large prospected trials of CHOP in NHL (10). In the large prospective analysis of CHOP compared with other, more aggressive chemotherapy schedules, the response of the small subgroup of elderly patients was not significantly different from younger adults (10, R. Fisher, personal communication). Four trials have specifically addressed the efficacy of CHOP chemotherapy in aggressive NHL in elderly patients (6-9). In these studies the complete response rate was between 50 and 60%. However, the 5 years overall survival (25-30%) was significantly worse when compared with younger patients, a difference that was due to both toxicity and a higher proportion of relapsing patients. Recently, a slightly better survival was reported in a single

Page 7 of 46

HOVON 46 NHL ________________________


arm study using VNCOP-B, a regimen that is administered during a brief time period. This study demonstrates that the outcome of NHL in elderly patients may be improved, provided that more efficacious regimens with less toxicity are used (11). Recently, the Dutch HOVON group as well as others have studied whether G-CSF may improve the dose-intensity of CHOP and thereby the therapeutic outcome in these patients. The results of these trials may help to define the future place of hematopoietic growth factors in NHL treatment (HOVON 25, unpublished results;12). In an interim analysis of the HOVON 25 study, performed in 303 patients, 68% completed the treatment according to schedule. 52% of the patients achieved a CR , of which 73/157 (47%) after 3 cycles of CHOP and 47% after 6-8 CHOP. Of 230 patients who had not reached a CR after 3 CHOP, 140 never achieved a CR on protocol or with rescue chemotherapy. The overall survival is 47% at 2 years, while the disease-free survival from CR of responding patients is 58% at 2 years. At this stage, 108/159 (68%) of deaths result from refractory NHL. These data indicate that CHOP as a single modality treatment in these elderly patients with NHL, although still the state of the art treatment, does not suffice for a long term survival. Currently, there are several ongoing new approaches to improve the long-term outcome of intermediate-/high-risk NHL in elderly patients. The German High-grade Non-Hodgkin’s lymphoma Study Group has compared CHOP + G-CSF as a 2-weekly schedule with standard CHOP q 3 weeks in patients of all ages. In the subgroup of patients > 60 yrs 2-weekly CHOP (n=110) as compared with 3-weekly CHOP (n=118) resulted in a better CR rate (74% vs 56%) and a better relapse-free survival at 2 yr (50% vs 40%). These differences were more eminent in the subgroup of patients with a high IPI (International Prognostic Index) score. More than 90% of the patients tolerated 2-weekly CHOP + G-CSF for 8 cycles without the necessity for dose-reduction. These investigators conclude that 2-weekly CHOP is a feasible and more effective treatment for NHL in this age group (M. Pfreundschuh, abstract 2000). A retrospective analysis of HOVON 25 demonstrated that, indeed the majority of the patients with CHOP + G-CSF have full hematological recovery at day 15. Patients in Hovon 25 study who did not have hematological recovery at day 15 Cycle

Patients (n)

% not recovered CHOP

CHOP + G-CSF

1

296

30

11

2

288

30

8

3

272

45

13

4

257

47

17

5

244

51

16

6

221

49

25

7

133

47

27

8

106

65

40

Thus, these data support the feasibility of 2-weekly CHOP in elderly patients.

Page 8 of 46

HOVON 46 NHL ________________________ 5.2


Induction therapy: addition of anti-CD20 (Rituximab)

Anti-CD20 (Rituximab) is a chimeric humanised mouse monoclonal antibody directed to the CD20 antigen which is present on B-lymphocytes. CD20 is also expressed by tumour cells in follicular lymphoma, in DLBCL and in MCL (13). Phase I-II studies of Rituximab in follicular NHL have shown an overall response of 50% and a progression-free survival of almost one year (14). In DLBCL treatment with Rituximab alone results in a response duration of 3 months. Phase I/II studies in patients with intermediate- and high-grade NHL using anti-CD20 combined with CHOP demonstrated 72% CR and 94% overall response (15,16,17). Recently the French GELA group has completed a randomized study of Rituximab combined with full-dose CHOP (8 cycles) in intermediate- and high-risk lymphoma. In this study of 400 patients, an interim analysis performed in 300 patients demonstrated that CHOP combined with Rituximab as compared with CHOP alone resulted in a significantly better CR/CRu rate (76% vs 60%), a better event-free survival at 1 year (69% vs 49%) and a better survival (83% vs 68%) (18). A recent, not yet published analysis of this study shows that the survival difference is still significant at 2 years follow-up (B. Coiffier, personal communication). There are several other ongoing randomized trials of CHOP and Rituximab in high-intermediate risk NHL, i.e. from the Southwest Oncology Group, the CALGB intergroup and a Genentech sponsored study, all exploring 3-weekly CHOP in defined groups of elderly patients. The combined results of these studies will define the benefits of Rituximab added to standard CHOP. Little is known about the optimal schedule of Rituximab in NHL. Analysis of patients in this and other protocols of Rituximab in (relapsed follicular) lymphoma has shown that 4 months after the last administration of Rituximab still significant circulating concentrations were present in the peripheral blood. The calculated half-life of the drug is well over 1 month (B. Coiffier, ASH abstract 593, 2000).

The proposed study is based on the fact that by adding G-CSF, the interval between CHOP schedules can be reduced from 3 to 2 weeks without a concomitant increase of toxicity, while increasing the CR rate and the overall survival. The poor results of 3-weekly CHOP in elderly patients should therefore be considered obsolete. Therefore, in this study 2-weekly CHOP + GCSF is regarded the standard treatment. The main study question will be to employ the benefits of 2-weekly CHOP in elderly patients with intermediate- and high-risk lymphoma while also increasing the treatment efficacy by adding a new therapeutic modality, i.e. anti-CD20 (Rituximab). It is expected that by combining the two modalities during a brief treatment period, the tolerability by elderly patients will be good and that the number of elderly patients that can be effectively treated, will increase.

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HOVON 46 NHL ________________________


6

Study objectives

♦

To assess in a randomized comparison the efficacy of Rituximab combined with 2-weekly CHOP + G-CSF in comparison with 2-weekly CHOP + G-CSF alone, on event free survival.

♦

As secondary objectives the effect of Rituximab on complete remission rate, overall survival and disease free survival will be evaluated.

♦

To evaluate the toxicity of Rituximab with 2-weekly CHOP + G-CSF in comparison with 2-weekly CHOP + G-CSF alone.

7

Study design

Details of all treatments (dose and schedule) are given in 9.1-9.5.

7.1

Remission induction

Patients with CD20-positive intermediate- or high-risk NHL (MCL, Follicular Lymphoma grade III or DLBCL) meeting all eligibility criteria (see 8.1) will be randomized on entry between:

Arm A:

8 cycles of CHOP q 2 weeks plus G-CSF (pegfilgrastim, Neulasta®) once per cycle

or Arm B:

8 cycles of CHOP q 2 weeks plus G-CSF (pegfilgrastim, Neulasta®) once per cycle combined with 6 administrations of Rituximab (Mabthera®)

Patients will be evaluated for response after 3 cycles of CHOP (all patients) and after 8 cycles of CHOP (if applicable, otherwise after last cycle administered). All patients who have not attained at least a PR after 3 cycles of CHOP, will go off protocol treatment.

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HOVON 46 NHL ________________________

8

Study population

8.1

Eligibility for registration


All eligible patients have to be registered and randomized before start of treatment (see paragraph 16).

8.1.1

Inclusion criteria

♦

Patients with a confirmed histologic diagnosis of NHL according to the WHO classification (Appendix A):

♦

!

Mantle cell lymphoma (MCL)

!

Follicular lymphoma (grade III) (FL III)

!

Diffuse large B-cell lymphoma (DLBCL)

Low-intermediate, high-intermediate or high risk NHL according to age-adjusted IPI score (appendix G)

♦

NHL must be CD20 positive.

♦

Age ≥ 65 years

♦

WHO performance status ≤ 2 (see appendix E)

♦

Written informed consent

8.1.2

Exclusion criteria

♦

Intolerance of exogenous protein administration

♦

Severe cardiac dysfunction (NYHA classification II-IV, appendix F) or LVEF < 45 %

♦

Significant renal dysfunction (serum creatinin ≥ 150 µmol/l), unless related to NHL

♦

Significant hepatic dysfunction (total bilirubin ≥ 30 µmol/l or transaminases ≥ 2.5 times normal level), unless related to NHL

♦

Suspected or documented Central Nervous System involvement by NHL

♦

Patients known to be HIV-positive

♦

Patients with active, uncontrolled infections

♦

Patients with uncontrolled asthma or allergy, requiring steroid treatment

♦

Prior treatment with chemotherapy, radiotherapy or immunotherapy for this lymphoma, except local radiotherapy in case of (potential) organ dysfunction by localized lymphoma mass or infiltration

♦

History of active cancer during the past 5 years, except basal carcinoma of the skin or stage 0 cervical carcinoma

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HOVON 46 NHL ________________________


9

Treatments

9.1

Remission induction treatment

CHOP chemotherapy + G-CSF Agent

Dose/day 2

Route

Days

i.v.

1

Cyclophosphamide

750 mg/m

Doxorubicin

50 mg/m2

i.v.

1

Vincristine

1.4 mg/m2, with a maximum of 2 mg 100 mg

i.v.

1

p.o.

1, 2, 3, 4, 5

6 mg

s.c.

2

Prednisone G-CSF (pegfilgrastim, Neulasta®)

Patients in both arms will be treated with 8 cycles of CHOP, every 2 weeks. In addition, they will receive G-CSF on day 2 during each cycle of CHOP.

Patients in arm B will also receive 6 administrations of Rituximab, at day 3 of cycles 1 and 2, and at day 1 of cycles 3 through 6 (after CHOP administration), see below.

Agent

Dose/day

Rituximab (Mabthera®)

2

375 mg/m with a maximum of 750 mg

Route

Day

i.v.

Cycle 1: day 3 Cycle 2: day 3 Cycle 3,4,5,6: day 1

Assessment of response after 3 cycles is described in 11.2. Patients who have not achieved at least a PR will go off protocol treatment. Patients in PR or CR after cycle 3 will receive another 5 cycles of CHOP + G-CSF (± Rituximab), every 2 weeks.

9.2

Dose modifications of CHOP

Dose modifications will not be made in the first course. During the next courses modifications of the treatment schedule will only be made in case of:

a)

Myelosuppression

If leucocytes are < 3 x 109/l and/or platelets < 100 x 109/l: delay course for one week. If leucocytes or platelets remain below these values, then the doses of doxorubicin and cyclophosphamide have to be reduced following the scheme:

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HOVON 46 NHL ________________________


Leucocytes x 109/l >3 and

Platelets x 109/l > 100

Cyclophosphamide

Doxorubicin

Vincristine

Prednison

100%

100%

100%

100%

2-3

and

> 100

75%

75%

100%

100%

1-2

or

> 50 < 100

50%

50%

100%

100%

<1

or

< 50

0%

0%

100%

100%

b)

Neurotoxocity

Dose modifications of vincristine are made at the discretion of the medical attendant.

c)

Cardiotoxicity

In case of documented doxorubicin induced cardiomyopathy developed during treatment, LVEF should be repeated. In case of a reduction of LVEF by > 15 % (absolute values, e.g. from 60% to 45%) the patient goes off protocol treatment.

9.3

Special management Rituximab administration

Antibody infusions may be given to patients in an outpatient clinic setting or following hospital admission as an inpatient. A peripheral or central intravenous (IV) line will be established. Vital signs (blood pressure, pulse, respiration, and temperature) should be monitored every 15 minutes during the first hour or until stable and then hourly until the infusion is discontinued and vital signs are stable. Premedication with paracetamol (500 mg) and/or antihistaminics (e.g. clemastine 2 mg) is allowed. The initial dose should be 50 mg/hr for the first hour. If no adverse event is seen, the dose may be escalated in 30 minutes intervals with increment steps of 50 mg/hr, to a maximum of 400 mg/hr. Patients may experience transient fever and rigors with infusion of chimeric anti-CD20 antibody. When any of the following events is noted, antibody infusion should be temporarily discontinued, the patient should be observed and the severity of the adverse events should be evaluated: ♦ fever > 38.5° C; ♦ mild/moderate rigors; ♦ mild/moderate mucosal congestion or edema; ♦ drop in systolic blood pressure > 30 mm Hg. The patient should be treated according to the best available local practices and procedures. Following observation, if the patients systems improve, the infusion should be continued, at ½ the previous rate. Following the antibody infusion, the IV line should be kept open for medications. If

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HOVON 46 NHL ________________________


there are no complications, the IV line may be discontinued after one hour of observation. If complications occur during infusion, the patient should be observed for two hours after the completion of the infusion. If no adverse event is seen with the previous infusion, the infusion rate at the start of following infusions can be increased to 100 mg/hr and if no further adverse event is observed the infusion rate can be increased with 30 minutes intervals with increment steps of 50 mg/hr to a maximum of 400 mg/hr.

9.4

Patients with detectable circulating tumor cells and Rituximab treatment

In patients with detectable circulating lymphoma cells, the initial rate of infusion should be reduced to 25 mg/hr. Patients with detectable circulating cells may experience transient fever and rigors, shortness of breath, and hypotension with infusion of chimeric anti-CD20 antibody. When these adverse events are noted, antibody infusion should be temporarily discontinued, the patient should be observed and severity of the adverse events should be evaluated. The patient should be treated according to the best available local practices and procedures. Following observation, if the patients symptoms improve, the infusion should be continued, initially, at ½ the previous rate. Upon resolution of all adverse events and in the judgement of the investigator, the patient may be gradually escalated to a maximum infusion rate of 400 mg/hr, and the remainder of the treatment can be carried out. Following the antibody infusion, the IV line should be kept open for medications. If there are no complications, the IV line may be discontinued after one hour of observation. If complications occur during infusion, the patient should be observed for two hours after the completion of the infusion.

9.5

Concomitant medication and treatment

a)

Drugs

Concomitant medication(s) introduced in the patient since the beginning of the treatment will be recorded on the Case Report Form (CRF) in case of any adverse event of CTC grade ≥ 2. Patients should receive full supportive care including blood transfusions and blood products, antibiotics, anti-emetic etc., where applicable. It is advised to administer granisetron (Kytril) 1 mg orally once or twice daily with each CHOP cycle. b)

Radiotherapy

Radiotherapy before start and during protocol treatment is permitted for localized problems, i.e. in case of potential or actual organ dysfunction by localized lymphoma mass or infiltration.

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HOVON 46 NHL ________________________


Additional radiotherapy after completion of the protocol is only allowed in case of bulky disease (> 10 cm) at diagnosis, with residual abnormalities at the end of protocol treatment.

10

End of protocol treatment

Reasons for going off protocol treatment are: 1.

No response after 3 CHOP

2.

Progression/relapse after initial response (i.e. before completion of treatment)

3.

Manifest cardiomyopathy (reduction of ejection fraction >15%)

4.

Other excessive toxicity requiring stopping of protocol treatment (including toxic death)

5.

No compliance of the patient (especially refusal to continue treatment)

6.

Intercurrent death

7.

Lost to follow-up

8.

Major protocol violation

9.

Normal completion of protocol treatment

11

Required clinical evaluation

Also see appendix B for a specification of staging and restaging evaluations.

11.1

Observations prior to start of treatment

♦

history (including B symptoms)

♦

physical examination (including WHO performance)

♦

laboratory tests (including Hb, WBC and differential, platelet count, sodium, potassium, calcium, creatinine, uric acid, bilirubin, glucose, alkaline phosphatase, γ-GT, ALAT, ASAT, LDH, protein, albumin, immuno-electrophoresis)

♦

routine urine analysis

♦

imaging (including chest X-ray, CT or MRI thorax and abdomen and echography of the cervical lymph node stations)

♦

lymph node biopsy for morphology and immunopathology of involved site

♦

immunophenotypering of lymph node for CD19, CD20, kappa/lambda, CD3, CD4, CD8

♦

cryopreservation of lymph node tissue for external PA review

♦

bone marrow aspirate and biopsy

♦

peripheral blood for cytology

♦

ABO and RhD blood group, irregular antibody screening, anti Hepatitis B and C

♦

Left ventricular ejection fraction (LVEF) or cardiac ultrasound/Doppler

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HOVON 46 NHL ________________________


11.2

Observations after 3 and 8 cycles of CHOP

♦

history (including B symptoms)

♦

physical examination (including WHO performance)

♦

laboratory tests (including Hb, WBC and differential, platelet count, sodium, potassium, creatinine, uric acid, bilirubin, glucose, alkaline phosphatase, γ-GT, ALAT, ASAT, LDH, protein, albumin, immuno-electrophoresis)

♦

routine urine analysis

♦

imaging of involved areas (including chest X-ray, CT or MRI thorax and abdomen and echography of the cervical lymph node stations)

♦

bone marrow aspirate and biopsy / peripheral blood (if initially positive)

♦

LVEF or cardiac ultrasound/Doppler

11.2.1

Response assessment after cycle 3 and cycle 8

Response will be formally evaluated after CHOP cycles 3 and 8 according to the criteria of response. The response criteria are in appendix B. All relevant information on drug dose, measurable lesions, tumor response and treatment related toxicity will be collected.

11.3

Observations during follow up.

Follow up for patients in CR or CRu will be every 3 months during the first two years, every 6 months the next two years and annually thereafter. After relapse patients will be followed until death. ♦

Physical examination (including WHO performance)

♦

Blood count, LDH

♦

Any clinically indicated examinations (thoracic and abdominal scan annually)

♦

Any documentation of abnormal events (e.g. secondary malignancies)

12

Toxicities

CHOP is a common used chemotherapeutic regimen with well-known side-effects. The most frequent side-effect is myelosuppression which may hamper patient adherence to the projected schedule of CHOP. It may be expected that, outside myelosupression, comparable side-effects will occur in both treatment arms. Side effects of Rituximab may include fever, rigors, mucosal congestion or edema, and drop in systolic blood pressure. These side effects are only observed during rapid infusion of Rituximab.

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HOVON 46 NHL ________________________


Special management is provided in 9.3. In patients who experience side effects the infusion time has to be restricted to 100 mg/hr.

Toxicities will be scored according to the NCI Common Toxicity Criteria, version 2.0 (Appendix D).

13

Reporting serious adverse events

An Adverse Event (AE) is any untoward medical occurrence or experience in a patient or clinical investigation subject which occurs during or following treatment regardless of the causal relationship. This can include any unfavorable and unintended signs (such as rash or enlarged liver), or symptoms (such as nausea or chest pain), an abnormal laboratory finding (including blood tests, x-rays or scans) or a disease temporarily associated with the treatment. Serious Adverse Events (SAE) are defined as any undesirable experience occurring to a patient, whether or not considered related to the treatment. Adverse events which are considered as serious are those which result in: ♦ death ♦ a life-threatening event (i.e. the patient was at immediate risk of death at the time the reaction was observed) ♦ hospitalization or prolongation of hospitalization ♦ severe/permanent disability ♦ a congenital anomaly

Note that any death, whether due to side effects of the treatment or due to progressive disease or due to other causes is considered as a serious adverse event. Unexpected Serious Adverse Events are those SAE’s of which the nature or severity is not consistent with information in the relevant source documents. For a medicinal product not yet approved for marketing in a country, a company’s Investigator’s Brochure will serve as a source document in that country. Reporting Serious Adverse Events During protocol treatment all deaths, all SAE’s that are life-threatening and any unexpected SAE must be reported to the HOVON Data Center by fax within 48 hours of the initial observation of the event. All details should be documented on the Serious Adverse Event and Death Report.

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HOVON 46 NHL ________________________


In circumstances where it is not possible to submit a complete report an initial report may be made giving only the mandatory information. Initial reports must be followed-up by a complete report within a further 14 calendar days and sent to the HOVON Data Center. All SAE Reports must be dated and signed by the responsible investigator or one of his/her authorized staff members.

At any time after the completion of protocol treatment, unexpected Serious Adverse Events that are considered to be possibly related to protocol treatment and ANY death (regardless the cause) must also be reported to the HOVON Data Center using the same procedure, within 48 hours after the SAE or death was known to the investigator.

The investigator will decide whether the serious adverse event is related to the treatment (i.e. unrelated, unlikely, possible, probable, definitely and not assessable) and the decision will be recorded on the serious adverse event form. The assessment of causality is made by the investigator using the following :

RELATIONSHIP

DESCRIPTION

UNRELATED

There is no evidence of any causal relationship

UNLIKELY

There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the patients clinical condition, other concomitant treatments).

POSSIBLE

There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the patients clinical condition, other concomitant treatments).

PROBABLE

There is evidence to suggest a causal relationship and the influence of other factors is unlikely.

DEFINITELY

There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out.

NOT

There is insufficient or incomplete evidence to make a clinical judgement

ASSESSABLE

of the causal relationship.

Page 18 of 46

HOVON 46 NHL ________________________


The HOVON Data Center will forward all reports within 24 hours of receipt to the study coordinator and the study central datamanager. The report of an SAE will be the signal for the central datamanager to ask the investigator or the responsible local datamanager to complete and send as soon as possible all relevant CRF’s for the involved patient with details of treatment and outcome. It is of utmost importance that all SAE’s (including all deaths due to any cause) are reported in a timely fashion. Patients without a report of an SAE are implicity considered alive without SAE. This information will be used in monitoring the incidence of SAE’s, the estimation of overall survival and monitoring of safety of experimental treatments.

14

Endpoints

Primary endpoint 1. Event-free survival (i.e. time from registration to induction failure (i.e. no CR or CRu on induction treatment), death or relapse whichever occurs first); the time to failure of patients with induction failure is set at one day.

Secondary endpoints 2. Complete response 3. Overall survival measured form the time of registration 4. Disease-free interval (duration of the first CR) measured from the time of achievement of CR to day of relapse or death from any cause (whichever occurs first). 5. Toxicity (according to Appendix D)

15

Forms and procedures for collecting data

15.1

CRF’s and schedule for completion

Form nr

Title

1

Registration & Randomization Form

2

On Study Form

3A

Original Pathology Form

3B

Central Pathology Form

4

Induction Treatment Form

5

Treatment Evaluation Form

6

Restaging Form

7A/B

Imaging Results Form

Page 19 of 46

HOVON 46 NHL ________________________ 8

Off Treatment Form

9

Follow Up Form

10

Side Effects Form

11

Infection Report Form

12

General Comments Form


Table for filling out forms

Forms 1 Registration & randomization

2

3A

3B

X

X1

X2

4

5

6

7A

7B

8

9

10

11

12

X

On study Induction Treatment

X X

X

X

(X) X

(X) X

End of treatment Follow up

(X)

(X)

X

(X)

X

(X)

(x) fill out if necessary, see instructions 1

by local pathologist

2

by central pathologist

Instructions for completion and sending in of the forms are specified in a separate document together with the forms. In order to be able to closely monitor the occurrence of untoward events and detect a difference in failure rate between the two induction treatments (see 17.3) it is of utmost importance that the CRF’s regarding induction treatment, especially for the first 100 patients, are submitted in a timely fashion i.e. within one month of completion of the induction treatment.

16

Registration and randomization

The patient should be registered immediately after satisfactory completion of screening tests and obtaining informed consent, and before the start of chemotherapy. Patients need to be registered at the HOVON Data Center of the University Hospital Rotterdam-Daniel by phone call: +31.10.4391568 or fax +31.10.4391028 Monday through Friday, from 09:00 to 17:00 or via the Internet via TOP (Trial Online Proces; http://www.hdc.hovon.nl/top). A logon to TOP can be requested at the HOVON Data Center for participants.

Page 20 of 46

HOVON 46 NHL ________________________


The following information will be requested at registration: 1.

Protocol number

2.

Institution name

3.

Name of caller/responsible investigator

4.

Patient’s initials or code

5.

Patient’s hospital record number

6.

Sex

7.

Date of birth

8.

Date of diagnosis of NHL

9.

WHO classification

10.

Age-adjusted IPI risk score

11.

PA number

12.

Eligibility criteria

All eligibility criteria will be checked with a checklist. Each patient will be given a unique patient study number. Patients will be randomized, stratified by center, WHO classification and IPI-score with a minimization procedure, ensuring balance within each stratum and overall balance. Patient study number and result of randomization will be given immediately by TOP or phone and confirmed by fax or email.

17

Statistical considerations

17.1

Patient number and power considerations

The target number of patients for this study is 400 to be accrued in 5 years. After entry of the last patient an additional follow up of 1 year is planned before a first final analysis. Based on the previous HOVON 25 NHL elderly study (in patients of 65 years and older) and the German study we expect that the CR rate (including CR unconfirmed) in the control arm (arm A) will be about 60% with an event free survival (EFS) at 3 years of 30%. The target number of 400 patients will give a power of 80% with a 1:1 randomization and a two-sided test at 5% significance level to detect an improvement in EFS with hazard ratio HR=0.70, which corresponds to an increase in the CR rate to 70% and an EFS at 3 years of 43% in the experimental arm (arm B).

17.2

Statistical analysis

All main analyses will be according to the intention to treat principle.

Page 21 of 46

HOVON 46 NHL ________________________

17.2.1


Efficacy analysis

The main endpoint for the comparison of the two treatment arms will be event free survival from randomization, with failure defined as failure to reach CR (including CRu) on protocol treatment, relapse after CR or death in first CR. Secondary endpoints will be complete response rate, overall survival from randomization and disease free survival from CR. Actuarial estimates of competing risks of failure (no CR, relapse after CR or death in CR1) will be made for each treatment arm. The tests for the difference in EFS, DFS and overall survival between the two treatment arms will be done with Cox regression analysis. The test for the difference in CR rate between the two treatment arms will be done with logistic regression.

17.2.2

Toxicity analysis

The analysis of treatment toxicity will be done primarily by tabulation of the incidence of side effects and infections with CTC grade 2 or more (appendix D) by treatment arm and cycle.

17.2.3

Additional analyses

Additional analyses involve the analysis of prognostic factors, especially age-adjusted IPI, with respect to CR rate, EFS and overall survival from randomization and DFS from CR. Logistic regression and Cox regression will be used for this purpose.

17.3

Interim analyses

Interim analyses are planned, primarily to guard against unfavourable results in the experimental arm (2-weekly CHOP + G-CSF and Rituximab). Results of the interim analyses will be presented confidentially to an independent data and safety monitoring board (DSMB). Only if the DSMB recommends that the study should be stopped or modified the results will be made public to the principal investigators for further decisions. Interim analyses are planned after 100 and 250 evaluable patients. Before the first interim analysis the CR/CRu rate and serious adverse event rate in both treatment arms will be closely monitored in order to pick up any (unexpected) trends, and after 50 evaluable patients the feasability (toxicity) of CHOP 14 will be evaluated. The main endpoint for the interim analyses is the failure rate on induction treatment. A patient counts as failure on induction treatment if the patient does not achieve CR/CRu on induction, or if the patient relapses or dies during protocol treatment.

Page 22 of 46

HOVON 46 NHL ________________________


At each interim analysis a detailed report will be generated and presented to the DSMB. The report includes by treatment arm the number of entered patients and at that time evaluable patients, treatment given, the number of failures, type of failures and incidence of SAE’s and other side effects and infections (CTC grade).

The DSMB is free in her public recommendations to the study coordinators and the confidential recommendations to the study statistician, but the following guidelines apply: 1.

Primary purpose of the interim analyses is to guard against a higher failure rate in the experimental arm compared with the standard induction arm. A higher failure rate in the experimental arm with a P-value < 0.10 is a good reason to recommend the stopping of the trial or recommendations for modifications.

2.

A benefit in terms of event free survival or overall survival for the experimental arm is in general no reason to recommend early stopping of the study, unless the associated Pvalue is very extreme (P<0.001) and the number of evaluable patients in each arm is at least 100.

17.4

Data and safety monitoring board

A Data and safety monitoring board will be installed before start of the study.

18

Ethics

18.1

Independent ethics committee or Institutional review board

The study protocol and any amendment that is not solely of an administrative nature will be approved by an Independent Ethics Committee or Institutional Review Board.

18.2

Ethical conduct of the study

The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki (South Africa Amendment 1996) and the ICH-GCP Guidelines of 17 January 1997.

18.3

Patient information and consent

Written Informed consent of patients is required before randomization. The procedure and the risks and the opinions for therapy in NHL will be explained to the patient.

Page 23 of 46

HOVON 46 NHL ________________________

19


Trial insurance

The HOVON insurance program covers all patients from participating centers in the Netherlands according to Dutch law (WMO). The WMO insurance statement can be viewed on the HOVON Web site www.hovon.nl. Individual participating centers from outside the Netherlands have to inform the HOVON about the national laws regarding the risk insurance of patients participating in a study. If necessary HOVON will extend the insurance to cover these patients.

Intergroup studies. The HOVON insurance program does not cover the risk insurance of patients from centers participating within another cooperative group taking part in an intergroup study. The other participating groups will cover the insurance of patients registered/randomized through their offices.

20

Publication policy

The final publication of the trial results will be written by the Study Coordinator(s) on the basis of the statistical analysis performed at the HOVON Data Center. A draft manuscript will be submitted to the Data Center and all co-authors (and the sponsor, where applicable) for review. After revision by the Data Center, the other co-authors (and the sponsor), the manuscript will be sent to a peer reviewed scientific journal.

Authors of the manuscript will include the study coordinator(s), the lead investigators of the major groups (in case of intergroup studies), investigators who have included more than 5% of the evaluable patients in the trial (by order of inclusion), the statistician(s) and the HOVON datamanager in charge of the trial, and others who have made significant scientific contributions.

Interim publications or presentations of the study may include demographic data, overall results and prognostic factor analyses, but no comparisons between randomized treatment arms may be made publicly available before the recruitment is discontinued.

Any publication, abstract or presentation based on patients included in this study must be approved by the study coordinator(s). This is applicable to any individual patient registered/randomized in the trial, or any subgroup of the trial patients. Such a publication cannot include any comparisons between randomized treatment arms nor an analysis of any of the study end-points unless the final results of the trial have already been published.

Page 24 of 46

HOVON 46 NHL ________________________

21


Glossary of abbreviations

(in alphabetical order) AE ALAT ASAT BM CHOP CKVO CR CRF CRu CR1 CT CTC DFS DLBCL DSMB ECOG EFS ENT EORTC FL III GCP G-CSF GELA γGT Hb HOVON HIV ICH IPI IV LDH LVEF MCL MRI NCI NHL NYHA OS

Adverse Event Alanine Amino Transferase Aspartate Animo Transferase Bone Marrow Cyclophosphamide, Doxorubicin, Vincristine (Oncovin), Prednisone `Commissie voor Klinisch Toegepast Onderzoek’ Complete Remission/Response Case Report Form Complete Remission unconfirmed First Complete Remission Computerized Tomography Common Toxicity Criteria Disease Free Survival Diffuse Large B-cell Lymphoma Data and Safety Monitoring Board Eastern Cooperative Oncology Group Event Free Survival Ear Nose Throat European Organization for Research and Treatment of Cancer Follicular Lymphoma grade III Good Clinical Practice Granulocyte Colony Stimulating Factor Groupe d'Etudes des Lymphomes de l'Adulte Gamma Glutamyl Transferase Hemoglobin Dutch-Belgian Hematology-Oncology Cooperative Group Human Immunodeficiency Virus International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use International Prognostic Index Intravenous Lactate Dehydrogenase Left Ventricular Ejection Fraction Mantle Cell Lymphoma Magnetic Resonance Imaging National Cancer Institute Non-Hodgkin’s Lymphoma New York Heart Association Overall Survival

Page 25 of 46

HOVON 46 NHL ________________________ PA PB PD PO PPD PR SAE SD SPD TOP US VNCOP-B WBC WHO WMO


Pathology Peripheral Blood Progressive Disease Per Os Product of the two largest Perpendicular Diameters Partial Response Serious Adverse Event Stable Disease Sum of the Products of the two largest perpendicular Diameters Trial Online Process Ultrasound Etoposide (VP16), Mitoxantrone (Novantrone), Cylophosphamide, Vincristine (Oncovin), Prednisone, Bleomycine White Blood Count World Health Organization ‘Wet Medisch-Wetenschappelijk Onderzoek met mensen’

Page 26 of 46

HOVON 46 NHL ________________________

22 1.


References Weisenburger DD. Epidemiology of non-Hodgkin’s lymphoma: Recent findings regarding an emergic epidemic. Ann Oncol 1994;5:s19-24.

2.

Greiner TC, Medeiros LJ, Jaffe ES. Non-Hodgkin’s lymphoma. Cancer 1995;75:370-380.

3.

Goss PE. Non-Hodgkin’s lymphomas in elderly patients. Leuk Lymph 1993;10:147-156.

4.

The Non-Hodgkin’s Lymphoma Classification Project, A clinical trial of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 1997;89: 3909-3918.

5.

The Non-Hodgkin’s Lymphoma Classification Project, Effect of age on the characteristics and clinical behavior of non-Hodgkin’s lymphoma patients. Ann Oncol 1997;8:973-978.

6.

Meyer RM, Browman GP, Samosh ML, Benger AM, Bryantlukosius D, Wilson WEC, Frank GL, Leber BF, Sternbach MS, Foster GA, Skingley P, Levine MN. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 1995;13:2386-2393.

7.

Sonneveld P, De Ridder H, Van der Lelie H, Nieuwenhuis K, Schouten H, Mulder A, Van Reijswoud L, Hop W, Löwenberg B. Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995;13:2530-2539.

8.

Bastion Y, Blay JY, Divine M, Brice P, Bordessoule D, Sebban C, Blanc M, Tilly H, Lederlin P, Deconinck E, Salles B, Dumontet C, Brière J, Coiffier B. Elderly patients with aggressive non-Hodgkin’s lymphoma: Disease presentation, response to treatment, and survival. A Groupe d’Etude des Lymphomes de l’Adulte; study on 453 patients older than 69 years. J Clin Oncol 1997;15:2945-2953.

9.

Tirelli U, Errante D, Van Glabbeke M, Teodorovic I, Kluin-Nelemans JC, Thomas J, Bron D, Rosti G, Somers R, Zagonel V, Noordijk EM. CHOP is the standard regimen in patients greater than or equal to 70 years of age with intermediate grade and high grade nonHodgkin’s lymphoma: Results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1998;16:27-34.

10.

Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Eng J Med 1993;328:1002-1006.

Page 27 of 46

HOVON 46 NHL ________________________ 11.


Zinzani PL, Storti S, Zaccaria A, Moretti L, Magagnoli M, Pavone E, Gentilini P, Guardigni L, Gobbi M, Fattori PP, Falini B, Lauta VM, Bendandi M, Gherlinzoni F, De Renzo A, Zaja F, Mazza P, Volpe E, Bocchia M, Aitini E, Tabanelli G, Tura S. Elderly aggressive-histology non-Hodgkin’s lymphoma: First-line VNCOP-B regimen experience on 350 patients. Blood 1999;94:33-38.

12.

Doorduijn JK, Van der Holt B, Van der Hem KG, Van Imhoff GW, Kramer MHH, Van Oers MHJ, Ossenkoppele GJ, Schaafsma MR, Verdonck LF, Verhoef GEG, Steijaert MMC, Löwenberg B, Sonneveld P. On behalf of the Dutch-Belgian Hemato Oncology Cooperative Group (HOVON). Randomized trial of granulocyte-colony stimulating factor (G-CSF) added to CHOP in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). ASH 2000, abstract 575.

13.

Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-c2b8) in patients with recurrent B-cell lymphoma. Blood 1994;84:24572466.

14.

Maloney DG, Smith B, Appelbaum FR. The anti-tumor effect of monoclonal anti-CD20 antibody therapy includes direct anti-proliferative activity and induction of apoptosis in CD20 positive non-Hodgkin’s lymphoma cell lines. Proc Amer Soc Hematol 1996.

15.

Maloney D, Grillo-Lopez A, Bodkin D, White C, Liles T, Royston L, Varns C, Rosenberg J, Levy R. IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed nonHodgkin’s lymphoma. J Clin Oncol 1997;15:3266-3272.

16.

Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, FeuringBuske M, Radford JA, Capdeville R, Diehl V, Reyes F. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 1998;92:1927-1932.

17.

Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI. Phase II study of Rituximab in combination with CHOP chemotherapy in patients with aggressive Non-Hodgkin’s lymphoma. J Clin Oncol 2001, 19:389-397.

18.

Coiffier B, Lepage E, Herbrecht R, Tilly H, Solal-Celigny P, Munck JN, Bouabdallah R, Lederlin P, Sebban C, Morel P, Haioun C, Salles G, Molina T, Gisselbrecht C. MabThera (Rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large Bcell lymphoma (DLCL): Interim results of a randomized GELA trial. ASH 2000, abstract 950.

19.

The international non-Hodgkin’s lymphoma prognostic factor’s project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Eng J Med 1993;329:987-994.

Page 28 of 46

Appendix A

HOVON 46 NHL ________________________ A.


NHL WHO classification

B-cell neoplasms WHO 1 2 3 4 5

♦ ♦ ♦ ♦ ♦

6 7 8 9 10 11

♦ ♦ ♦ ♦ ♦ ♦

12 13

♦ ♦

Precursor B-cell lymphoblastic leukaemia / lymphoma B-cell chronic lymphocytic leukaemia / small lymphocytic lymphoma B-cell prolymphocytic leukaemia Lymphoplasmocytic lymphoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type Nodal marginal zone lymphoma (+/- monocytoid B cells) Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) Plasma cell myeloma / Plasmocytoma Follicular lymphoma; grade I, grade II, grade III Mantle-cell lymphoma Diffuse large B-cell lymphoma (subtypes: mediastinal, intravascular, primary effusion lymphoma) Burkitt's lymphoma Unclassifiable

T-cell neoplasms WHO 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦

Precursor T-cell lymphoblastic leukaemia / lymphoma T-cell prolymphocytic leukaemia T-cell granular lymphocytic leukaemia Aggressive NK-cell leukaemia Adult T-cell leukaemia / lymphoma (HTLV1+) Extranodal NK / T-cell lymphoma, nasal-type Enteropathy type T-cell lymphoma Hepatosplenic γ / δ T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome Anaplastic large cell lymphoma, primary cutaneous type Peripheral T-cell lymphoma (not otherwise characterized) Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma (T- and null-cell types), primary systemic type Unclassifiable

Page 29 of 46

Appendix B

HOVON 46 NHL ________________________ B.


HOVON Staging and Response Criteria for Non Hodgkin’s Lymphomas

This document describes the minimally required staging and evaluation procedures and response criteria that will be applied in all HOVON NHL studies. It is based on international working group recommendations (JCO, Vol.17, 1999, pp1244-1253). Response is currently assessed on the basis of clinical, radiologic, and pathologic (i.e., bone marrow) criteria. CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, and pelvic CT scans are recommended even if those areas were not initially involved because of the unpredictable pattern of recurrence in NHL. Immunophenotyping of blood or bonemarrow has not been included as standard mimimum requirement for the staging and restaging of lymphoma, even though it may be done standard in some centers (Hanson, Blood, Vol 94, 1999, pp 3889-3896). It may be a requirement in specific studies involving monoclonal antibodies. Staging and restaging procedures Only minimal requirements are specified. A. Staging at on study before start of treatment - History (including B symptoms) - WHO Performance status - Physical examination - Laboratory tests Hb, WBC. differential, platelet count, LDH Calcium, creatinine, uric acid, glucose, albumin, bilirubine, ALAT paraprotein by immuno-electrophoresis quantitative immunoglobulins only if immuno-electrophoresis abnormal Hepatitis-B in case of abnormal liver function tests HIV test - Lymph node biopsy for morphology and immunopathology - Bone marrow biopsy (≥ 20 mm biopsy core) for histopathology - Bone marrow aspirate for cytology - Peripheral blood for cytology - Imaging - CT thorax and abdomen including pelvis - US cervical region strongly recommended (Br J Hem. 88 (3) 626-8, 1994); alternative: CT cervical region - Consultation of ear-nose-throat specialist if indicated (i.e. complaints or gastro-intestinal lymphoma) - Gastroscopy if indicated (i.e. localization ENT, thyroid) - Lumbal punction if indicated (i.e. localization testis, nasopharynx or brain)

B. Restaging for the evaluation of treatment Restaging for the evaluation of treatment should be performed within 2 months after the end of treatment to assess response. Additional moments of restaging, e.g. after 3 cycles of CHOP, are specified in the study protocol. History (including B-symptoms) WHO Performance status Physical examination Laboratory tests - Hb, WBC, platelet count, LDH - Repeat previously abnormal tests Bone marrow biopsy (≥ 20 mm biopsy core) for histopathology if involved previously Bone marrow aspirate for cytology if involved previously Peripheral blood for cytology if involved previously -

Page 30 of 46

Appendix B

HOVON 46 NHL ________________________ -


Imaging CT thorax and abdomen including pelvis US of cervical region; alternative: CT cervical region Assessment of other localizations only if involved previously

C. Restaging during follow up to determine remission status (until progression) In case of CRu (see below) repeat CT 2-4 months after last CT for response evaluation. - Physical examination - WHO Performance status - Laboratory tests - Hb, WBC, platelet count, LDH - Only if indicated, i.e. LDH elevation or clinical signs of progression: - Bone marrow biopsy (≥ 20 mm biopsy core) for histopathology (if indicated) - Bone marrow aspirate for cytology (if indicated) - Peripheral blood for cytology (if indicated) - Imaging CT thorax and abdomen including pelvis (if indicated) US of cervical region; alternative CT of cervical region (if indicated)

• • • •

• • • • •

o.i. r.

Staging & Remission Status Evaluation On Study Evaluation of Treatment x X History x X WHO performance status x X Physical examination Laboratory tests ! Hb x X ! WBC x X ! Differential x o.i. ! Platelet count x X ! LDH x X ! Calcium x o.i. ! Creatinine x o.i. ! Uric acid x o.i. ! Glucose x o.i. ! Bilirubine x o.i. ! ALAT x o.i. ! Albumin x o.i. ! Immuno-electrophoresis x o.i. ! Quantitative immunoglobulins o.i. o.i. ! Hepatisis-B x ! HIV test x x o.i. Lymph node biopsy x o.i. BM biopsy x o.i. BM aspirate x o.i. PB for cytology Imaging ! CT thorax x X ! CT abdomen including pelvis x X ! US/CT cervical region r. r. ! ENT consultation o.i. o.i. ! Gastroscopy o.i. o.i. ! Lumbal punction o.i. o.i. on indication strongly recommended

Page 31 of 46

Follow up x x x x x x x

o.i. o.i. o.i. o.i. o.i. o.i. o.i. o.i. o.i. o.i.

Appendix B

HOVON 46 NHL ________________________


Bone marrow evaluation Bone marrow biopsy must be adequate (≥ 20 mm biopsy core). A bone marrow aspirate and biopsy should always be performed at diagnosis. If positive they should be repeated to determine response. They should also be performed in case of new abnormalities in the peripheral blood. Bone marrow biopsies should be scored as - positive unequivocal cytologic or architectural evidence of malignancy - negative no aggregates or only a few well-circumscribed lymphoid aggregates - indeterminate increased number or size of aggregates without cytologic or architectural atypia The bone marrow report should be reported not only as positive or negative for lymphoma, but the percentage of invasion and the lymphoma subtype should be indicated, the latter to describe any discordance with the nodal disease.

Measurable disease and size of disease. Response evaluation is primarily based on bi-dimensionally measurable nodes, nodal masses or nodules in liver or spleen. Nodes with largest diameter ≤ 1 cm are considered normal and not pathologic. The size of a single node, nodal mass or nodule is defined as the product of the two largest perpendicular diameters (PPD). Nodes of which only one dimension is specified are considered as circular for the calculation of PPD size. If after treatment a nodal mass consisting of individual confluent nodes breaks up in separate nodes the sum of the PPD of the separate nodes must be compared with the size of the pretreatment nodal mass. All nodules in liver and spleen are considered pathologic, irrespective of size. The sum of the PPD (SPD) of a set of indicator lesions is used as a quantitative measure for response evaluation. The indicator lesions have to be chosen from the nodes and nodal masses in the following way. If the number of nodes or nodal masses before treatment is 6 or less, all these are considered as indicator lesions. If the number of nodes or nodal masses is more than 6, a minimum number of at least 6 indicator lesions have to be chosen. These nodes or nodal masses should be selected according to the following features: a) they should be among the largest dominant sites b) they should be clearly measurable in at least two perpendicular dimensions, c) they should be from as disparate regions of the body as possible d) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved. The choice of the indicator lesions should be made before start of treatment. All indicator lesions must be numbered and measured bidimensionally before start of treatment and at the evaluation times specified in the protocol. The location and size must be documented and reported in the CRF.

Assessable disease Assessable disease are considered all abnormalities that are not bidimensionally measurable, e.g. positive bone marrow or peripheral blood.

Page 32 of 46

Appendix B

HOVON 46 NHL ________________________


Response criteria Complete respons (CR) requires the following: 1. Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy 2. Normal LDH (i.e. ≤ ULN). An elevated LDH detracts from a CR unless it is attributable to causes not related to NHL, e.g. hemolysis. 3. - All nodes and nodal masses must have reduced in size to ≤ 1.0 cm in greatest transverse diameter, or - If some nodes have regressed to a size between 1.0 and 1.5 cm in greatest transverse diameter from a size over 1.5 cm, while none have a size over 1.5 cm, the SPD of the indicator lesions must have regressed by more than 75%. 3. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable and/or no longer considered enlarged on physical examination. However, no normal size can be specified, because of the difficulties in accurately evaluating splenic size. Similarly, other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size. 4. Any nodules in liver or spleen must have disappeared. 5. If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site.

CR/unconfirmed (CRu) includes those patients who fulfill criteria 1, 2, 4 and 5 above, but with one or more of the following features/exceptions: 1. A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the PPD size. Individual nodes that were previously confluent must have regressed by more than 75% in their SPD size compared with the size of the original mass. The SPD size of the indicator lesions must have regressed with more than 75%. 2. Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia). In case of apparent CRu it is recommended to perform, if possible, a cytological punction or biopsy of a residual lymph node mass to determine the cytopathological status. It is also recommended in case of CRu to repeat CT or US of the residual lesion after 2-4 months. Partial response (PR) requires the following: 1. ≥ 50% decrease in SPD of the indicator lesions. 2. ≥ 50% decrease in SPD of splenic and hepatic nodules if present and bi-dimensionally measurable at start of treatment. 3. No increase in the size of any single node, nodule, liver, or spleen by more than 25%. 4. No new sites of disease. 5. All patients who meet the criteria for CR or CRu except for an LDH >ULN that is not attributable to other causes than NHL or with remaining but decreased nodules in liver or spleen, or with remaining assessable disease are classified as PR. Stable disease (SD) is defined as less than a PR (see above) but is not progressive disease (see below). Progressive disease (PD) requires the following 1. ≥50% increase in the PPD-size of any at baseline identified abnormal node, nodal mass or nodule. 2. Appearance of any new lesion during or at the end of therapy.

Page 33 of 46

Appendix B

HOVON 46 NHL ________________________


Endpoints during follow up Progression of disease is defined for all patients, irrespective of response on treatment. The following criteria apply: 1. ≥ 50% increase from nadir in the PPD-size of any previously identified abnormal node. 2. Appearance of any new lesion. Relapse requires the following: 1. Previous achievement of CR or CRu. 2. Progression of disease as defined above. Note: 1. Relapse is the same as progression of disease after CR or CRu. 2. An abnormal or increasing abnormal LDH, not attributable to other causes than NHL, is not sufficient evidence for the determination of progression. Imaging studies must be performed in such a case. 3. Note the difference between PD as response category and Progression of disease as event during or after treatment. All patients whose best response on treatment is PD, per definition also have reached the endpoint Progression of disease. But also other patients with a better response may eventually show progression of disease. Failure is defined as 1. either no complete respons (i.e. no CR or CRu) on treatment or 2. relapse

Progression-free survival Disease-free survival

Definitions of End Points for Clinical Trials Response Category Definition All patients Death from any cause All patients Failure or death from any cause All patients Disease progression or death from NHL CR, CRu Time to relapse

Response duration

CR, CRu, PR

Time to next treatment Cause-specific death

All patients

End Point Overall survival Event-free survival

All patients

Time to relapse or progression Time when new treatment is needed Death related to NHL

Page 34 of 46

Point of Measurement Entry onto trial Entry onto trial Entry onto trial First documentation of response First documentation of response Entry onto trial Entry onto trial

Appendix C

HOVON 46 NHL ________________________ C.


Ann Arbor staging classification

Stage

Definition

I

Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)

II

Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE)

III

Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIISE)

IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement

B symptoms The absence or presence of fever, night sweats, and/or unexplained loss of 10% or more of body weight in the six months preceding admission are to be denoted in all cases by the suffix letter A or B, respectively. Extranodal involvement Involvement of extra lymphatic tissue on one side of the diaphragm by limited direct extension from an adjacent nodal site is classified as extranodal extension and denoted by suffix letter E. The E category may also include an apparently discrete single extranodal deposit consistent with the extension from a regionally involved node. More extensive extranodal disease, e.g. multiple extranodal deposits, is classified as stage IV. A single extralymphatic site as the only site of disease should be classified as IE. Notes 1. For the purpose of defining the number of anatomical lymph node regions the following areas are considered as one region: All nodes at one side of the neck are considered as in one region, i.e. consisting of the subregions supraclavicular, cervical, submandibular, occipital, preauricular and postauricular. The axillary region includes the infraclavicular nodes. The mediastinum is considered as one region, including the subcarinal and pericardial nodes. 2. The lung-hilus is considered as a separate region. Thus involvement of both the mediastinum and a hilar localisation implies stage II disease. 3. Hilar nodes should be considered lateralized and when involved on both sides constitute stage II disease.

Page 35 of 46

Appendix D

HOVON 46 NHL ________________________ D.


Common toxicity Criteria

The grading of toxicity and adverse events will be done using the NCI Common Toxicity Criteria, CTC version 2.0, revised March 23, 1998. A complete document (19 pages) may be downloaded from the following sites:

http://ctep.info.nih.gov/ctc3/default.htm http://www.eortc.be (under Documents) http://www.hovon.nl

A hardcopy may be obtained from the HOVON Data Center on request.

Page 36 of 46

Appendix E

HOVON 46 NHL E.

_______________________


ZUBROD-ECOG-WHO Performance Status Scale

0

Normal activity

1

Symptoms, but nearly ambulatory

2

Some bed time, but to be in bed less than 50% of normal daytime

3

Needs to be in bed more than 50% of normal daytime

4

Unable to get out of bed

Page 37 of 46

Appendix F

HOVON 46 NHL ________________________ F.


NYHA* scoring list

Grade 1

No breathlessness

Grade 2

Breathlessness on severe exertion

Grade 3

Breathlessness on mild exertion

Grade 4

Breathlessness at rest

The *New York Heart Association functional and therapeutic classification applied to dyspnoea

Page 38 of 46

Appendix G

HOVON 46 NHL ________________________ G.


Age-adjusted International Prognostic Index

The age-adjusted international prognostic index (IPI) distinguishes 4 risk groups of patients according to their Ann Arbor stage, WHO performance status and LDH (19).

Risk factors are: !

Ann Arbor stage III or IV

!

WHO performance status 2-4

!

LDH > 1x Upper limit of normal (ULN)

The age-adjusted IPI: !

Low risk

!

Low-intermediate risk : 1 risk factor

!

High-intermediate risk : 2 risk factors

!

High risk

: 0 risk factors

: 3 risk factors

Page 39 of 46

Appendix H

HOVON 46 NHL ________________________ H.


Patiënteninformatie

Patiënten-informatie behorende bij de studie: A randomized phase III study of chimeric antiCD20 monoclonal antibody (Rituximab) with 2-weekly CHOP chemotherapy in elderly patients with intermediate- or high-risk non-Hodgkin’s lymphoma. Een klinische studie naar het effect van Rituximab met twee wekelijkse chemotherapie (CHOP) bij patienten met een snel groeiend Non-Hodgkin Lymfoom

Inleiding

Geachte heer, mevrouw,

Uw behandelend arts heeft u voorgesteld aan het hierboven genoemde onderzoek deel te nemen en al het één en ander uitgelegd. Uw toestemming of weigering moet u kunnen baseren op goede voorlichting onzerzijds. Daarom ontvangt u deze schriftelijke informatie, die u rustig kunt (her) lezen en in eigen kring bespreken. Ook daarna kunt u altijd nog vragen voorleggen aan de artsen die aan het einde van deze informatie genoemd staan.

Uw medische situatie en de bestaande mogelijkheden tot behandeling Bij u is de diagnose non-Hodgkin lymfoom (NHL) gesteld. Dit is een kwaadaardige aandoening van de lymfeklieren. In uw geval is er sprake van een stadium II, III of IV, hetgeen inhoudt dat de ziekte reeds in een gevorderd stadium is. Patiënten zoals u krijgen in het algemeen van tijd tot tijd grotendeels poliklinisch toegediende behandelingen met chemotherapie en soms ook bestraling. Hoewel met deze aanpak groei van het lymfoom kan worden teruggedrongen en bij ongeveer 50% van de patiënten het lymfoom tijdelijk verdwijnt, blijft de kans op definitieve genezing uiteindelijk kleiner dan 50%. De medische wetenschap blijft daarom zoeken naar betere methoden.

Doel en achtergrond van het onderzoek Uw deelname wordt gevraagd voor een fase III studie (zie bijgesloten folder getiteld: wetenschappelijk onderzoek bij patiënten met kanker). Het doel van een dergelijke studie is om te onderzoeken of een nieuwe behandelingsvorm een essentiële verbetering betekent vergeleken met de huidige behandeling. De nieuwe aanpak bestaat uit behandeling

met

chemotherapie aangevuld met

een nieuw,

geregistreerd

geneesmiddel, Rituximab. Dit laatste middel is een antilichaam gericht tegen een eiwit (het zgn. CD-20 antigeen) dat aanwezig is op de oppervlakte van kwaadaardige lymfoomcellen. In deze fase III studie wordt de helft van de patiënten behandeld met 8 kuren chemotherapie (CHOP) en de

Page 40 of 46

Appendix H

HOVON 46 NHL ________________________


andere helft van de patiënten krijgt dezelfde chemotherapie gecombineerd met 6 toedieningen Rituximab. Door middel van loting wordt bepaald welke behandeling u zult krijgen. Uzelf en de behandelend arts hebben hierop geen invloed. Als u wilt deelnemen aan dit onderzoek is er dus 50% kans dat u op de gebruikelijke manier wordt behandeld.

Behandelingsplan: De behandeling bestaat uit 8 chemotherapiekuren (CHOP: Cyclofosfamide, Adriamycine, Vincristine en Prednison) welke met tussenpozen van twee weken op de polikliniek worden gegeven. Cyclofosfamide, Adriamycine en Vincristine worden ingespoten en Prednison wordt in tabletvorm dagelijks gedurende 5 dagen ingenomen. Na 3 kuren wordt geëvalueerd in hoeverre het lymfoom heeft gereageerd. Ditzelfde gebeurt opnieuw na 8 kuren.

Arm A: als u in deze arm behandeld wordt, zult u gedurende 16 weken 8 chemotherapiekuren (CHOP) ontvangen. Deze kuren worden 1 x per 2 weken toegediend. Daarnaast krijgt u een eenmalige toediening van G-CSF, een hormoon dat het herstel van de beenmerg- en bloedcellen stimuleert. G-CSF wordt eenmaal per kuur toegediend door middel van een onderhuidse injectie. Arm B: indien u volgens deze arm behandeld wordt ontvangt u chemotherapie en G-CSF zoals beschreven bij arm A. In aanvulling op CHOP en G-CSF wordt u behandeld met 6 toedieningen Rituximab. Dit nieuwe geneesmiddel is een antilichaam gericht tegen eiwit (het zgn. CD-20 antigeen) dat aanwezig is op de oppervlakte van kwaadaardige lymfoomcellen. Rituximab wordt toegediend op dag 3 resp. 1 van de chemotherapiekuren 1 tot en met 6. Het middel wordt toegediend per infuus, hetgeen ongeveer 4 uur duurt.

Extra onderzoek en controle: Het vaststellen van de resultaten van de behandeling gebeurt aan de hand van lichamelijk onderzoek, bloedonderzoek, beenmergonderzoek en röntgenonderzoek inclusief CT-scans. U blijft daarna onder regelmatige controle van de specialist. Voor de studie is geen extra onderzoek nodig, wel worden uw ziektegegevens bijgehouden. Tevens is het van belang om vast te stellen of er bijwerkingen zijn opgetreden en zo ja, in welke mate. Hier zal u regelmatig naar gevraagd worden tijdens uw bezoek op de polikliniek.

Bijwerkingen Nadere informatie over algemene bijwerkingen van chemotherapie kunt u vinden in de folder over chemotherapie van het Koningin Wilhelmina Fonds (Nederlandse Kankerbestrijding).

Page 41 of 46

Appendix H

HOVON 46 NHL ________________________


Niet alle mogelijke bijwerkingen zijn hierbij vermeld. Het is ook niet zo dat alle genoemde bijwerkingen met zekerheid bij elke patiënt zullen optreden. Bij het optreden van onbegrepen klachten of verschijnselen is het aangewezen om te overleggen met Uw behandelend arts.

De belangrijkste bijwerking van de CHOP chemotherapie is tijdelijke onderdrukking van de normale bloedcelaanmaak, waardoor een tijdelijk tekort aan rode bloedcellen, witte bloedcellen en bloedplaatjes kan ontstaan. De rode bloedcellen worden zo nodig aangevuld met transfusies. De tekorten aan witte bloedcellen worden behandeld met G-CSF injecties. Er blijft echter een klein risico dat u tijdens de CHOP kuren een verhoogde vatbaarheid voor infecties heeft. Wanneer er koorts optreedt in combinatie met een gebrek aan witte bloedcellen zult u, zonodig in het ziekenhuis, behandeld worden met antibiotica. Een eventueel tijdelijk tekort aan bloedplaatjes wordt opgevangen door bloedplaatjestransfusies, zodat u zo min mogelijk risico loopt spontane bloedingen te krijgen. Voorts kunnen tintelingen in de vingers en soms een doof gevoel in de voeten optreden alsmede obstipatie. Dit zijn bijwerkingen van Vincristine, welke van tijdelijke aard zijn. CHOP behandeling leidt vrijwel altijd tot tijdelijke kaalheid. Rituximab kan tijdens de toediening milde en tijdelijke bijwerkingen hebben, welke bestaan uit koorts, koude rillingen, hoofdpijn, een gevoel van moeheid, soms jeuk, en tijdelijke roodheid van de huid. Daarnaast komt ook soms misselijkheid voor en een geringe bloeddrukdaling. Echter, vrijwel al deze bijwerkingen zijn te voorkomen door het infuus langzaam te laten lopen. Om deze reden wordt het infuus gedurende 4 uur toegediend, en wordt Paracetamol en soms anti-allergische medicatie toegediend. De combinatie van CHOP met Rituximab heeft geen extra risico’s.

Voor- en nadelen Op dit moment kan niet worden vastgesteld welke van de twee behandelingsarmen een betere kans op genezing biedt. Indien u besluit aan de studie deel te nemen brengt dit met zich mee dat er op regelmatige tijdstippen controles plaatsvinden. Er vindt geen extra onderzoek plaats, tenzij na uw uitdrukkelijke toestemming.

Vertrouwelijkheid (Privacy) Tot uw persoon herleidbare onderzoeksgegevens kunnen slechts met uw toestemming door daartoe bevoegde personen worden ingezien. Deze personen zijn medewerkers van het onderzoeksteam, medewerkers van de Inspectie voor de Gezondheidszorg of bevoegde inspecteurs van een buitenlandse overheid, en leden van de Medisch Ethische Toetsings Commissie. Inzage kan nodig zijn om de betrouwbaarheid en kwaliteit van het onderzoek na te

Page 42 of 46

Appendix H

HOVON 46 NHL ________________________


gaan. Onderzoeksgegevens zullen worden gehanteerd met inachtneming van de Wet Bescherming Persoonsgegevens en het privacyreglement van het Erasmus MC. Persoonsgegevens die tijdens deze studie worden verzameld, zullen worden vervangen door een codenummer. Alleen dat nummer zal gebruikt worden voor studiedocumentatie, in rapporten of publicaties over dit onderzoek. Slechts degene, die de sleutel van de code heeft (de onderzoeker of de behandelend arts) weet wie de persoon achter het codenummer is. De gegevens worden, indien u daar toestemming voor geeft, gedurende 15 jaar bewaard.

Schade De opdrachtgever van dit onderzoek, de Stichting HOVON (Hemato-Oncologie voor Volwassenen Nederland), heeft u verzekerd in verband met eventuele schade die u zou kunnen lijden als gevolg van uw deelname aan dit onderzoek. Het betreft de schade door overlijden of letsel die zich openbaart gedurende de deelname aan dit onderzoek en deze verzekering is een zogenaamde risico-verzekering, wat inhoudt dat de verzekering ongeacht of het onderzoek verwijtbaar onzorgvuldig is geweest, de schade door overlijden of letsel uit zal keren tot maximaal de daarvoor gestelde bedragen. Het bedrag waarvoor de verzekering is gesloten is maximaal € 453.781,00 voor de schade per proefpersoon, met een maximum van € 6.806.704,00 voor de schade van alle proefpersonen tezamen die deelnemen aan het onderzoek, en € 9.075.605,00 voor de totale schade die zich per verzekeringsjaar bij proefpersonen heeft geopenbaard bij alle onderzoeken die opdrachtgever per verzekeringsjaar laat uitvoeren. Indien bovengenoemde bedragen de schade niet volledig dekken en aangetoond kan worden dat de uitvoering van het onderzoek onzorgvuldig is geweest dan kunt u hiernaast ook het ziekenhuis dat opdracht gegeven heeft tot het onderzoek of het ziekenhuis waar het onderzoek is uitgevoerd aansprakelijk stellen.

De verzekering dekt niet de: schade waarvan op grond van de aard van het onderzoek (nagenoeg) zeker was dat deze zich bij de proefpersoon zou voordoen; schade die zich bij nakomelingen openbaart als gevolg van een nadelige inwerking van het onderzoek op het genetisch materiaal van de proefpersoon; schade door aantasting van de gezondheid van de proefpersoon die zich ook zou hebben geopenbaard wanneer de proefpersoon niet aan dit onderzoek had deelgenomen; schade, die het gevolg is van het niet volledig opvolgen door de proefpersoon van aanwijzingen zoals deze in de patiënteninformatiebrief beschreven staan.

Page 43 of 46

Appendix H

HOVON 46 NHL ________________________


De verzekering is afgesloten bij Zurich Schade (contactpersoon: dhr. R.J. van Nunspeet) te Den Haag onder de voorwaarden voor de verzekering van proefpersonen no. 01121999, onder polisnummer 624.469.703.

Weigeren voor en tijdens het onderzoek Het is, zoals gezegd, niet precies bekend welke van de twee behandelingen de beste is. Daarom heeft uw arts u verteld over het doel van dit onderzoek en u gevraagd om er aan mee te werken. U bent uiteraard vrij om uw medewerking aan dit onderzoek te weigeren. Als u besluit niet mee te doen, zal u de gebruikelijke “standaard”-behandeling voorgesteld worden. Ook indien u nu toestemming geeft, kunt u die later zonder opgave van redenen weer intrekken. Wat u ook besluit, het zal geen consequenties hebben voor de verzorging en begeleiding van uzelf en uw familie. De behandeling zal zo nauwkeurig mogelijk volgens vooropgesteld plan verlopen. Het kan natuurlijk gebeuren dat uw lichamelijke reacties of nieuw ontdekte feiten ons tot veranderingen dwingen. Die zullen direct met u besproken worden, zodat u de gelegenheid krijgt te overwegen al of niet met het onderzoek door te gaan. Wel vragen wij van u de voorschriften van uw behandelend arts goed op te volgen en u niet, zonder diens medeweten, elders te laten behandelen. Tenslotte, u bent verzocht deel te nemen aan medisch wetenschappelijk onderzoek. Dat onderzoek wordt uitgevoerd nadat goedkeuring is verkregen van de Raad van Bestuur/directie van het ziekenhuis na positief oordeel van de Medisch Ethische Commissie. De voor dit onderzoek internationaal vastgestelde richtlijnen zullen nauwkeurig in acht worden genomen.

Hoe te handelen bij klachten Als u klachten heeft over het onderzoek, kunt u dit melden aan de onderzoeker. Wilt u dit liever niet, dan kunt u contact opnemen met de onafhankelijke klachtencommissie van het ziekenhuis: …

Nadere informatie Mocht u verdere vragen hebben, dan kunt u die voorleggen aan uw behandelend specialist of aan: .....[naam/namen betrokken specialisten] ..... ..... Het onderzoek wordt gecoördineerd door Prof. Dr. P. Sonneveld van de afdeling hematologie van het AZR en Prof. Dr. P.C. Huijgens van het Academisch Ziekenhuis der Vrije Universiteit te Amsterdam. Voor meer informatie kunt u ook contact opnemen met een onafhankelijk arts die zelf niet bij het onderzoek betrokken is, maar wel deskundig is op het gebied van dit onderzoek:

Page 44 of 46

Appendix H

HOVON 46 NHL ________________________


Prof. Dr. R. Pieters, afdeling Kindergeneeskunde locatie Erasmus MC - Sophia Kinderziekenhuis tel: 010-4636496.

*Bijlagen: (Nederlandse Kankerbestrijding) -

Folder Wetenschappelijk onderzoek bij patiënten met kanker (Nederlandse Kankerbestrijding)

-

Folder Non-Hodgkin lymfomen (Nederlandse Kankerbestrijding)

-

Folder Instituut voor Gezondheidsethiek

Page 45 of 46

Appendix H

HOVON 46 NHL ________________________


TOESTEMMINGSVERKLARING voor deelname aan het wetenschappelijk onderzoek: Een gerandomiseerde fase III studie van chimeer anti-CD20 monoclonaal antilichaam (Rituximab) met 2-wekelijkse CHOP chemotherapie in oudere patiënten met intermediair of hoog-risico non-Hodgkin’s lymfoom.

Ik ben naar tevredenheid over het onderzoek geïnformeerd. Ik heb de schriftelijke informatie goed gelezen. Ik ben in de gelegenheid gesteld om vragen te stellen over het onderzoek. Mijn vragen zijn naar tevredenheid beantwoord. Ik heb goed over deelname aan het onderzoek kunnen nadenken. Ik heb het recht mijn toestemming op ieder moment weer in te trekken zonder dat ik daarvoor een reden behoef te geven. Ik stem vrijwillig toe met deelname aan het onderzoek. Ik geef toestemming mijn persoonsgegevens en mijn lichaamsmateriaal (indien van toepassing) na afloop van de studie gedurende maximaal 15 jaar te bewaren. Naam

: ...................................................................................................................

Adres

: ...................................................................................................................

Woonplaats

: ...................................................................................................................

Geboortedatum : ...................................................................................................................

Handtekening

: .......................................... Datum: ...........................................................

Ondergetekende verklaart, dat de hierboven genoemde persoon zowel schriftelijk als mondeling over het bovenvermelde onderzoek geïnformeerd is. Hij/zij verklaart tevens, dat een voortijdige beëindiging van de deelname door bovengenoemde persoon, van geen enkele invloed zal zijn op de zorg die hem of haar toekomt. Naam

: ....................................................................................................................

Functie

: ....................................................................................................................

Handtekening

: ........................................... Datum: ...........................................................

Dit formulier is bestemd voor onderzoek met meerderjarigen, die wilsbekwaam zijn. Bij dit soort onderzoek moet door de betrokkenen zelf toestemming worden verleend.

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AZR, 04 Dec Amendment 2 : 1 October 2003 approved METC Erasmus MC, 05 Nov

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