PROTOCOL. Amendment 1 : 19 September 2001 approved METC EUR/AZR, 04 Dec Amendment 2 : 1 October 2003 approved METC Erasmus MC, 05 Nov.

Transcriptie

1 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 AE ROTTERDAM The Netherlands tel fax First version : 1 August 2000 Final version : 19 June 2001 Date of activation : 28 November 2001 METC approved : METC EUR/AZR /2001/120, 24 July 2001 CKTO approved : CKVO , 9 July 2001 Amendment 1 : 19 September 2001 approved METC EUR/AZR, 04 Dec Amendment 2 : 1 October 2003 approved METC Erasmus MC, 05 Nov Page 1 of 46

2 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 + Rituximab at day 3 CHOP + G-CSF CHOP + G-CSF + Rituximab at day 1 Not at least PR At least PR Induction cycles IV-VIII CHOP + G-CSF At least PR CHOP + G-CSF + Rituximab at day 1 CHOP + G-CSF CHOP + G-CSF + Rituximab at day 1 CHOP + G-CSF CHOP + G-CSF + Rituximab at day 1 CHOP + G-CSF CHOP + G-CSF CHOP + G-CSF CHOP + G-CSF Off protocol treatment Follow up Page 2 of 46

3 2 Table of contents Page 1 Scheme of study Table of contents Synopsis Investigators and study administrative structure Pathology review Introduction Elderly patients with NHL Induction therapy: addition of anti-cd20 (Rituximab) Study objectives Study design Remission induction Study population Eligibility for registration Inclusion criteria Exclusion criteria Treatments Remission induction treatment Dose modifications of CHOP Special management Rituximab administration Patients with detectable circulating tumor cells and Rituximab treatment Concomitant medication and treatment End of protocol treatment Required clinical evaluation Observations prior to start of treatment Observations after 3 and 8 cycles of CHOP Response assessment after cycle 3 and cycle Observations during follow up Toxicities Reporting serious adverse events Endpoints Forms and procedures for collecting data CRF s and schedule for completion Registration and randomization Page 3 of 46

4 17 Statistical considerations Patient number and power considerations Statistical analysis Efficacy analysis Toxicity analysis Additional analyses Interim analyses Data and safety monitoring board Ethics Independent ethics committee or Institutional review board Ethical conduct of the study Patient information and consent Trial insurance Publication policy Glossary of abbreviations References Appendices A. NHL WHO classification B. HOVON Staging and Response Criteria for Non Hodgkin s Lymphomas C. Ann Arbor staging classification D. Common toxicity Criteria E. ZUBROD-ECOG-WHO Performance Status Scale F. NYHA* scoring list G. Age-adjusted International Prognostic Index H. Patiënteninformatie Page 4 of 46

5 3 Synopsis Study phase Study objectives Patient population Study design Duration of treatment Number of patients Adverse events Planned start and end of recruitment Phase III Evaluation of the effect of anti-cd20 (Rituximab) combined with 2-weekly CHOP + G-CSF in comparison to 2-weekly CHOP + G-CSF alone 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) Prospective, multicenter, randomized Expected duration of treatment is 16 weeks 400 patients registered and randomized Adverse events will be documented if observed, mentioned during open questioning, or when spontaneously reported Start of recruitment: III 2001 End of recruitment: III 2006 Page 5 of 46

6 4 Investigators and study administrative structure Responsibility Name Affiliation/Address Study Coordinators P. Sonneveld P.C. Huijgens Writing Committee J.W. Baars A. van Leeuwenhoek Hospital, Amsterdam D.H. Biesma St. Antonius Hospital, Nieuwegein J.K. Doorduijn, P. Sonneveld University Hospital Rotterdam-Dijkzigt P.C. Huijgens University Hospital Free University, Amsterdam G.W. van Imhoff University Hospital Groningen M.H.H. Kramer General Hospital Eemland, Amersfoort M. van Marwijk-Kooy Isala Clinic, Zwolle M.H.J. van Oers Academic Medical Center, Amsterdam M.R. Schaafsma Medical Spectrum Twente, Enschede H.C. Schouten University Hospital Maastricht M.B. van t Veer University Hospital Rotterdam-Daniel L.F. Verdonck UMCU, Utrecht P.W. Wijermans Leyenburg Hospital, The Hague R. Willemze 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: Pathology review A central review of the diagnosis is performed for each case by Dr. K.H. Lam ( lam@path.azr.nl), 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 Page 6 of 46

7 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 . 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 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) (HOVON- 25, 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

8 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 Thus, these data support the feasibility of 2-weekly CHOP in elderly patients. Page 8 of 46

9 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 + G- CSF 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. Page 9 of 46

10 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 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: or Arm B: 8 cycles of CHOP q 2 weeks plus G-CSF (pegfilgrastim, Neulasta ) once per cycle 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. Page 10 of 46

11 8 Study population 8.1 Eligibility for registration All eligible patients have to be registered and randomized before start of treatment (see paragraph 16) 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 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 Page 11 of 46

12 9 Treatments 9.1 Remission induction treatment CHOP chemotherapy + G-CSF Agent Dose/day Route Days Cyclophosphamide 750 mg/m 2 i.v. 1 Doxorubicin 50 mg/m 2 i.v. 1 Vincristine 1.4 mg/m 2, with a i.v. 1 maximum of 2 mg Prednisone 100 mg p.o. 1, 2, 3, 4, 5 G-CSF (pegfilgrastim, Neulasta ) 6 mg s.c. 2 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 Route Day Rituximab (Mabthera ) 375 mg/m 2 with a maximum of 750 mg 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 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 10 9 /l and/or platelets < 100 x 10 9 /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: Page 12 of 46

13 Leucocytes Platelets Cyclophosphamide Doxorubicin Vincristine Prednison x 10 9 /l x 10 9 /l > 3 and > % 100% 100% 100% 2-3 and > % 75% 100% 100% 1-2 or > 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 Page 13 of 46

14 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. Page 14 of 46

15 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 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 Page 15 of 46

16 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 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 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. Page 16 of 46

17 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. Page 17 of 46

18 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 UNRELATED UNLIKELY POSSIBLE PROBABLE DEFINITELY NOT ASSESSABLE DESCRIPTION There is no evidence of any causal relationship 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). 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). There is evidence to suggest a causal relationship and the influence of other factors is unlikely. There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out. There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship. Page 18 of 46

19 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

20 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 2 3A 3B A 7B Registration & randomization X On study X X 1 X 2 X (X) Induction Treatment X X X X (X) (X) (X) End of treatment X X (X) Follow up X (X) (x) fill out if necessary, see instructions 1 2 by local pathologist 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: or fax Monday through Friday, from 09:00 to 17:00 or via the Internet via TOP (Trial Online Proces; A logon to TOP can be requested at the HOVON Data Center for participants. Page 20 of 46

21 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 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) Statistical analysis All main analyses will be according to the intention to treat principle. Page 21 of 46

22 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 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 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 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

23 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 P- value is very extreme (P<0.001) and the number of evaluable patients in each arm is at least 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 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 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

24 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 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

25 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

26 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

27 22 References 1. Weisenburger DD. Epidemiology of non-hodgkin s lymphoma: Recent findings regarding an emergic epidemic. Ann Oncol 1994;5:s Greiner TC, Medeiros LJ, Jaffe ES. Non-Hodgkin s lymphoma. Cancer 1995;75: Goss PE. Non-Hodgkin s lymphomas in elderly patients. Leuk Lymph 1993;10: 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: 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: 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: 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: 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: 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 non- Hodgkin 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: 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: Page 27 of 46

28 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: 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 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: 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 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 non- Hodgkin s lymphoma. J Clin Oncol 1997;15: Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feuring- Buske 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: 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: 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 B- cell lymphoma (DLCL): Interim results of a randomized GELA trial. ASH 2000, abstract 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: Page 28 of 46

29 Appendix A HOVON 46 NHL Version: 1 October 2003 A. NHL WHO classification B-cell neoplasms WHO 1 Precursor B-cell lymphoblastic leukaemia / lymphoma 2 B-cell chronic lymphocytic leukaemia / small lymphocytic lymphoma 3 B-cell prolymphocytic leukaemia 4 Lymphoplasmocytic lymphoma 5 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type 6 Nodal marginal zone lymphoma (+/- monocytoid B cells) 7 Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) 8 Plasma cell myeloma / Plasmocytoma 9 Follicular lymphoma; grade I, grade II, grade III 10 Mantle-cell lymphoma 11 Diffuse large B-cell lymphoma (subtypes: mediastinal, intravascular, primary effusion lymphoma) 12 Burkitt's lymphoma 13 Unclassifiable T-cell neoplasms WHO 21 Precursor T-cell lymphoblastic leukaemia / lymphoma 22 T-cell prolymphocytic leukaemia 23 T-cell granular lymphocytic leukaemia 24 Aggressive NK-cell leukaemia 25 Adult T-cell leukaemia / lymphoma (HTLV1+) 26 Extranodal NK / T-cell lymphoma, nasal-type 27 Enteropathy type T-cell lymphoma 28 Hepatosplenic γ / δ T-cell lymphoma 29 Subcutaneous panniculitis-like T-cell lymphoma 30 Mycosis fungoides/sézary syndrome 31 Anaplastic large cell lymphoma, primary cutaneous type 32 Peripheral T-cell lymphoma (not otherwise characterized) 33 Angioimmunoblastic T-cell lymphoma 34 Anaplastic large cell lymphoma (T- and null-cell types), primary systemic type 35 Unclassifiable Page 29 of 46