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3rd

Nordic Mantle Cell Lymphoma Protocol, version February 2007

Amendment 1, 2 and 3 included

NLG-MCL-III NORDIC LYMPHOMA GROUP

www.nordic-lymphoma.org

3RD

NORDIC MANTLE CELL LYMPHOMA PHASE II

PROTOCOL

EudraCT number: 2005-002003-17

HIGH-DOSE THERAPY WITH AUTOLOGOUS STEM CELL SUPPORT IN

FIRST LINE TREATMENT OF MANTLE CELL LYMPHOMA – 90

Y-IBRITUMOMAB TIUXETAN IN COMBINATION WITH BEAM OR

BEAC TO IMPROVE OUTCOME FOR PATIENTS NOT IN CR AFTER

INDUCTION TREATMENT.

Writing committee:

Nordic lymphoma group representatives

- Arne Kolstad, Norway

- Anna Laurell, Sweden

- Erkki Elonen, Finland

- Christian Geisler, Denmark

Protocol secretariat and registration:

Office of Clinical Research, The Norwegian

Radium Hospital Montebello

N-O310 Oslo

Norway

Phone: (+47) 22 93 57 57 E-mail: bente.kvisgaard@radiumhospitalet.no

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Writing committee:

Nordic lymphoma group representatives - Arne Kolstad, Dept of Oncology, The Norwegian Radium Hospital, Montebello,

N-0310 Oslo, Norway. E-mail: arne.kolstad@radiumhospitalet.no

- Anna Laurell, Dept of Oncology, Academic Hospital, Uppsala, SE 75185, Sweden.

E-mail: anna.laurell@akademiska.se

- Erkki Elonen, Dept of Haematology, Helsinki University Central Hospital, Fin-

00029, Helsinki, Finland. E-mail: erkki.elonen@hus.fi

- Christian Geisler, Dept of Haematology 4042, Finsen Center, DK 2100 Copenhagen,

Denmark. E-mail: christian.geisler@rh.hosp.dk

Central Pathology Review Board: - Elisabeth Ralfkiær, Dept of Pathology, Rigshospitalet, DK 2100 Copenhagen,

Denmark. E-mail: elisabeth.ralfkiaer@rh.hosp.dk

- Marja-Liisa Karjalainen-Lindsberg, Dept of Pathology, Helsinki University Central Hospital, Fin 00290, Helsinki, Finland. E-mail: Marja-Liisa.Karjalainen-

Lindsberg@hus.fi

- Jan Delabie, Dept of Pathology, The Norwegian Radium Hospital, 0310 Oslo,

Norway. E-mail: jan.delabie@labmed.uio.no

- Christer Sundstrom, Dept of Pathology, Uppsala University Hospital, SE-75185

Uppsala, Sweden. E-mail: christer.sundstrom@akademiska.se

- Mats Ehinger, Depart of Cytology and Pathology, Helsingborg Hospital, SE-25187

Helsingborg, Sweden. E-mail: mats.ehinger@helsingborgslasarett.se

Protocol Secretariat: Office of Clinical Research, The Norwegian Radium Hospital N-0310 Oslo, Norway

Phone: (+47) 22 93 57 57. E-mail: bente.kvisgaard@radiumhospitalet.no

Molecular Biology: Niels Smedegaard Andersen, Rigshospitalet, Copenhagen, Denmark.

Telephone +45 35 45 17 33, Fax +4535454841. E-mail: nanders@rh.dk

Dosimetry: Arne Skretting, Dept of Nuclear Medicine, The Norwegian Radium Hospital, 0310

Oslo.

Telephone +47 22 93 40 00. E-mail: arne.skretting@radiumhospitalet.no

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Table of contents Page 1. Synopsis of study 4 2. Study background 6 3. Objectives: 8 Primary objectives 8 Secondary objectives 8 4. Diagnosis 8 5. Methodology 8 6. Patient selection and registration 9 Registration and CRFs 9

Inclusion criteria 9 Exclusion criteria 10

7. Treatment 10 Induction therapy 10 Stem cell harvest 11 High-dose regimens 11 Rituximab therapy post-transplant 12 8. Toxicity and treatment modifications 12 Rituximab 12 Cytostatic agents 12 Criteria for discontinuation of treatment 13 9. Tests performed at diagnosis 13 10. Test performed at response evaluation 13 11. Criteria for evaluation and end-points 14 Evaluation criteria 14 End-point criteria 15 12. Reporting adverse events 15 13. Study duration 17 14. Criteria for study discontinuation 17 15. Statistical considerations 17 16. Publication rules 18 17. Ethical aspects 18 18. References 20. Appendix 1-13 Appendix 1 WHO Performance Status Scale 22 Appendix 2 WHO Recommendations for grading of toxic effects 23 Appendix 3 Molecular study form 25

Appendix 4 Rituximab administration 26 Appendix 5 On site radiolabeling 27

Appendix 6 Yttrium labelling work-sheet 31

Appendix 7 Indium labelling work-sheet 33 Appendix 8 90Y ibritumomab tiuxetan administration 35 Appendix 9 Dosimetry 36 Appendix 10 Flow-charts 37 Appendix 11 Ordering forms for Zevalin, Yttrium, Indium 40 Appendix 12 Drug ordering and delivery 42

Appendix 13 Participating centres 43 Appendix 14 Amendments 46

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1. Synopsis of the study

HIGH-DOSE THERAPY WITH AUTOLOGOUS STEM CELL SUPPORT IN FIRST LINE

TREATMENT OF MANTLE CELL LYMPHOMA – 90

Y-IBRITUMOMAB TIUXETAN IN COMBINATION WITH BEAM OR BEAC TO

IMPROVE OUTCOME FOR PATIENTS NOT IN CR AFTER INDUCTION TREATMENT.

Number of centres and location: Open for centres in Sweden, Norway, Denmark and Finland. Study design: Open label phase II multi-centre study Sample size: 150 evaluable patients Objectives:

Primary objective: 1. To investigate time to treatment failure (TTF) for patients receiving Zevalin/BEAM(C)

Secondary objectives: 1. To investigate safety and toxicity 2. TTF with only BEAM(C), without Zevalin 3. Overall survival time. 4. Time to progression. 5. Response rates. 6. Value of PET-scan in staging and restaging 7. Molecular response rates. 8. Molecular response and progression-free survival time after post-transplant Rituximab. 9. Microarray analysis.

Inclusion criteria: 1. Age 18 - 65 years. 2. Histologically confirmed (according to the WHO classification) mantle cell lymphoma

stage II-IV at time point of diagnosis. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cycline-D1 and most cases will have t(11;14) translocation.

3. No previous treatment for lymphoma except radiotherapy or one cycle of any regimen and except patients treated in the previous phase II study who can be transferred to NLG-MCL-III before evaluation at week 15.

4. WHO performance status of 0 – 3. 5. Life expectancy of more than 3 months. 6. Written informed consent.

Exclusion criteria: 1. Severe cardiac disease: cardiac function grade 3-4 (Appendix 1). 2. Impaired liver, renal or other organ function not caused by lymphoma, which will

interfere with the treatment. 3. Pregnancy/lactation 4. Men or woman of reproductive potential not agreeing to use acceptable method of birth

control during treatment and for six moths after completion of treatment.

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5. Known HIV positivity 6. Any other prior malignancy than non-melanoma skin cancer or stage 0 (in situ) cervical

carcinoma. 7. Known seropositivity for HCV, HbsAg or other active infection uncontrolled by

treatment. 8. Psychiatric illness or condition which could interfere with their ability to understand the

requirements of the study. Treatment Patients receive alternating treatment with maxi-CHOP (three courses) and high-dose Ara-C (two courses) with Rituximab included, except for the first maxi-CHOP. In case of a CR, CRu or PR at evaluation, mobilization with Ara-C and G-CSF and in vivo purging (Rituximab x 2) and then stem cell harvest is done. Patients in CRu or PR are treated with Zevalin prior to high-dose BEAM or BEAC, patients in CR only get BEAM/BEAC. During follow-up, a positive flow cytometry and/or positive PCR in the bone marrow leads to four weekly doses of Rituximab iv. Statistics The aim of the Nordic MCL-III study is to improve TTF for patients who do not respond with a CR prior to high-dose therapy to a level comparable to those in CR, based on findings from the recent Nordic MCL-II study. Here the FFS after 3 years was 63% for those in PR/CRu prior to transplant, compared to 85% in CR patients. With 150 assessable patients and the assumption that 50% will be in PR/CRu after induction treatment (as for MCL-II) the power will be > 90% for detecting an improvement in 3 year TTF of 22% (from 63% to 85%) for the PR/CRu group (significance level p=0,05, two-tailed).

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2. Study background Mantle cell lymphoma has for decades been considered to have the worst outcome of all non-Hodgkins lymphomas with a median survival of 2-3 years and a 5-year survival of 20%. So far, no curative options are available (Weisenburger et al 1996, NHL Classification Project 1997). This is a B-cell neoplasia, clinically often with widespread disease including bone marrow infiltration and involvement of extranodal sites. A characteristic cytogenetic aberration is detectable in most patients, the t(11;14) by which the cyclin D1 gene on chromosome 11 is brought under the control of the enhancer of the IgH gene on chromosome 14, leading to cyclin D1 protein overexpression (Weisenburger et al 1996). The poor prognosis of mantle cell lymphoma may be gradually changing, as new approaches have emerged. Primary high-dose therapy and autologous stem cell transplantation (ASCT) after induction treatment with hyperCVAD (CHOP components + high-dose Cytarabine and Methotrexate (MTX)) appeared particularly promising (Khouri et al 1998). Results of a European randomised study using CHOP-like therapy followed by ASCT versus interferon therapy have now shown longer disease-free survival with ASCT (Hiddeman et al 2001). Several groups, including the Nordic Lymphoma group, have through well-designed studies managed to achieve promising results and efforts are being made to develop curative regimens. The benefit of myeloablative approaches is by many investigators considered to be clear. The first Nordic MCL phase-II protocol, using maxi-CHOP for induction therapy, followed by high-dose therapy with BEAM or BEAC, showed 79% survival 3 years from the time of diagnosis (Geisler et al 2000). The 3-year failure-free survival, however, was lower (24%) partly due to 10 early treatment failures during induction therapy. In previously untreated patients, the toxicity of myeloablative treatment programs does not exceed that of the conventional intensive therapy (Khouri et al 1998, Magni et al 2000, Geisler et al 2000). Results from the first Nordic MCL phase-II study, and particularly when comparing with the second study, strongly suggests that the quality of the pre-transplant remission is the most important factor to determine duration of remissions post-transplant (Andersen et al. 2003). Presence of tumour cells in the purged grafts did not seem to be of importance. Thus, when the second and still ongoing Nordic study was designed, high-dose Ara-C and rituximab was included in the induction regimen. Rituximab was also applied for in vivo purging in this protocol. So far, more than 150 patients have been entered into this phase II study. Preliminary results show much higher response rates and a significant proportion of PCR-negative bone-marrow samples after transplant. So far, 98 (91%) out of 114 evaluable patients achieved a CR/CRu post-transplant. Moreover, 53 (87%) out of 61 evaluable patients became PCR negative in bone marrow post-transplant. Of the 25 stem cell products investigated so far, 22 were PCR negative. Thus, intensification of the induction therapy appears feasible with improvements of results. Tumour-cell contamination of the stem-cell product is a problem in MCL, and purging is more difficult in this disease than in other B-cell lymphomas (Andersen et al 1997). It has been shown (Jacquy et al 1999) that tumour cells are also mobilised to the blood during peripheral blood-stem-cell mobilisation, up to one log more than the number of steady-state circulating tumour cells. This may explain the difficulty of effective purging in MCL, as experienced in the first Nordic MCL study. Mantle cell lymphoma cells express the CD20 antigen and the monoclonal anti-CD20 antibody rituximab has documented activity in MCL given as single drug as well as in combination with conventional chemotherapy, in both untreated and previously treated patients (Coiffier et al 1998, Foran et al 2000). Promising results have been reported when combining standard chemotherapy like CHOP or fludarabine-based regimens with rituximab (Hiddemann et al. 2003). Also as in-vivo purging, in combination with stem-cell mobilizing

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chemotherapy, rituximab leads to a significant improvement of the purging efficacy (Magni et al 2000). Oliver Press and his group in Seattle have for several years worked to develop protocols with high-dose anti-CD20 radioimmunotherapy (131I-tositumomab) together with cytostatic agents as conditioning regimen with stem cell support in non-Hodgkin B-cell lymphomas (Press et al. 2000). The safety and long-term results of this approach have shown to be very good, and although a benefit has not yet been well documented in mantle cell lymphoma it is reasonable to believe that this might be the case. Behr and co-workers presented data at the Eighth Conference on Radioimmunodetection and Radioimmunotherapy of Cancer in 2001 suggesting that high-dose radioimmunotherapy with 131I rituximab gives promising results in mantle cell lymphoma. Another study by Winther and colleagues (2002) included radioimmunotherapy in conditioning regimens followed by autologous stem cell transplant. This strategy was both feasible and well tolerated. There has been concern as to whether the addition of 90Y-ibritumomab tiuxetan to BEAM high-dose therapy might lead to unexpected toxicity. Fung and colleagues presented data during the ASH-meeting in San Diego 2003 supporting the notion that this combination is safe. They showed that older patients who received 90Y-ibritumomab tiuxetan at 0.4 mCi/kg (median 32 mCi) one week before BEAM, and then autologous stem cell transplantation one week after this did not have more transplant-related toxicity than expected from regular BEAM. Finally, Nedemanee and co-workers recently published a paper combining high dose of Zevalin with high-dose etoposide and cyclophosphamide with autologous stem cell support in relapsed non-Hodgkins lymphoma. They found no increase in transplant-related toxicity or marrow engraftment The Nordic Lymphoma group has shown that it is possible to cooperate to include a large number of patients with this rare diagnosis into clinical trials (approx. 30-40 pts per year). It is fair to assume that by including 90Y-ibritumomab tiuxetan, even more centers in the Nordic countries will enter patients into our third Nordic study. In the second Nordic study, about half of the patients reached PR or CRu prior to transplant and had a three-year failure free survivial of 63%, compared to 85% in patients for patients in CR pre-transplant. We now aim to improve results in the PR/CRu group by including 90Y-ibritumomab tiuxetan as part of the high-dose regimen for this patient group. Since the design of this new study will only differ from the last by the addition of 90Y-ibritumomab tiuxetan, a meaningful comparison can be made between results from the second and third MCL-study.

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3. Objectives of the study

Primary objective: 1. The primary efficacy variable is the evaluation of failure-free survival time of mantle cell

lymphoma patients in PR or CRu after induction therapy and then receiving treatment with 90Y-ibritumomab tiuxetan combined with high-dose BEAM/BEAC.

Secondary objectives:

1. To evaluate safety and tolerability of adding 90Y-ibritumomab tiuxetan to BEAM/BEAC high-dose therapy for patients in PR or CRu after induction therapy.

2. To evaluate failure-free survival time of mantle cell lymphoma patients in CR after induction therapy and then receiving treatment with high-dose BEAM/BEAC without including 90Y-ibritumomab tiuxetan

3. To evaluate overall survival time for both patient groups. 4. To evaluate time to progression for both patient groups. 5. To evaluate response rates for both patient groups. 6. To evaluate the value of PET-scan in staging and restaging 7. To evaluate molecular response rate (percentage of patients negative for t(11;14)

rearrangement or patient-specific Ig heavy chain PCR) after induction therapy and post-transplant for both patient groups.

8. To evaluate the molecular response and progression-free survival time of patients who are PCR+ post-transplant (with increasing signal) or convert from PCR- to PCR+ in the bone marrow during follow-up and then receive 4 regular weekly doses of rituximab.

9. To evaluate lymphoma tissue gene expression by microarray analysis as a tool to predict outcome.

4. Diagnosis: A histological diagnosis of mantle cell lymphoma as established by the local pathologist of each participant or: Small-cell malignancy with a CD5+, CD23- B-cell phenotype, and a histological appearance compatible with mantle cell lymphoma. In all cases a central pathology revision, including cyclin D1 staining will be done later.

5. Methodology: This is a prospective, multicenter, multinational phase II clinical trial to determine the efficacy and safety of combining 90Y-ibritumomab tiuxetan and high-dose BEAM or BEAC with autologous stem cell support in first line treatment of mantle cell lymphoma. Patients in PR or CRu after induction treatments with maxi-CHOP, high-dose Ara-C and Rituximab and with less than 25% bone marrow involvement, and who have a sufficient blood stem-cell harvest, will receive Rituximab 250 mg/m2, one week later 90Y-ibritumomab tiuxetan (0.4 mCi/kg) and then one week thereafter start ordinary BEAM or BEAC high-dose therapy followed by autologous stem cell support. Patients in CR after induction treatment will receive high-dose BEAM or BEAC without the addition of 90Y-ibritumomab tiuxetan. Patients who do not reach PR, CRu or CR after induction therapy will not go on to stem cell harvest and high-dose therapy.

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Time to treatment failure, progression free survival and overall survival will be assessed during the study follow-up period. In the case of no evidence of disease progression restaging will be carried out every third month during the first two years and then every six months until 5 years. CT-scans and molecular analysis of bone marrow will be performed before and after induction therapy, at 3, 6 and 12 months and then every 6 months until 5 years of follow-up. PET-scan is recommended done before start of therapy, obligatory at evaluation after induction for patients in PR/CRu and recommended at 3 month follow-up after therapy (only for PR/CRu patients who had a positive PET at evaluation prior to transplant). The safety and tolerability of combining BEAM/BEAC high-dose therapy with 90Y-ibritumomab tiuxetan in PR and CRu patients will be assessed by way of clinical investigation and relevant laboratory parameters at restaging visits. Lymphoma tissue gene expression by microarray analysis will be performed at a later stage and correlated to outcome. 6. Patient registration and selection: Registration and CRFs Fill in inclusion form in the CRF book. Registration is done by telephoning the study secretariat: Office of Clinical Research

The Norwegian Radium Hospital

Montebello

0310 Oslo

Phone: (+47) 22935757 The secretariat will give you a unique registration number for the patient. These are to be written on all CRFs that you send to the secretariat. Mail the inclusion form (CRF1) to the secretariat. After registration of the patient, you will receive a receipt. How and when to send CRFs Send by post the CRFs as soon as they are completed, this also applies to the inclusion form (CRF1). If the CRFs are not received by the secretariat in time, a reminder will be sent. The CRFs for pathology should be handled as written on the forms. Inclusion criteria:

1. Age 18 - 65 years. 2. Histologically confirmed (according to the WHO classification) mantle cell lymphoma

stage II-IV at time point of diagnosis. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cycline-D1 and most cases will have t(11;14) translocation.

3. No previous treatment for lymphoma except radiotherapy or one cycle of any regimen and except patients treated by the previous phase II study, who can be transferred to NLG-MCL-III before evaluation at week 15.

4. WHO performance status of 0 – 3.

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5. Life expectancy of more than 3 months. 6. Written informed consent.

Exclusion criteria:

1. Severe cardiac disease: cardiac function grade 3-4 (Appendix 1). 2. Impaired liver, renal or other organ function not caused by lymphoma, which will

interfere with the treatment. 3. Pregnancy/lactation 4. Men or woman of reproductive potential not agreeing to use acceptable method of birth

control during treatment and for six moths after completion of treatment. 5. Known HIV positivity 6. Any other prior malignancy than non-melanoma skin cancer or stage 0 (in situ) cervical

carcinoma. 7. Known seropositivity for HCV, HbsAg or other active infection uncontrolled by

treatment. 8. Psychiatric illness or condition which could interfere with their ability to understand the

requirements of the study. Inclusion criteria for high-dose therapy +/- Zevalin:

1. Patients in PR, CRu or CR according to “international workshop to standarize response criteria in non-Hodgkins lymphomas” after induction therapy with maxi-CHOP, high-dose Ara-C and rituximab

2. Stem cell harvest of > 2 x 106 CD34+ cells/kg . 3. For those in PR or CRu 90Y-ibritumomab tiuxetan will be added to the standard high-dose

regimens BEAM or BEAC.

Exclusion criteria before high-dose therapy.

1. Failure to harvest > 2 x 106 CD34+ cells/kg from peripheral blood. Bone marrow can be allowed as stem cell support in such cases.

2. Patients who have not reached PR, CRu or CR after induction treatment. 3. More than 25% tumour cells in the bone marrow by bone marrow biopsy 4. Significant pleural or intraperitoneal effusions (for pts planned for Zevalin). 5. Patients who have not recovered from toxicity of induction therapy.

7. Treatment Induction therapy: Three series of maxi-CHOP alternating with three series of Ara-C, of which all except the first course of maxi-CHOP should be combined with Rituximab, will be performed before high-dose therapy. Interval between cycles should be three weeks. Patients who have already received one cycle of a different regimen can still be included. Maxi-CHOP: Cyclophosphamide 1200 mg/m2 iv in 100 ml NaCl 9mg/ml, 20 min infusion time, day 1 (Uromitexan 240 mg/m2 iv at 0, 4 and 8 hours after cyclophosphamide)

Doxorubicin 75 mg/m2 iv in 100 ml Glucose 50mg/ml, 20 min infusion time, day 1 Vincristine 2 mg iv in 50 ml NaCl 9 mg/ml, 10 min infusion time, day 1 Prednisolone 100 mg total po day 1-5

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Ara-C: Standard dose and schedule; 3 g/m2 (2 g/m2 for patients older than 60 years) iv every 12 hours for 2 days, in 500 ml Glucose 50mg/ml, given as 1-hour infusions. Steroid eye droplets are given day 1-3. Rituximab: 375 mg/m2 Rituximab iv at day 1 of each course of maxi-CHOP (except the first) and Ara-C. Guidelines for Rituximab treatment, see appendix 4. Filgrastim (5 µg/kg on day 4 – 12) or PEG-filgrastim (6 mg on day 4) will be given sc after each course of chemotherapy. Stem cell harvest: The third course of Ara-C is used for mobilization of stem cells. Filgrastim (10 µg/kg/day sc) should be given from day 4 until stem cell harvest is completed. A minimum of 2 x 106 CD34 cells/kg is necessary to go on to high-dose therapy. For patients who do not mobilize the proper amount of stem cells from blood, a regular bone marrow harvest can be performed.

In vivo purging: Rituximab 375 mg/m2 is given at days 1 and 9 of the mobilization cycle with Ara-C, before stem cell harvest. Additional cycle of chemotherapy When necessary for logistic reasons, the patients can receive one additional course of maxi-CHOP with Rituximab before start of high-dose therapy.

High-dose chemo/radioimmunotherapy: A. Patients in PR or CRu after induction treatment will receive an infusion with Rituximab

250 mg/m2 at day 1. One week later a therapeutic infusion of 90Y-ibritumomab tiuxetan at a dose of 0.4 mCi/kg (max 32 mCi total dose), preceded by Rituximab 250 mg/m2 will be given. One week after this the standard BEAM or BEAC high-dose regimen will be started. Reinfusion with autologous stem cells at a dose of > 2 x 106/kg CD34+ cells will then follow. After the first 10 patients have been treated with the combination of radioimmunotherapy and high-dose chemotherapy, an evaluation of toxicity will be performed. Only in the case of no unexpected findings will the study go on to treat more patients in PR or CRu after induction treatment with 90Y-ibritumomab combined with BEAM or BEAC. If desirable, an estimate of 10-15 patients treated with Zevalin at The Norwegian Radium Hospital and possibly a few selected other centres will receive a standard dose of 111In-Ibritumomab tiuxetan shortly after the first infusion of Rituximab. Dosimetry will be done by gamma camera scans and SPECT at day 4 and 6 primarily in order to measure radioactivity up-take by tumour.

B. Patients in CR after induction treatment will go on to high-dose chemotherapy (BEAM or BEAC) without 90Y-ibritumomab tiuxetan.

BEAM: BCNU 300 mg/m2 (day 1) Etoposide 200 mg/m2 (days 1-4 or 2-5) Ara-C 200-400 mg/m2 (days 1-4 or 2-5)

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Mephalan 140 mg/m2 (day 5 or 6)

BEAC: BCNU 300 mg/m2 (day 1) Etoposide 100-200 mg/m2 (days 1-4 or 2-5) Ara-C 200-400 mg/m2 (days 1-4 or 2-5) Cyclophosphamide 6000 mg/m2 (day 5 or 6) or 1500 mg/m2 (day 2-5) Etopofos in equivalent doses can be used instead of etoposide. Other variants of the high-dose regimens BEAM or BEAC may be used, according to centre routines. Filgrastim (5 ug/kg/day) sc may be given from day 4 after reinfusion of stem cells and until neutrophil recovery. Rituximab treatment post-transplant Patients in CR who continues to be positive with an increasing signal by PCR and/or flow cytometry in BM post-transplant or convert to flow+ or PCR+ during follow-up without evidence of clinical relapse will receive four weekly treatments with Rituximab 375 mg/m2. BM samples should be drawn again 2-3 months after completion of Rituximab therapy for flow cytometry and PCR-analysis. A later molecular relapse may also be treated with 4 new doses of Rituximab. Molecular monitoring will be continued according to protocol.

8. Toxicity and treatment modifications Rituximab – dose adjustment and reporting serious adverse events There will be no reductions or escalations of the Rituximab dose. If an infusion related or hypersensitivity reaction to Rituximab is seen, the infusion rate of drug administration is altered as described in Appendix 4. The total dose administered remains the same in such cases. In case of a serious or life threatening reaction, the infusion should be terminated and such adverse event reported. Cytostatic agents Haematological and non-haematological toxicity will be graded according to the WHO Common Toxicity Criteria. In the case of vincristine associated neuropathy grade 2, the dose is reduced to 50%, and if grade 3, vincristine is stopped in all further cycles. Chemotherapy will be withheld in patients experiencing other grade 2 or 3 non-haematological toxicity until the patient has recovered from the toxicity. In case of nausea/vomiting, drug therapy may be continued with concomitant administration of appropriate non-steroid anti-emetics. If at the start of a subsequent maxi-CHOP chemotherapy cycle (day 21 from start of last treatment) cell numbers are too low (neutrophil counts < 1.0 x 109/l and/or platelet counts < 75 x 109/l), the next chemotherapy course should be postponed until acceptable values have been reached (neutrophils > 1.0 x 109/l and/or platelets > 75 x 109/l). Blood counts should be repeated no later than after three days. If acceptable values are achieved within one week, the subsequent course of maxi-CHOP will be given with full dosage. If neutrophils and / or platelets counts still are low the following dose modifications are applied for maxi-CHOP:

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Neutrophils (109/l)

Platelets (109/l)

Cyclophosphamide (%)

Doxorubicin (%)

Vincristine (%)

Prednisone (%)

> 1.0 and > 75 100 100 100 100 0.5-1.0 or 50 - 75 50 50 100 100 < 0.5 or < 50 0 0 100 100 The cytarabine dose is reduced to 50% if one of the following criteria is reached: 1) Serum creatinine level > 130 mmol/l 2) Alkaline phosphatase (ALP) > 3 times upper limit. When neutrophils < 0,5 x 109/l and or platelets < 50 x 109/l, the next cytarabin cycle should be postponed until these values have been reached and then given at full dose. When dose reductions otherwise are considered, one of the members of the writing committee should be contacted.

Criteria for discontinuation of study treatment In absence of unacceptable toxicity or other cause for discontinuation (see below), patients will receive study treatment as outlined above. The following events are deemed sufficient cause to terminate study treatment. � Severe (grade 4) non-haematologic toxicity except alopecia � The patients own wish to terminate study treatment � If the responsible physician thinks a change of therapy would be in the best interest of the

patient 9. Tests performed at diagnosis:

- Clinical examination and complete medical history - Full blood count, biochemistry (urea, creatinine, bilirubin, ALAT, ALP, albumin, LDH) - Plasma for storage - Biopsy of tumour tissue for morphology and immunochemistry, frozen tissue for storage

and later micro-array analysis - Bone marrow biopsy for morphology and immunochemistry and aspiration for

flowcytometry - Bone marrow and blood to Copenhagen for molecular biology including PCR for t(11;14) - CT-scans of thorax and abdomen/pelvis (and neck, if involved by lymphoma) - PET-scan advisable - ENT-examination when thought necessary by the responsible physician - Gastroscopy when thought necessary by the responsible physician

10. Tests performed at response evaluation:

- Clinical examination and complete medical history - Blood tests as above - Bone marrow biopsy and flow cytometry, and molecular biology as above. - CT-scan of regions involved with lymphoma at baseline. - PET-scan is obligatory for patients in PR/CRu at evaluation.

Response evaluation will be performed after five series of chemotherapy, every third month during the first two years post-transplant, then every sixth month until five years or until relapse. CT-scans and bone marrow samples are done at 3 and 6 and 12 months and then every 6 months

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until five years or until relapse. Repeated PET-scan at 3 months post-transplant is advisable for PR/CRu patients who had a positive PET-scan prior to transplantation.

10b. Tests performed at stem-cell harvest: Samples must be secured in the blood bank for later MRD analysis in Copenhagen (appendix 3). Samples from each harvest day or pooled samples will be shipped to Copenhagen at a later time point agreed upon by the investigator and the Molecular Lab. in Copenhagen.

11. Criteria for evaluation and endpoints

Evaluation criteria (Cheson et al. 1999)

Complete remission (CR) Disappearance of all disease-related symptoms and measurable lesions, including normalisation of other abnormal initial parameters (if any) such as biochemical abnormalities definitely assignable to NHL (e.g. s-LDH), X-rays and bone marrow. All lymph nodes must have regressed to < 1.5 cm in their largest transverse diameter and to < 1.0 cm for those nodes which were 1.1 to 1.5 cm before treatment. Complete remission unconfirmed (CRu) The criteria of a CR are fulfilled, except that residual lymph node(s) mass greater than 1.5 cm have regressed by more than 75% in the sum of the products of the two largest perpendicular diameter(s). A CRu should when possible be assigned to a CR or PR by histological examination. Partial remission (PR) Decrease of at least 50% in the sum of the product of the two largest perpendicular diameters in all measurable and evaluable lesions and disappearance of disease-related symptoms with no lesion increasing 25% or more in size and without any new lesions appearing. No change/stable disease (NC) The patient does not qualify for complete or partial remission or progressive disease.

Progressive disease (PD) Increase in size of 25% or more of the product of the two largest perpendicular diameters of one or more measurable and evaluable lesions during treatment or the occurrence of new lesions. Relapse During follow-up the occurrence of relapse in patients previously registered as being in CR will be registered. The following data will be registered: 1. Relapse yes/no

if yes: 2. Date of relapse 3. Site of relapse 4. Type of relapse: - in previously involved nodal area/-s - in previously uninvolved nodal area/-s - in previously involved extra nodal area/-s

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- in previously uninvolved extra nodal area/-s NB: At relapse, every centre is free to initiate further treatment according to local guidelines. At this point the patient will exit the study, although centres are encouraged to keep sending in follow-up forms to allow establishing the overall survival time. Endpoint criteria Time to treatment failure Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as 1 day.

Overall survival (all causes of death) Time from the intention-to-treat date to the date of death. Patients still alive or lost to follow-up are censored at the last date they were known to be alive.

Time to progression Time from the first assessment within 3 months of completion of therapy that documents response to the date of disease progression or relapse. Otherwise, the patients are censored at the last date of follow up. Patients still alive in a CR or lost to follow-up are censored at the last date they were known to be alive. Patients who die due to causes other than NHL are censored at the date of death.

Cause of death During the study and after its completion the cause of death will be registered according to the following cause-of-death criteria:

1. Lymphoma 2. Treatment toxicity 3. Secondary malignancy 4. Other disease not related to 1, 2 or 3 5. Other cause

12. Reporting serious adverse events (p15) All serious adverse events (SAE) occurring during the treatment period and until the end of the last treatment administration will be reported in the serious adverse event form (CRF 12). SAE are defined as any undesirable experience occurring to a patient, whether or not considered related to the treatment. Adverse events are considered serious when they result in:

- Death - Life threatening event - Unplanned or prolonged hospitalisation* - Severe/permanent disability

16

- A congenital anomaly * Except for hospitalisation caused by neutropenia, thrombopenia and fever, which is considered to be expected

haematological toxicity.

Serious adverse events related to the investigational drug, Zevalin, can be defined as SUSAR (serious unexpected adverse reaction) or SAR (serious adverse reaction). A SUSAR is not consistent with information in the relevant source documents. All other treatments given in the protocol are considered standard of care for mantle cell lymphoma. Both the investigator who reports the SAE and sponsor (Arne Kolstad) must assess whether a SAE is a SUSAR or not. Events that are considered to be SUSAR by one or both of, it must be reported to the authorities as such. SAEs related to the standard therapies of the protocol and other events not considered as SUSAR should only be included in sponsor’s summary SAE reports to the authorities in the participating countries. During the protocol treatment all SAE’s must be reported by the investigator to the sponsor (Arne Kolstad) at The Norwegian Radium Hospital by e-mail or by fax without delay and within 24 hours after the initial observation of the event. All details should be documented on the Serious Adverse Event Form (CRF 12). At any time after the completion of protocol treatment, all SAEs must also be reported to the sponsor using the same procedure. An evaluation is made by the investigator and sponsor whether this is a SUSAR (for those who received Zevalin) and has to be reported to the authorities in the participating countries. In case of SUSAR the sponsor is responsible for reporting to the National Medical Agency (NMA) and Ethics Committee (EC) in the country where it occurred, and for notifying national coordinators, the clinical research office at the Norwegian Radium Hospital, Schering and the principal investigators in his country within 7 calender days (15 days for a non-fatal non-life-threatening event) of being aware of the event. A follow-up report should be sent within an additional 8 days. Summary reports including all SUSARs and SARs should be sent by the sponsor to the authorities in all participating countries at regular intervals, according to the local legislation. Once a year the sponsor is responsible for sending a complete list of all SUSARs, SARs and SAEs in the study, together with a safety report to the NMA and EC in all the participating countries, the clinical research office, all investigators and Schering. The following definitions will be applied to make the assessment of causality between the event and the study treatment: RELATIONSHIP DESCRIPTION UNRELATED There is no evidence of any causal relationship UNLIKELY There is little evidence to suggest 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

17

treatments). POSSIBLE There is some evidence to suggest a causal relationship (e.g. the

event occurred 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 patient’s 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 ASSESSABLE There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship.

13. Study duration: The protocol aims to begin in the second half of 2005. Recruitment based on the previous two Nordic mantle cell studies is estimated to be 30-40 patients per year. This means that it will take 4 years to include 150 patients. The patients will then be followed for 5 years. The results will be compared with those of the previous phase II Nordic study, which is identical in design, except for the introduction of radioimmunotherapy as part of the conditioning regimen in patients who reach PR or CRu after induction therapy.

14. Criteria for study discontinuation After the first 10 patients in PR or CRu after induction treatment have received the combination of Y90-ibritumomab tiuxetan and BEAM or BEAC, an evaluation of toxicity will be performed. Only in the case of no unexpected findings will the study go on to include more patients for the combined radioimmunotherapy/chemotherapy treatment. At all points of the study discontinuation will be considered in case of severe treatment-related toxicity and treatment-related deaths. 15. Statistical considerations Analysis The main analysis will include those registered patients that have started the protocol treatment. Time to Treatment Failure, as well as the secondary endpoints Overall Survival and Time to Progression, will be presented using Kaplan-Meier plots, and differences between groups will be tested by log-rank tests. The effect of clinical and biological prognostic factors will be analysed by means of Cox regression. Toxicity will be shown in descriptive tables. The study results will be compared with historical data, e.g. the 2. Nordic MCL study. The inclusion criteria for the two studies are identical and so are the treatments except for the addition of 90Y-ibritumomab to the high-dose regimen in PR and CRu patients of the third Nordic MCL study.

18

The aim of the 3. Nordic MCL study is to improve TTF for patients who do not respond with a CR prior to high-dose therapy to a level comparable to those in CR, based on findings from the 2. Nordic MCL study. In this study the FFS after 3 years was 63% for those in PR/CRu prior to transplant, compared to 85% in CR patients. The inclusion criteria for the two studies are identical and so are the treatments except for the addition of 90Y-ibritumomab to the high-dose regimen in PR and CRu patients of the 3. Nordic MCL study. With 150 assessable patients and the assumption that 50% will be in PR/CRu after induction treatment (as for the 2. Nordic study) the power will be > 90% for detecting an improvement in 3 year TTF of 22% (from 63% to 85%) for the PR/CRu group (significance level p=0,05, two-tailed).

16. Publication rules Manuscripts based on this protocol will be made according to the "Vancouver System": Uniform Requirements for Manuscripts Submitted to Medical Journals (latest updated version 2000: www. Icmj.org). Authorship is based on important contributions to: • Idea, planning or modifying the protocol, collection, analysis or interpretation of data • Writing or critically revising the manuscript • Acceptance of the final manuscript. All three aspects must be covered. The chairman of the writing committee is the main responsible for accomplishing the goals of the protocol, and will also be responsible for writing the manuscript. In that case he will be 1st author. If important contributions from members of the study group warrant separate publications, the contributor in question will be first author on that article. Members of the writing committee are expected to fulfil the above criteria and to be co-authors. Members of the Pathology Board, and molecular biologists who do important cross sectional work, will all be co-authors. As 150 patients may enter this study from 20-30 centers in the Nordic Area it cannot be guaranteed that all who contribute clinically to the study, will be co-authors. All other contributors to the study will be listed in a special section of the article, including representatives of all participating clinical departments and blood banks: "Members and centres of the the Nordic Lymphoma Group". All manuscripts will be distributed to the contributors prior to submission for publication.

17. Ethical aspects Patient protection The responsible investigator will ensure that this study is conducted in agreement with either the declaration of Helsinki (Tokyo, Venice and Hong Kong amendments), or the laws and the regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the guidelines for Good Clinical Practice issued by the European Union. As a pre-requirement for implementation, the protocol will have to be approved by the local, regional or national Ethical Review Boards according to the existing national and local regulatory requirements. Informed consent All patients will be informed of the aims of the study, including the possible adverse events, the procedures involved and the possible hazards to which he/she will be exposed. They will be informed as to the strict confidentiality of their data, but that their medical records will be

19

reviewed for trial purposes by authorised individuals other than their treating physician. It will be emphasised that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. Documented informed consent must be obtained for all patients included in the study before they are registered. In accordance with the guidelines of Good Clinical Practice the “consent must be documented either by the subject’s dated signature or by the signature of an independent witness who records the subject’s assent”.

20

18. References Andersen NS, Donovan JW, Borus JS et al. Failure of immunologic purging in mantle cell lymphoma assessed by polymerase chain reaction detection of minimal residual disease. Blood 1997;90:4212-4221 Andersen et al. Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant. Eur J Haematol 2003, 71(2); 73-80. Behr et al. High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Cancer 2002, feb 15, vol 94, no 4, 1363 Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphoma. J Clin Oncol 1999; 19: 1244-53. Coiffier B, Haioun C, Ketterer N et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: A multicenter phase II study. Blood 1998;92:1927-32 Foran JM, Cunningham D, Coiffier B et al. Treatment of mantle cell lymphoma with Rituximab (chimeric anti-CD20 antibody): Analysis of factors associated with response. Ann Oncol 2000;11 suppl 1:117-121. Fung HC et al. A new preparative regimen for older patients with aggressive CD20 positive B-cell lymphoma utilizing standard dose Yttrium-90 Ibritumomab (Zevalin) radioimmuntherapy (RIT) combined with high-dose BEAM followed by autologous hematopoietic stem cell transplantation (AHCT): Targeted intensification without increased transplant-related toxicity. Blood 2003, November 16, no 11. Abstract 870 Geisler C, Elonen E, Johnson A, Kolstad A, Andersen NS for the Nordic Lymphoma Group: Primary autologous stem cell transplantation for mantle cell lymphoma: Clinical and molecular response. Blood 2000;96: 794a (abstract #3432) Hiddeman et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation leads to significant prolongation of the event-free survival in patients with mantle cell lymphoma (MCL) – results of a prospective randomized European Intergroup study. Blood 2001, 98, Hiddemann et al. Rituximab plus chemotherapy in follicular and mantle cell lymphoma. Semin Oncol 2003, Feb; 30 (suppl 2); 16-20 Khouri et al. Hyper-CVAD and high-dose methotrexate/cytarabin followed by stem cell transplantation: an active regimen for aggressive mantle cell lymphoma. J Clin Oncol 1998; 16:3803-9 Jacquy C, Lambert F, Soree A et al. Peripheral blood stem cell contamination in mantle cell non-Hodgkin’s lymphoma: The case for purging? Bone Marrow Transplantation 1999;23:681-6

21

Magni M, Di Nicola M, Devizzi L et al. Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent Lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood 2000; 96: 864-869. Nademanee A, Forman S, Molina A, Fung H et al. A phase I/II trial of high-dose yttrium-90 ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplant in patients with poor-risk or relapsed non-Hodgkins lymphoma. Blood 2005, prepublished online June 7. Press OW and Rasey J. Principles for radioimmunotherapy for hematologists and oncologists. Semin Oncol 2000, 27:62-73 The Non-Hodgkin’s Lymphoma Classification project. A Clinical evaluation of the International Lymphoma Study Group Classification of non-Hodgkin’s lymphoma. Blood 1997;89:3909-18. Weisenburger DD, Armitage JO. Mantle cell lymphoma: An entity comes of age. Blood 1996;87:4483-94. Winther et al. Zevalin dose-escalation followed by high-dose BEAM and autologous stem cell transplantation in non-Hodgkins lymphoma. Blood 2002, vol 100, no 11, abstract 1597

22

Appendix 1

WHO Performance Status Scale

Grade Performance status 0 Able to carry out all normal activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out light work 2 Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours 3 Capable of only limited self-care; confined to bed or chair more than 50%

of waking hours 4 Completely disabled; cannot carry on any self-care; totally

confined to bed or chair

23

Appendix 2

WHO recommendations for grading of acute and subacute toxic effects

Grade Grade Grade Grade Grade 0 1 2 3 4

Hematological (adults)

Hemoglobin ≥ 110 g/l 95-109 g/l 80-94 g/l 65-94 g/l <65 g/l ≥6.8 mmol/l 5.8-6.7 mmol/l 4.95-5.8 mmol/l 4.0-4.9 mmol/l <4.0 mol/l Leuko(1000 mmol/mm³) ≥4.0 3.0-3.9 2.0-2.9 1.0-1.9 <1.0 Granulo (1000 mmol/mm³) ≥2.0 1.5-1.9 1.0-1.4 0.5-0.9 <0.5 Platelets (1000 mmol/mm³) >100 75-99 50-74 25-49 <25 Haemorrhage none petechiae mild blood loss gross blood loss debilitating blood loss Gastrointestinal

Bilirubin ≤ 1.25 x Na 1.26-2.5 x Nª 2.6-5 x Nª 5.1-10 x Nª > 10 x Nª Aminotransferases (ASAT, ALAT) ≤ 1.25 x Nª 1.26-2.5 x Nª 2.6-5 x Nª 5.1-10 x Nª > 10 x Nª Alkaline phosphatase ≤ 1.25 x Nª 1.26-2.5 x Nª 2.6-5 x Nª 5.1-10 x Nª > 10 x Nª Oral no change soreness/ erythema, ulcers; ulcers; requires alimentatio erythema can eat solids liquid diet only not possible Nausea/vomiting none nausea transient vomiting requiring intractable extra therapy vomiting Nausea/vomiting with none nausea transient vomiting requiring intractable Prophylactic antiemetics vomiting extra therapy vomiting Diarrhoe none transient tolerable intolerable haemorrhagic < 2 days but >2 days requiring therapy dehydration Renal

Blood creatinine ≤ 1.25 x Na 1.26-2.5 x Na 2.6-5 x Na 5-10 Na >10 x Na 1+ 2-3+ 4+ Proteinuria no change < 0.3 g% 0.3-1.0 g% >1.0 g% nephrotic < 3 < 3-10 g/l > 10 g/l syndrome Haematuria no change microscopic gross gross + clots obstructive uropathy Pulmonary no change mild symptoms excertional dyspnoea at rest complete

dyspnoe bed rest required Fever with drug none fever < 38 °C fever 38°C-40°C fever > 40°C fever with hypotensi o Allergic no change oedema bronchospasm; bronchospasm anaphylaxis no parenteral parenteral the- therapy rapy required

24

APPENDIX 2 continued

Who recommendations for grading of acute and subacute toxic effects

Grade Grade Grade Grade Grade 0 1 2 3 4 Cutaneous no change erythema dry desquamation moist desquama- exfoliative vesiculation, tion, ulceration dermatitis; pruritus necrosis

requiring surgical intervent.

Hair no change minimal hair moderate, patchy complete alopecia non-rev loss alopecia but reversible alopecia Infection (specify site) none minor infection moderate infection major infection major infection

with hypotension

Cardiac

Rhythm no change sinus tachycardia, unifocal PVC, multifocal PVC ventricular >110 at rest arterial arrhythmia tachycardia Function no change asymptomatic, transient symptomatic symptomatic but abnormal symptomatic dysfunction dysfunction cardiac sign dysfunction; no responsive to non-responsive therapy required therapy to therapy Pericarditis no change asymptomatic symptomatic; tamponade tamponade; effusion no tap required tap required surgery require Neurotoxicity State of consciousness alert transient somnolence somnolence >50% coma lethargy >50% of waking of waking hours hours Peripheral none paraesthesias severe paraes- intolerable paralysis and/or decreased thesias and/or paraesthesias tendon reflexes mild weakness and/or marked motor loss Constipationb none mild moderate abdominal distension and distension vomiting Painc none mild moderate severe intractable With prophylactic none mild moderate severe intractable analgetics

a: Upper limit of normal value of population under study. b: This does not include constipation resulting from narcotics c: Only treatment-related pain is considered, not disease-related pain. The use of narcotics in grading pain, depending upon the tolerance level of the patient.

25

Appendix 3

Molecular studies

Use a copy of this form whenever molecular samples are submitted to Copenhagen. To: The Hematology Laboratory 4041

Leukemia and Lymphoma Marker Section

Rigshospitalet

DK Copenhagen

Denmark Attention Lone Bredo Pedersen/Niels Smedegaard Andersen Phone + 45 35453826, Fax +45 3545 4780 email: lone.bredo.pedersen@rh.regionh.dk Please find enclosed samples from our patient: Patient initials and 3-digit number:………………… Who is being treated according to the Third Nordic MCL Protocol Samples are taken date:………………….. and consist of: 10 ml bone-marrow aspirate, anticoagulated Frozen tumor tissue 50 ml blood, anticoagulated Stem cell product Sincerely, Signature:………………………………Hospital:………………………Country………………. Handling of biological material

50 ml of peripheral venous blood and 10 ml of bone marrow aspirate should be collected in a sterile tube containing EDTA as an anticoagulant. The sample should be sent by mail to Copenhagen for arrival in less than 72 hours. Please label the tubes, and avoid shipment that will arrive at week-ends. Peripheral stem cell product should be frozen in DMSO and kept frozen until shipment. At least 107 cells from each harvest day or pooled througout the harvest should be shipped and tubes marked with accurate numbers of cells in each tube. Shipment on dry ice at request, avoid arrival at week-end. Frozen tumor tissue for micro-array analysis should be kept frozen at -70 C and shipped on dry ice at request. Important: Please fax a copy of this form at the day of shipment.

26

Appendix 4

Rituximab administration

Caution: Do not administer Rituximab as an intravenous push or bolus injection.

Hypersensitivity reactions may occur whenever protein solutions such as Rituximab are admin-istered. Premedication, consisting of paracetamol (acetaminophen) and diphenhydramine should be administered before each infusion of Rituximab. Rituximab should be administered intravenously through a dedicated line at an initial rate of 50 mg/hr. If hypersensitivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. If hypersensitivity or infusion-related events develop, the infusion should be temporarily slowed or interrupted. The patient should be treated according to the appropriate standard of care. The infusion can be continued at one-half the previous rate after symptoms have abated (see table below). Subsequent Rituximab infusion can be administered at an initial rate of 100 mg/hr, and increased at 30 minute intervals by 100 mg/hr increments to a maximum of 400 mg/hr.

Rituximab Infusion Rate Adjustments

Infusion Rate

Fever

Rigors

Mucosal Congestion/

Edema

Hypotension

(or) → (or) → (or) →

Decrease 1/2 >38.0°C Mild Mild Mild

Interrupt* Treatment

>39.0°C Moderate Moderate Mild to Moderate

*Interrupt antibody infusion until adverse clinical events have resolved; resume the antibody infusion at a

rate not to exceed the initial rate of infusion and escalate as tolerated.

27

Appendix 5 See appendix 6 and 7 for worksheets

On site radiolabeling and quality control

Ibritumomab tiuxetan

The murine anti-CD20 monoclonal antibody ibritumomab is an IgG1 kappa antibody. It is pro-duced in Chinese hamster ovary (CHO) cells in suspension culture. The purified antibody is then joined covalently to the chelating agent tiuxetan (conjugated antibody “ibritumomab tiuxetan”). Ibritumomab tiuxetan is provided as part of the radiolabeling kit in form of a 2 ml glass vial containing 2 ml (3.2 mg) of ibritumomab tiuxetan at a concentration of 1.6 mg/ml in low metal normal saline.

Radioisotopes yttrium-90 and indium-111

90YCl and 111InCl used for preparing 90Y-ibritumomab tiuxetan and 111In-ibritumomab tiuxetan will be obtained from vendors identified by Schering AG. All lots of isotopes are sterile, pyrogen-free, and supplied in septum vials designed to maintain these conditions.

Preparation of 90

Y-/111

In-Ibritumomab tuixetan

Conjugated ibritumomab tiuxetan will be radiolabeled with 90Y and 111In using a radiolabeling kit. The radiolabeling kit is provided by Schering AG to the study center. All kit components have been tested for sterility and pyrogenicity. The kit consists of the following components: • 3 ml glass vial containing 2 ml (3.2 mg) of ibritumomab tiuxetan at a concentration of

1.6 mg/ml in low metal normal saline

• 3 ml glass vial containing 2 ml low-metal 50 mM sodium acetate.

• 10 ml glass vial containing 10 ml formulation buffer (PBS containing 7.5% human serum albumin and 1 mM DTPA, pH 7.2)

• 10 ml glass vial (empty)

90Y /

111In labeled ibritumomab tiuxetan is prepared as follows using the

radiolabeling kit. 1. Using a 1 ml sterile syringe, transfer volume of sodium acetate equivalent to 1.2 times the

volume of 1480 MBq (40 mCi) 90Y / 204 MBq (5.5mCi) 111In to the empty 10 ml glass septum vial

2. Transfer 1480 MBq (40 mCi) 90Y chloride (pharmaceutical grade in 0.04 to 0.05 M HCl) / 204 MBq (5.5mCi) 111In chloride (pharmaceutical grade in 0.04 to 0.05 M HCl) using a sterile 1 ml syringe, mix by inversion.

3. Using a 2 ml syringe, transfer 1.3 ml (1.0 ml for labeling with 111In) of ibritumomab tiuxetan; mix by inversion and incubate 5 min (30 min for labeling with 111In).

4. Using a 10 ml syringe add formulation buffer to achieve a total volume of 10 ml; mix by inversion. Store at 2 to 8°C until administered to patient.

28

5. 90Y- and 111In ibritumomab tiuxetan may be directly infused during 10 minutes by stopping the flow from the IV bag and injecting the radiolabeled antibody directly into the infusion port. A 0.22 microm filter must be on line between the syringe and the infusion port.

Radiochemical purity assay

After preparation of 90Y- or 111In-ibritumomab tiuxetan, a radiochemical purity assay will be performed at the clinical site for release purposes. The assay insures that an acceptable per-centage of the radioisotope is chelated by the antibody conjugate. An instant thin-layer chromatographic assay using a commercial kit (Biodex) is available for use. In this assay, conjugated antibody remains at the origin whereas tiuxetan or DTPA-chelated yttrium advances with the solvent front. The amount of radioactivity remaining at the origin bound to the antibody conjugate is expressed as a percentage of the total amount of radioactivity applied to the strip. The Radiochemical Purity by Instant Thin Layer Chromatography (ITLC) shall be done according to the following procedure at room temperature. NB: The results of the assay for

each patient must be documented on the radiolabeling worksheets provided

The release specification for radiochemical purity is ≥95% for both 90Y and 111In ibritumomab tiuxetan. The radiopharmacist at the clinical site will record release test results. Based on the results, he/she will release or reject the 90Y / 111In ibritumomab tiuxetan dose for patient use.

Required materials not supplied:

• 1 ml insulin syringe with a 25-26 G needle

• ITLC-SG, e.g., Biodex “Tec-Control” kit, part number 151-770

• Single or multichannel analyzer

1. Set region of interest of single or multichannel analyzer to incorporate channels 140-1000 keV.

2. Using a 1 ml insulin syringe, place a hanging drop (7-10 µl) onto the ITLC-SG strip at its 1.4

0.8 ml

0.9% NaCl

90Y-/ 111In-ibritumomab tiuxetan

Origin

Line

Cut

Line

Solvent

Front

Line

Dark

Green

�

� �

Origin Line 1.4 cm

Cut Line 3.5 cm

Solvent Front

Line 5.0 cm

ITLC-SG Strip

6 cm

# 1

# 2

0.5 cm

29

cm mark “origin.” Spot one strip at a time and run the procedure on three ITLC-SG strips. A 1:100 dilution may be necessary if the instrument deadtime is appreciable.

3. Fill developing chamber with 0.8 ml of bacteriostatic free 0.9% NaCl. The volume of 0.9% NaCl should not touch the 1.4 cm origin line.

4. Place ITLC-SG strip into developing chamber and allow the solution to migrate past the 5 cm “Solvent Front” line. Do not allow ITLC-SG strip to adhere to the side of the developing chamber. See illustration below.

5. Remove ITLC-SG strip and cut in half at the 3.5 cm “Cut-Line.” Count each half of the ITLC-SG strip in a multi-channel or single channel analyzer counter for one-minute (cpm). Subtract background counts and use corrected counts.

6. Calculate the radiochemical purity % as follows:

Radiochemical purity % =

7. Repeat process three times and take the average percentage of the radiochemical purity.

The release specification for the average radiochemical purity is >95% for both 90

Y- and 111

In-ibritumomab tiuxetan.

�

x 100 (cpm #1)

(cpm #1) + (cpm #2)

�#2

#1

DTPA-bound Yttrium-[90]

90Y-/111In-ibritumomab tiuxetan

#2

#1

One minute count

30

Clinical release testing for 90Y- and 111In-ibritumomab

tiuxetan

Version 1.2 January 2006, 3rd

Nordic Mantel Cell Lymphoma Phase II Study

Patient no.: ____________ Initials: _________ Date (dd-mm-yyyy): __________

1. Determine the total activity of the 10 ml-reaction vial using a

calibrated dose calibrator:

Measured radioactivity: ____________ MBq

2. Determine the percent radioincorporation Follow the instructions in Appendix 5 to the study protocol.

Net Counts # 1 Net Counts # 2 % Radiochemical Purity*)

Strip 1

Strip 2

Strip 3

AVERAGE

*) % Radiochemical Purity = ____cpm # 1 x 100____ (cpm # 1 + cpm # 2) The release specification for the average radiochemical purity is ≥95% for both 90

Y- and 111

In-ibritumomab tiuxetan.

Signature: _______________________ Date: ________________

Origin Line 1.4 cm

Cut Line 3.5 cm

Solvent Front

Line 5.0 cm

ITLC-SG Strip

6 cm

# 1

# 2

0.5 cm

31

Appendix 6

Radiolabeling protocol, 90Y - ibritumomab tiuxetan

Version 1.2 January 2006, 3rd

Nordic Mantel Cell Lymphoma Phase II Study

Patient no.: ____________ Initials: ________ Date (dd-mm-yyyy): __________

Radiolabeling kit batch no.: ________________ Exp. date: _____________

Yttrium-90 batch no.: _____________________ Exp. date and time: ____________

Calculation steps

1. Volumic activity of the 90YCl (refer to delivery note) ________ MBq/ml

2. Total volume in vial ________ ml

3. Total activity in the vial at calibration time (refer to delivery note) ______ MBq

4. Date and time of calibration (Central European Time, CET) _______________

5. Date and time of radiolabeling ______________ local time = __________ CET

6. Time between calibration and radiolabeling _________ hours

7. Decay factor __________

8. Calculated activity at radiolabeling (initial activity × decay factor) ______ MBq

9. Measured activity in your calibrator at the time of labeling ___________ MBq

10. Check that the activity you are measuring in your dose calibrator is consistent with the calculation above

11. Calculate the volume of yttrium-90 containing 1480 MBq required at the time of radiolabeling: 1480 MBq ÷ actual measured activity × volume indicated on the delivery note = ______________ ml

12. Prior to labeling, check the activity present in the 1 ml syringe

13. Calculate the volume of 50 mM sodium acetate to be added to reaction vial: volume yttrium-90 _________ ml × 1.2 = ____________ ml sodium acetate

14. Calculate the volume of formulation buffer to be added to reaction vial

Step A: _______ ml sodium actetate + ________ yttrium-90 chloride + 1.3 ml ibriutumomab tiuxetan solution = ___________ ml

Step B: Total reaction volume 10 ml - _______ ml (calculated in step A) = ____________ ml formulation buffer

Labeling procedure

1. Before radiolabeling, bring the Zevalin kit to room temperature.

2. Under aseptic conditions

a. draw up sodium acetate in 1 ml “insulin” syringe

b. draw up ibritumomab tiuxetan in 2 ml syringe (needle Ø 0.9-1.2 mm)

c. draw up formulation buffer in 10 ml syringe (needle Ø 0.9-1.2 mm, length 4 cm)

3. Transfer sodium acetate to the reaction vial. Roll the reaction vial to ensure complete coating of the inner surface of the vial

32

4. Using a shielded 1 ml “insulin” syringe with a 4 cm needle, draw up required volume of yttrium-90 to contain 1480 MBq. Do not turn vial upside down while drawing up yttrium-90 NB! Prolonged contact of yttrium-90 with a steel needle is disadvantageous and can affect the labeling efficiency

5. Measure activity in the 1 ml “insulin” syringe using appropriate calibration factor Activity in the 1 ml “insulin” syringe ___________ MBq

6. Transfer yttrium-90 to the reaction vial. Roll the vial (in a sealed shielded pot), to ensure coating of the inner surface of the reaction vial. Do not shake the reaction vial

7. Transfer ibritumomab tiuxetan solution to the reaction vial carefully, to avoid foaming. Gently roll the vial again to ensure coating of the inner surface of the reaction vial. Do not shake the reaction vial. Start pre-set timer immediately

8. Incubate at room temperature for 5 minutes (± 1 minute)

9. After a 5 minute incubation period, add the formulation buffer very carefully to the reaction vial (risk for foaming) to terminate the reaction

10. Activity in the reaction vial _______ MBq at (date and time)____________

11. Perform quality check according to separate instructions

Activity to be administered to patient

1. Calculate the prescribed activity for the patient

2. 14.8 MBq × __________ kg = ______________ MBq. NB: Maximum 1184 MBq

3. Calculate the activity in the reaction vial at the time of administration

4. = activity in step 22 × decay factor for the hours since it was last measured

5. = __________ MBq × ________ = _________ MBq

6. Calculate the volume of the activity prescribed for the patient:

7. Activity for patient__________ MBq ÷ activity in the reaction vial at the time of administration _________ MBq × 10 ml = _________ml

8. Draw up calculated volume of patient’s activity using 10 ml syringe. It is recommended to withdraw the patient dose from the vial immediately prior to administration. If this is not possible, calculate volume to be withdrawn according to decay. Store at 2-8°C up to 8 h.

9. Total activity in the 10 ml syringe = _________ MBq in ________ ml at _____________ hour (CET)

Signature: _______________________ Date: ________________

33

Appendix 7.

Radiolabeling protocol, 111In - ibritumomab tiuxetan

Version 1.2 January 2006, 3rd

Nordic Mantel Cell Lymphoma Phase II Study

Patient no.: ____________ Initials: ________ Date (dd-mm-yyyy): __________

Radiolabeling kit batch no.: _______________ Exp. date: _____________

Indium-111 batch no.: ____________________ Exp. date and time: ____________

Calculation steps

1. Volumic activity of the 111InCl (refer to delivery note) ________ MBq/ml

2. Total volume in vial ________ ml

3. Total activity in the vial at calibration time (refer to delivery note) ______ MBq

4. Date and time of calibration (Central European Time, CET) _______________

5. Date and time of radiolabeling ______________ local time = __________ CET

6. Time between calibration and radiolabeling _________ hours

7. Decay factor __________

8. Calculated activity at radiolabeling (initial activity × decay factor) ______ MBq

9. Measured activity in your calibrator at the time of labeling ___________ MBq

10. Check that the activity you are measuring in your dose calibrator is consistent with the calculation above

11. Calculate the volume of indium-111 containing 204 MBq required at the time of radiolabeling: 204 MBq ÷ actual measured activity × volume indicated on the delivery note = ______________ ml

12. Prior to labeling, check the activity present in the 1 ml syringe

13. Calculate the volume of 50 mM sodium acetate to be added to reaction vial: volume indium-111__________ ml × 1.2 = _________ ml sodium acetate

14. Calculate the volume of formulation buffer to be added to reaction vial

Step A: _______ ml sodium actetate + ________ yttrium-90 chloride + 1.0 ml ibriutumomab tiuxetan solution = ___________ ml

Step B: Total reaction volume 10 ml - _______ ml (calculated in step A) = ____________ ml formulation buffer

34

Labeling procedure

1. Before radiolabeling, bring the Zevalin kit to room temperature.

2. Under aseptic conditions

a. draw up sodium acetate in 1 ml “insulin” syringe

b. draw up ibritumomab tiuxetan in 2 ml syringe (needle Ø 0.9-1.2 mm)

c. draw up formulation buffer in 10 ml syringe (needle Ø 0.9-1.2 mm, length 4 cm)

3. Transfer sodium acetate to the reaction vial. Roll the reaction vial to ensure complete coating of the inner surface of the vial

4. Using a shielded 1 ml “insulin” syringe with a 4 cm needle, draw up required volume of indium-111 to contain 204 MBq. Do not turn vial upside down while drawing up indium-111

5. Measure activity in the 1 ml “insulin” syringe using appropriate calibration factor. Activity in the 1 ml “insulin” syringe ___________ MBq

6. Transfer indium-111 to the reaction vial. Roll the vial (in a sealed shielded pot), to ensure coating of the inner surface of the reaction vial. Do not shake the reaction vial

7. Transfer ibritumomab tiuxetan solution to the reaction vial carefully, to avoid foaming. Gently roll the vial again to ensure coating of the inner surface of the reaction vial. Do not shake the reaction vial. Start pre-set timer immediately

8. Incubate at room temperature for 30 minutes (± 5 minute)

9. After a 30 minute incubation period, add the formulation buffer very carefully to the reaction vial (risk for foaming) to terminate the reaction

10. Activity in the reaction vial _______ MBq at (date and time)____________

11. Perform quality check according to separate instructions

Activity to be administered to patient

1. A dose of 185 MBq should be used for radioimaging.

2. Calculate the activity in the reaction vial at the time of administration

3. Activity at the end of radiolabeling × decay factor for the hours since the activity was measured = __________ MBq × ________ = _________ MBq

4. Calculate the volume indium-111 containing 185 MBq:

5. 185 MBq ÷ activity in the reaction vial at the time of administration _____ MBq × 10 ml = _________ml

6. Draw up calculated volume using 10 ml syringe. It is recommended to withdraw the patient dose from the vial immediately prior to administration. If this is not possible calculate volume to be withdrawn according to decay. Store at 2-8°C up to 12 h.

7. Total activity in the 10 ml syringe = _________ MBq in ________ ml at _____________ hour (CET)

Signature: _______________________ Date: ________________

35

Appendix 8

90Y-ibritumomab tiuxetan administration

The therapy dose with 90Y-ibritumomab tiuxetan will be administered one week after the first dose of Rituximab (250 mg/m2). Each patient will receive one therapeutic dose of 14.8 MBq/kg (0.4 mCi/kg) total body weight of 90Y-ibritumomab tiuxetan (max. 1184 MBq or 32 mCi), preceded by Rituximab iv. The exact dose of 90Y-ibritumomab tiuxetan will be based on the patient’s weight during the baseline evaluation according to table below. A maximum dose of 1184 MBq (32 mCi) of

90Y will be administered to those patients whose

body weight exceeds 80 kg.

Dosing of 90

Y-ibritumomab tiuxetan

Weight 14.8 MBq (0.4 mCi) 90

Y/kg

≤ 80 kg Dose will be calculated using actual body weight

>80 kg 1184 MBq (32 mCi) Maximum Dose

90Y-ibritumomab tiuxetan will be administered intravenously as a slow intravenous (i.v.) push over 10 minutes. 90Y-ibritumomab tiuxetan may be directly infused by stopping the flow from the i.v. bag and injecting the radiolabeled antibody directly into the line. A 0.22 micron filter must be on line between the patient and the infusion port. Flush the line with at least 10 ml of normal saline after 90Y-ibritumomab tiuxetan has been infused. One week after the radioimmunotherapy has been performed, the BEAM high-dose regimen is started for patients who achieved a PR or CRu following induction chemotherapy. Patients in CR proceed directly to BEAM or BEAC without 90Y-ibritumomab tiuxetan.

36

Appendix 9

Tumor-dosimetry This procedure will be performed at the discretion of the study centre in Oslo and possibly a few more centres for an estimated number of 5-10 patients.

111In-ibritumomab tiuxetan administration

185 MBq (5mCi) of 111In-ibritumomab tiuxetan will be used for radioimaging. The imaging dose of 111In-ibritumomab tiuxetan will be administered by a 10 minute slow IV push injection. 111In-ibritumomab tiuxetan may be directly infused by stopping the flow from the IV bag and injecting the radiolabeled antibody directly into the line. A 0.22 micron filter must be on line between the patient and the infusion port. Flush the line with at least 10 ml of normal saline after 111In-ibritumomab tiuxetan has been infused. Radioimaging schedule In the study tumor dosimetry can be conducted in Oslo and a few other sites for patients prior to receiving 90Y-ibritumomab tiuxetan. We will attempt to perform tumour dosimetry based on gamma-camera and SPECT images performed 4 and 6 days after indium administration. For tumour dosimetry to be possible, CT-images (or a calculated tumour volume) must be available. Details of the method and calculations involved to define tumour up-take of radiolabeled antibody will not be outlined in this protocol.

37

Appendix 10

Protocol: 3.Nordic MCL-study

Pas. name:

Phase II study with high-dose therapy +/- Zevalin for Mantle cell lymphoma

Flow sheet-1

Before therapy

Months Within Within 3 5 6

Weeks 4 2 0 3 6 9 12 15 17 19 20 21 22 25

Date

Medical history x x x x x x x x x x x x x X

Adverse events x x x x x x x x x x x X

Physical examination x x x x x x x x x x x x X

Hgb. Leuk with diff Tromb. x x x x x x x x x x x x X

Creat. ASAT, ALAT, ALP, LD

Bilir. Albumin,

x x x x x x x x x x x x X

Pregnancy test (fertile women) x

CT collum, thorax, abdomen,

pelvis with contrast

x X1

PET-scan X2 X2

Bone marrow biopsy x x

Bone marrow and blood flow

cytometry

x x

Bone marrow and blood for

molecular biol

x x

Serum for freezing x

Lymphoma tissue fixed and

frozen

X

Maxi-CHOP + Rituximab X3 x x

Ara-C + Rituximab x x X4

Harvest of peripheral stem cells X

111In-ibritumomab tiuxetan for

dosimetry

X5

Rituximab alone X6 x

90Y-inbritumomab tiuxetan for

therapy

X7

BEAM/BEAC high-dose regimen X8

Reinfusion of autologous stem

cells

x

Therapy completed X

1 CT of areas involved with lymphoma prior to therapy.

2 PET-scan is recommended before start of therapy and obligatory at 15 weeks evaluation when PR or CRu.

3 No Rituximab at first cycle of maxi-CHOP

4 Two doses of Rituximab, at days 1 and 9 respectively

5 Only for patients in CRu/PR receiving Zevalin at designated centres, if desirable

6 Only for pts receiving Zevalin

7 Only pts in CRu or PR receive Rituximab at weeks 19 and 20 and Zevalin at week 20

8 Pts in CR (no Zevalin) can start BEAM/BEAC in week 19

38

Protocol: 3.Nordic MCL-study

Pas. name:

Phase II study with high-dose therapy +/- Zevalin for Mantle cell lymphoma

Flow sheet-2

Months after stem cells

reinfused

3 6 9 12 15 18 21 24 30 36 42 48 54 60

Date

Medical history x x x x x x x x x x x x x X

Physical examination x x x x x x x x x x x x x X

Hgb. Leuk with diff Tromb. x x x x x x x x x x x x x X

Creat. ASAT, ALAT, ALP, LD Bilir.

Albumin,

x x x x x x x x x x x x x X

CT collum, thorax, abdomen, pelvis

with contrast1

x x x x x x x x x x X

PET-scan2 x

Bone marrow biopsy3 x x x x x x x x x x X

Bone marrow and blood flow

cytometry

x x x x x x x x x X

Bone marrow and blood for

molecular biol (Copenhagen)

x x x x x x x x x x X

1 CT of areas involved with lymphoma before start of therapy 2 PET/CT optional, but recommended for patients in PR/CRu with pos PET pre-transplant 3 Bone marrow biopsy only at 3 months and when involved with lymphoma last time analysed

39

ix8

Inclusion

Maxi - CHOP

Ara – C + Rituximab

Maxi – CHOP + Rituximab

Ara – C + Rituximab

Maxi – CHOP + Rituximab

Evaluation

PR/CRu

SD/PD

Ara – C + Rituximab x 2

Harvest stem cells

Zevalin

BEAM

Stem Cells

Follow up

Rituximab x 4 when PCR/flow +

BM

Off study

Follow up

CR

Ara – C + Rituximab x 2

Harvest stem cells

No Zevalin

BEAM

Stem Cells

Follow up

Rituximab x 4 when PCR/flow +

BM

Follow up

40

Appendix 11

Nordic Mantel Cell Lymphoma Protocol III Ordering form Zevalin, Ytracis and indium Valid for Denmark, Norway and Sweden

Instructions: Please, send this form by e-mail to: order.ytracis@schering.de

Norway: fill in this form, but please also inform IFE Fax: +4763803021

You will get order confirmation on the Thursday the week before planned injection.

Deadline: 10 days before planned injection

For questions, please call logistics manager at Schering Nordiska tel: +46 8 728 42 36

Investigator:

Patient number: Patient initials:

Required number of Zevalin (ibritumomab tiuxetan) kits:

2 kits if dosimetry, 1 kit if no dosimetry

Indium for dosimetry (370 MBq): Yes/no:

If yes, planned date of injection: dd/mm/yyyy

Ytracis (yttrium) for treatment (1850 MBq): Yes/no:

Planned date of injection: dd/mm/yyyy

Delivery address for Zevalin:

Pharmacy address:

Contact person: Phone no:

Delivery address for isotopes: (In Norway this is IFE)

Contact person: Phone no:

Customer address for isotopes: (if not the same as delivery address)

Contact person: Phone no:

Order sent by:

SCHERING NORDISKA AB

41

Nordic Mantel Cell Lymphoma Protocol III Ordering form Zevalin and Ytracis Valid for Finland

Instructions: To order Zevalin, please send this form by e-mail to: order.ytracis@schering.fi

To order Ytracis, please send this form by e-mail to orders@mapmedical.fi

You will get order confirmation on the Thursday the week before planned injection.

Deadline: 10 days before planned injection

For Zevalin questions, please call product manager for Zevalin, tel: +35897088372 or logistics coordinator tel: +35897088354 For Ytracis questions, please call MAP Medical Technologies Oy, tel: +358143345212

Investigator: Patient number: Patient initials:

Required number of Zevalin (ibritumomab tiuxetan) kits:

Ytracis (yttrium) for treatment, 1850 MBq:

Planned date of injection: dd/mm/yyyy

Delivery address for Zevalin:

Pharmacy address: Contact person: Phone no:

Delivery address for isotopes:

Contact person: Phone no:

Order sent by:

SCHERING OY +3589708811

42

Appendix 12. Drug ordering and delivery

Please use the correct ordering form (appendix 11) to mail the order to Schering 10 days or

more before planned treatment with 90

Y-labeled ibritumomab tiuxetan. The Zevalin kit will

arrive in time at the Pharmacy and Yttrium will arrive on Wednesday afternoon, the day

before treatment. In case of planned dosimetry with 111

In-labeled ibritumomab tiuxetan,

the order should be placed 10 days or more before the dosimetric dose of Indium, which

will arrive on Wednesday afternoon the day before this. Two Zevalin kits should be

ordered when dosimetry is planned.

Treatment with 90

Y-labeled ibritumomab tiuxetan should allways be planned done on

Thursday or Friday.

By e-mail

Investigator fills in the ordering form

Schering OY

MAP

Schering Nordiska

AB

Indium – Mallincrodt, Stockholm Amersham, Oslo

Zevalin – KD, Göteborg

Ytracis – CIS Bio, France

Local pharmacy

Dept of Nucl Med

Dept of Nucl Med

Local pharmacy

Dept of Nucl Med

Dept of Nucl Med

Wednesday 12:00 at the latest

Thursday Wednesday pm

Wednesday pm

7 days 7 days

Indium – Not applicable

Zevalin – Tamro, Helsinki

Ytracis – CIS Bio, France

43

Appendix 13 – Participating centres numbered Norway

01 Department of Oncology, The Norwegian Radium Hospital, N-0310, Oslo, Norway Arne Kolstad, Grete Fossum Lauritzsen. E-mail: arne.kolstad@radiumhospitalet.no/akolstad@stanford.edu 02 Department of Oncology, Ulleval University Hospital, Oslo, Norway Bjørn Østenstad E-mail: bjorn.ostenstad@ulleval.no 03 Department of Oncology, Haukeland University Hospital, N-5021 Bergen, Norway Øystein Fluge, Roald Ekanger Email: oystein.fluge@helse-bergen.no 04 Department of Oncology, St. Olavs University Hospital, Trondheim, Norway. Unn-Merethe Fagerli, Ragnar Telhaug E-mail: unn.merete.fagerli@stolav.no 05 Department of Oncology, University Hospital of Tromsø, N-9038 Tromsø, Norway. Martin Maisenhølder E-mail: martin.maisenholder@unn.no 06 Department of Haematology and Oncology, University Hospital of Stavanger, N-4068 Stavanger, Norway. Peter Meyer, Sverre Galdal E-mail: mepe@sus.no Sweden

07 Department of Oncology, Uppsala University Hospital, SE 751 85 Uppsala, Sweden. Anna Laurell, Gunilla Enblad. E-mail: anna.laurell@akademiska.se 08 Department of Oncology, University Hospital of Linköping, SE 581 85 Linköping, Sweden Annika Håkansson, Anders Rådlund. E-mail: annika.hakansson@lio.se 09 Department og Hematology, Karolinska University Hospital, SE 171 76 Stockholm, Sweden Marie Nordström, Eva Kimby, Per Ljungman. E-mail: marie.nordstrom@karolinska.se

44

10 Department of Oncology, University Hospital of Norrland, SE 981 85 Umeå, Sweden Beatrice Malmer, Göran Edbom, Martin Erlanson. E-mail: beatrice.malmer@onkologi.umu.se 11 Department of Haematology, Sahlgrenska University Hospital, SE 412 45 Göteborg, Sweden Herman Nilsson-Ehle, Dick Stockelberg. E-mail: herman.n-ehle@vgregion.se 12 Department of Oncology, Central Hospital of Karlstad, SE 651 85 Karlstad, Sweden Lena Malmberg, Sten-Åke Lindahl. E-mail: lena.malmberg@liv.se 13 Department of Oncology, Lund University Hospital, SE 75185 Lund, Sweden Mats Jerkeman, Carsten Rose, Ola Linden. E-mail: mats.jerkeman@onk.lu.se 14 Department of Oncology, University Hospital of Malmö, SE 214 20 Malmö, Sweden Kristina Arnljots, Carina Nordquist, Anders Lindblom. E-mail: kristina.arnljots@skane.se 15 Department of Oncology, University Hospital of Örebro, SE 701 85 Örebro, Sweden Lars Andreasson, Martin Helsing, Ørjan Jerlstrøm. E-mail: lars.andreasson@orebroll.se

16 Department of Hematologym, Kärnsjukhuset i Skövde, SE 541 85, Skövde, Sweden Jaan Vaart E-mail: jaan.vaart@vgregion.se 17 Lidköping Hospital, SE 531 85 Lidköping, Sweden Martin Hjort E-mail: martin.hjort@vgregion.se 18 Department of Hematology, Medisinklinikken Borås, SE 50 182, Sweden Hans Back E-mail: hans.back@vgregion.se Finland

19 Department of Haematology, Helsinki University Hospital, 00029 Helsinki, Finland Erkki Elonen E-mail: erkki.elonen@hus.fi 20 Department of Medicine, Kuopio University Hospital, 50211 Kuopio, Finland Esa Jantunen

45

E-mail: esa.jantunen@kuh.fi 21 Department of Oncology, Oulu University Hospital, 90029 OYS, Finland Outi Kuittinen E-mail: outi.kuittinen@ppshp.fi 22 Department of Oncology, Tampere University Hospital, 33521 Tampere, Finland Tuula Lehtinen E-mail: tulla.lehtinen@pshp.fi 23 Department of Oncology and Radiotherapy, Turku University Central Hospital, 20521 Turku, Finland Sirkku Jyrkkiö E-mail: sirkku.jyrkkio@tyks.fi Denmark

24 Department of Haematology L4042, Finsen Center, DK-2100, Copenhagen, Denmark Christian Geisler, Peter Brown E-mail: christian.geisler@rh.hosp.dk 25 Department of Haematology, Herlev University Hospital, DK 2730 Herlev, Denmark Per Boye Hansen E-mail: peboha01@herlevhosp.kbhamt.dk 26 Department of Haematology, Århus University Hospital, DK 8000 Århus, Denmark Anne Marie Boesen E-mail: anne.boesen@aas.auh.dk 27 Department of Haematology, Aalborg University Hospital, Aalborg, Denmark Georg Thorsell, Ilse Christiansen E-mail: aas.ku2e@nja.dk 28 Odense University Hospital, DK 5000 Odense C, Denmark Dorte Gillstroem E-mail: dorte.balle.gillstroem@ouh.fyns-amt.dk

46

Appendix 14

Amendment 1 – September 2005.

A. Dosimetry with Indium-111 Ibritumomab Tiuxetan. Dosimetry was originally planned for the first 10 patients included in the study and receiving Zevalin. This is now changed and dosimetry is optional and can be done in a limited number of patients treated in Oslo and eventually a few other sites. The protocol and patent information has been adjusted according to this.

B. SAE reporting Haematologic toxicity leading to days in hospital with neutropenic fever or other problems related to low blood counts is an expected consequence of this line of treatment. SAE-reports should not be sent when such problems occur, but rather in the case of hospitalization for other serious unexpected events. The protocol has been adjusted accordingly.

Amendment 2 – January 2006.

A. PET-scan The members of the Mantle cell lymphoma group of the Nordic Lymphoma Group has decided that a PET-scan should be performed in patients who are in PR or CRu at evaluation after induction therapy. It is also recommended to do a PET-scan before initiation of therapy and in case of positive PET at evaluation, this is recommended to be repeated three months after transplant. The protocol and patient information has been adjusted.

B. Work-sheets for Indium and Yttrium labelling. Standard work-sheets for labelling of anti-CD20 monoclonal antibody with isotopes has been developed and included in the protocol as appendixes.

Amendment 3 – February 2007

A. Reporting adverse events Reason for change: The existing protocol text (section 12) is not consistent with EU legislation (1). The purpose of the amendment is to bring the protocol in accordance to the revised guidance, section 4.2. Sponsor’s responsibilities, ensuring that sponsor is notified of all SAE in order to assess the unexpectedness and/or to recognize new patterns of side-effects not previously reported.

Proposed new text: 12. Reporting serious adverse events (p15)

All serious adverse events (SAE) occurring during the treatment period and until the end of the

last treatment administration will be reported in the serious adverse event form (CRF 12). SAE

are defined as any undesirable experience occurring to a patient, whether or not considered

related to the treatment. Adverse events are considered serious when they result in:

47

- Death

- Life threatening event

- Unplanned or prolonged hospitalisation*

- Severe/permanent disability

- A congenital anomaly

* Except for hospitalisation caused by neutropenia, thrombopenia and fever, which is considered to be expected haematological toxicity.

Serious adverse events related to the investigational drug, Zevalin, can be defined as SUSAR

(serious unexpected adverse reaction) or SAR (serious adverse reaction). A SUSAR is not

consistent with information in the relevant source documents. All other treatments given in the

protocol are considered standard of care for mantle cell lymphoma. Both the investigator who

reports the SAE and sponsor (Arne Kolstad) must assess whether a SAE is a SUSAR or SAR.

Events that are considered to be SUSAR or SAR by one or both of, it must be reported to the

authorities as such. SAEs related to the standard therapies of the protocol and other events not

considered as SUSAR or SAR should only be included in sponsor’s summary SAE reports to the

authorities in the participating countries.

During the protocol treatment all SAE’s must be reported by the investigator to the sponsor

(Arne Kolstad) at The Norwegian Radium Hospital by e-mail or by fax without delay and within

24 hours after the initial observation of the event. All details should be documented on the

Serious Adverse Event Form(CRF 12).

At any time after the completion of protocol treatment, all SAEs must also be reported to the

sponsor using the same procedure. An evaluation is made by the investigator and sponsor

whether this is a SUSAR (for those who received Zevalin) and has to be reported to the NMA and

EC.

In case of SUSAR the sponsor is responsible for reporting to the national authorities according

to local legislation, and for notifying principal investigators, the clinical research office at the

Norwegian Radium Hospital, Schering and the principal investigators in his country within 7

calender days (15 days for a non-fatal non-life-threatening event) of being aware of the event. A

follow-up report should be sent within an additional 8 days. Summary reports including all

SUSARs and SARs should be sent by the sponsor to the authorities in all participating countries

at regular intervals, according to the local legislation. Once a year the sponsor is responsible for

sending a complete list of all SUSARs, SARs and SAEs in the study, together with a safety report

to the national medical agencies and ethics comities in all the participating countries, the

clinical research office, all investigators and Schering.

The following definitions will be applied to make the assessment of causality between the event

and the study treatment:

RELATIONSHIP DESCRIPTION

UNRELATED There is no evidence of any causal relationship

UNLIKELY There is little evidence to suggest 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).

48

POSSIBLE There is some evidence to suggest a causal relationship (e.g. the event

occurred 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 patient’s 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 ASSESSABLE There is insufficient or incomplete evidence to make a clinical judgement of

the causal relationship.

References:

1. Detailed guidance in the collection, verification and presentation of adverse reaction

reports arising from clinical trials on medicinal products for human use. European

Commission, revision 2, April 2006.

B. Analysis of the stem cell product for minimal

residual disease Reason for change: by a mistake the analysis performed of the stem cell products to identify minimal residual disease by molecular methods was not described in the protocol. This has now been added in section 10 of the protocol as shown below:

10b. Tests performed at stem-cell harvest:

Samples must be secured in the blood bank for later MRD analysis in Copenhagen (appendix 3).

Samples from each harvest day or pooled samples will be shipped to Copenhagen at a later time

point agreed upon by the investigator and the Molecular Lab. in Copenhagen

C. Change in the patient information

Reason for change: The patient information is not complete in regards to possible negatie

effects of the monoclonal antibody rituximab. This treatment is used in combination with

chemotherapy prior to transplant and to treat patients who develop signs of molecular

relapse after transplant. Rituximab is in general very well tolerated. However, rare cases of

neutropenia, hypogammaglobulinemia and infectious problems have been described, and

we would like to specify this in the patient information.

This has now been included in the patient information