randomized phase ii trial on primary chemotherapy … · ielsg 32 protocol – version 1.2 – may...

INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP

RANDOMIZED PHASE II TRIAL ON PRIMARY CHEMOTHERAPY WITH HIGH-DOSE METHOTREXATE AND HIGH-DOSE CYTARABINE WITH OR WITHOUT THIOTEPA, AND WITH OR WITHOUT RITUXIMAB, FOLLOWED BY BRAIN IRRADIATION vs. HIGH-DOSE CHEMOTHERAPY SUPPORTED BY AUTOLOGOUS STEM CELLS TRANSPLANTATION FOR IMMUNOCOMPETENT PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA EudraCT number 2009-012432-32

STUDY CHAIRMEN

Andrés J. M. Ferreri Unit of Lymphoid Malignancies Department of Oncology San Raffaele H Scientific Institute, Milan, Italy E-mail [email protected]

Gerald Illerhaus Department of Hematology and Oncology University Medical Center, Freiburg, Germany E-mail [email protected]

CO-CHAIRMEN

Michele Reni, Milan, Italy Juergen Finke, Freiburg, Germany Emanuele Zucca, Franco Cavalli, Bellinzona Switzerland

DATA MANAGEMENT

Elena Porro, Cristina Morinini IELSG Studies Coordination IOSI, Ospedale San Giovanni CH 6500 Bellinzona, Switzerland Phone 0041 91 811 9040 Fax 0041 91 811 9182 E-mail [email protected]

Version 1.2 May 26, 2009

PATHOLOGY REVIEW PANEL CHAIR

Maurilio Ponzoni Unit of Lymphoid Malignancies Pathology Unit San Raffaele H Scientific Institute, Milan, Italy E-mail [email protected]

Martina Deckert Department of Neuropathology University of Cologne, Germany E-mail [email protected]

RADIOLOGY REVIEW

Andrea Falini Department of Neuroradiology San Raffaele H Scientific Institute, Milan, Italy Phone 0039 02 2643 2213 E-mail [email protected]

NEUROPSYCHOLOGIST

Monica Falautano Psychology Unit, Department of Neurology San Raffaele H Scientific Institute, Milan, Italy Phone 0039 02 2643 2870 Fax 0039 02 2643 2946 E-mail [email protected]

STATISTICIAN

Valter Torri Istituto di Ricerche Farmacologiche Mario Negri Milan, Italy E-mail [email protected]

IELSG 32 PROTOCOL – Version 1.2 – May 26, 2009 page 2 / 34

TABLE OF CONTENT

1. BACKGROUND AND INTRODUCTION .......................................................................................................4 1.1 BACKGROUND ...........................................................................................................................................4 1.2 DRUGS ..................................................................................................................................................... 5 1.2.1 Methotrexate ............................................................................................................................................5 1.2.2 Cytarabine ................................................................................................................................................6 1.2.3 Rituximab .................................................................................................................................................6 1.2.4 Thiotepa ...................................................................................................................................................6 1.2.5 Carmustine (BCNU) ..................................................................................................................................7 1.3 RATIONALE ................................................................................................................................................7

2. OBJECTIVES OF THE TRIAL ...................................................................................................................... 8 2.1 GENERAL OBJECTIVES ..................................................................................................................................8 2.2 END POINTS ...............................................................................................................................................8 2.2.1 Primary endpoint at first randomization .....................................................................................................8 2.2.2 Primary endpoint at second randomization ................................................................................................8 2.2.3 Secondary endpoints .................................................................................................................................8

3 TRIAL DESIGN ......................................................................................................................................... 9 3.1 STUDY FLOWCHART ....................................................................................................................................9 3.2 DURATION OF THE STUDY...........................................................................................................................10

4 PATIENT SELECTION CRITERIA ...............................................................................................................10 4.1 TARGET POPULATION.................................................................................................................................10 4.2 INCLUSION CRITERIA .................................................................................................................................10 4.3 EXCLUSION CRITERIA .................................................................................................................................11

5 STAGING WORK-UP AND PRE-TREATMENT TEST ..................................................................................11

6 REGISTRATION AND RANDOMIZATION PROCEDURE .............................................................................12 6.1 FIRST RANDOMIZATION AND STRATIFICATION ..............................................................................................12 6.2 SECOND RANDOMIZATION AND STRATIFICATION .........................................................................................12

7 PRIMARY CHEMOTHERAPY ...................................................................................................................13 7.1 CHEMOTHERAPY REGIMENS (First randomization) .........................................................................................13 7.2 LEUKAPHERESIS AND CRYOPRESERVATION ..................................................................................................13 7.2.1 Patients with insufficient stem cell harvest ...............................................................................................13 7.3 DRUG SUPPLY ..........................................................................................................................................13

8 CONSOLIDATION THERAPY (Second randimization) ................................................................................14

9 TOXICITY ...............................................................................................................................................14 9.1 EVALUATION OF TOXICITY...........................................................................................................................14 9.2 EXPECTED TOXICITY ...................................................................................................................................14 9.2.1 Expected adverse events with methotrexate ...........................................................................................14 9.2.2 Expected adverse events with cytarabine ................................................................................................14 9.2.3 Expected adverse events with thiotepa ...................................................................................................14 9.2.4 Expected adverse events with carmustine (BCNU) ..................................................................................15 9.2.5 Expected adverse events with Thiotepa ...................................................................................................15 9.3 DOSE MODIFICATIONS ACCORDING TO HEMATOLOGIC TOXICITY......................................................................15 9.4 DOSE MODIFICATIONS ACCORDING TO NON-HEMATOLOGIC TOXICITY .............................................................16 9.5 TREATMENT-RELATED NEUROTOXICITY ........................................................................................................16 9.6 SERIOUS ADVERSE EVENTS (SAE) .................................................................................................................16 9.6.1 Definition of adverse event .....................................................................................................................16 9.6.2 Definition of serious adverse event .........................................................................................................17 9.7 REPORTING OF SERIOUS ADVERSE EVENTS ....................................................................................................17

10 CRITERIA OF EVALUATION .....................................................................................................................17 10.1 ASSESSMENT OF RESPONSE .........................................................................................................................17 10.1.1 General method .....................................................................................................................................17 10.1.2 Whole-brain MRI protocol .......................................................................................................................18 10.1.3 Schedule of response evaluation .............................................................................................................18 10.2 RESPONSE DEFINITION ...............................................................................................................................18 10.2.1 Patients for whom response has not been assessed ...............................................................................18


11 LABORATORY TEST AND FOLLOW-UP ...................................................................................................19 11.1 DURING TREATMENT .................................................................................................................................19 11.2 AFTER THE END OF TREATMENT ..................................................................................................................19 11.3 AFTER PROGRESSION OF THE DISEASE ..........................................................................................................19 11.4 SUMMARY TABLE .....................................................................................................................................19

12 CONCOMITANT TREATMENTS - ANTIMICROBIAL PROPHYLAXIS............................................................20

13 SALVAGE THERAPY AFTER CHEMOTHERAPY ........................................................................................20

14 PREMATURE TREATMENT WITHDRAWAL ..............................................................................................20

15 PATHOLOGY REVIEW ............................................................................................................................21

16 STATISTICAL CONSIDERATIONS .............................................................................................................21 16.1 STATISTICAL DESIGN AND SAMPLE SIZE ....................................................................................................... 21 16.2 ANALYSIS OF OUTCOME ............................................................................................................................21 16.3 DEFINITION OF SURVIVAL ENDPOINTS ..........................................................................................................21 16.4 PRELIMINARY SAFETY ANALYSIS .................................................................................................................22

17 ETHICAL CONSIDERATIONS ...................................................................................................................22 17.1 PATIENT PROTECTION ................................................................................................................................22 17.2 SUBJECT IDENTIFICATION ...........................................................................................................................22 17.3 INFORMED CONSENT .................................................................................................................................22 17.4 CONDITIONS FOR MODIFYING AND TERMINATING THE STUDY .........................................................................22

18 INSURANCE ...........................................................................................................................................23

19 PUBLICATION POLICY ............................................................................................................................23 20 STUDY ACKNOWLEDGEMENT ...............................................................................................................24 21 FORMS AND PROCEDURES FOR COLLECTING DATA .............................................................................25 21.1 CASE REPORT FORMS AND SCHEDULE FOR COMPLETION ................................................................................25 21.2 SHIPMENT FORM FOR PATHOLOGY REVIEW ..................................................................................................25 22 REFERENCES ..........................................................................................................................................26 APPENDIX A ECOG Performance Status ................................................................................................... 28 APPENDIX B Study drug administration .................................................................................................... 29 APPENDIX C Toxicity criteria ..................................................................................................................... 30 APPENDIX D Mini Mental Status Examination (MMSE).............................................................................. 31 APPENDIX E IPCG Neuropsychological tests ..............................................................................................33 APPENDIX F IPCG Response Criteria.........................................................................................................34


1. BACKGROUND AND INTRODUCTION 1.1 BACKGROUND Primary central nervous system lymphomas (PCNSL) are rare aggressive malignancies, representing 4% of intracranial neoplasms and 4-6% of extranodal non-Hodgkin's lymphomas (NHL). The progressive increase of the incidence observed in the last decades and the difficulties in obtaining the same promising results observed in systemic NHL constitute a relevant challenge. Several questions regarding the optimum therapeutic management of PCNSL remain open. Prognosis of PCNSL patients is poor, median survival of untreated patients is 1.5-3.3 months1. Surgical resection has only a diagnostic role, and stereotactic biopsy has progressively replaced other surgical procedures1. Historically, radiotherapy (RT) has been the standard treatment for PCNSL, producing a response rate of 60-97%, a median survival of 14 months, a 5-yr survival of 3-26%, and a significant improvement in neurological symptoms, performace status (PS) and quality of life2. Despite the high complete remission rate, almost all patients treated only with RT relapse after a few months1. Relapse is local in 93% of cases, even within the RT field3. A study of the Radiation Therapy Oncology Group (RTOG) has demonstrated that RT alone is unable to achieve local disease control even with higher radiation doses2. Additionally, hyperfractionation and accelerated RT do not improve survival, while they increase treatment-related toxicity2,4. In spite of the disappointing outcome previously reported with RT as exclusive treatment, this strategy remains a valid alternative for elderly patients with organ dysfunction or patients with poor PS who are ineligible for chemotherapy. The addition of chemotherapy to RT has been recommended to improve survival of PCNSL patients5,6. The superiority of combined strategy is suggested by three large retrospective multicentre surveys reporting therapeutic results in over 1000 patients treated in Europe and Japan7-9. These studies uniformly showed that high-dose methotrexate (≥ 1g/m2; HD-MTX) is the most efficient known cytostatic, while any regimen without HD-MTX is associated with outcomes no better than with RT alone5,6. Although a survival advantage for HD-MTX-based chemotherapy followed by RT has not been fully proven, a randomized trial comparing this strategy to RT alone would likely be unacceptable to the majority of clinicians, and the combined approach should be retained as the first-choice strategy. Several studies attempted to improve outcome by adding other drugs to HD-MTX10. However, at least partially due to their poor blood-brain barrier (BBB) penetration, the most effective drugs against NHL, doxorubicin and cyclophosphamide, are associated with unsatisfactory results11-13. Since the addition of CHOP to HD-MTX produces similar results to HD-MTX alone14,15, while increases toxicity, the CHOP regimen has been abandoned in PCNSL. Recently, the first randomized phase II trial with completed accrual on the primary chemotherapy in PCNSL documented a clear advantage associating high-dose cytarabine (HD-Ara-C) to HD-MTX, if compared to HD-MTX alone16. In fact, ORR rate in the association arm (experimental arm) was 69%, compared to 46% in the single drug arm (control arm); conversely, toxicity in the experimental arm was more relevant (mainly hematological), but not enough to constitute a concrete clinical problem. There are some preliminary evidence in PCNSL literature supporting a role for rituximab, an anti-CD20 hybrid monoclonal antibody useful against different types of B cell lymphomas. In fact, the addition of rituximab to CHOP has significantly improved therapeutic results in patients with diffuse large B-cell lymphoma17, the commonest histological category of PCNSL. However, there are many doubts about the capability of this antibody to cross the BBB and the large French randomized trial comparing CHOP with R-CHOP did not show any role for this drug to prevent CNS dissemination18. An ongoing study of the Eastern Cooperative Oncology Group (ECOG-E1F05, ClinicalTrials.gov identifier: NCT00335140) suggest that rituximab can be active against relapsed PCNSL (T. Batchelor, personal communication), while a prospective phase II trial from the MSKCC demonstrates that the rituximab-methotrexate combination is feasible and active19, but the precise role of rituximab in PCNSL remains to be defined, perhaps in a randomized study. Consolidation after chemotherapy probably represents the best role for RT, although the optimal field and doses have not been identified5,6. Since PCNSL is often multifocal, the target for RT is the whole brain, whereas the added value of the “tumour-bed boost” is questionable2. The inclusion of the posterior two-thirds of the orbits into the radiation field is advisable20. The radiation dose should be decided on the basis of response to primary chemotherapy, and, until definitive conclusions from well-designed trials are available, RT parameters should follow the widely accepted principles used for other aggressive NHL. Doses of 36-45 Gy or 36 Gy are advisable respectively in patients with or without residual disease after primary chemotherapy5,6.


The combined chemoradiation therapy is associated with relevant risk of severe neurotoxicity, which as disabling as the lymphoma itself and associated with a 30% of related mortality. Some authors suggested to avoid consolidation with whole-brain radiotherapy (WBRT), mostly in elderly patients, with the aim to minimize this risk, however, formal studies confirming the value of this strategy have not been reported. Some investigators proposed to replace WBRT with other strategies as consolidation treatment. High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is one of these proposed strategies. In a multicenter French trial, patients with PCNSL relapsed after first-line treatment with a HD-MTX-containing regimen have been treated with intensive chemotherapy followed by ASCT. Twenty-six of 27 patients who completed the planned treatment achieved a CR. With a median follow-up of 36 months, the median overall survival was 18.3 months in the overall population, and 58.6 months among transplanted patients21. Similar strategies have been used as part of front-line treatment in PCNSL patients with encouraging results, mostly when thiotepa-based conditioning regimens have been used22. The addition of WBRT after a sequential HD-MTX and HDaraC + thiotepa induction followed by high-dose BCNU/thiotepa and ASCT has been associated with a high incidence of severe neurotoxicity22-24. As a consequence, a German Group proposed to avoid consolidation WBRT in patients in CR after ASCT to reduce this severe complication, obtaining encouraging results that deserve further investigation23. Benefit and side effects of these consolidative strategies, that is conventional WBRT and high-dose chemotherapy supported by ASCT, deserve to be compared in a randomized trial to draw definitive conclusions on the role of consolidation both on efficacy and neurotoxicity in patients with newly diagnosed PCNSL. 1.2 DRUGS 1.2.1 Methotrexate (MTX) MTX functions as an antimetabolite by reversibly inhibiting dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. The most favourable administration schedule for MTX in PCNSL remains to be defined, due to the wide range of different doses (1-8.4 g/m2) used in prospective trials and to its frequent association with different drugs and/or RT. The timing of MTX administration has been analysed in a single small series and no significant difference in terms of survival or toxicity was observed between the administration of 3.5 g/m2 every 3 weeks or every 10 days25. MTX enters the cells in part by an active transport mechanism and is bound as polyglutamate conjugates. During longer periods of drug exposure, a higher polyglutamate formation rate is observed and more cells enter into phase S, resulting in an increased cytotoxicity. In a study comparing 3- vs. 6-hour infusions of MTX, the former was significantly associated with a higher response rate and increased CSF levels, while no difference in survival was observed26. The optimal MTX schedule seems to be an initial rapid administration to overcome the distribution phase of clearance followed by a 3-hour infusion for doses ≤ 5 g/m2. Patients with renal or hepatic insufficiency require a reduced MTX dose. Peak serum levels occur within 30 to 60 min with parenteral doses; maximal myelosuppression occurs within 7 to 10 days; duration of tumor response and hematopoietic effects is 7 to 14 days; protein binding is 50%; cerebrospinal fluid concentrations are 1% of the simultaneous serum concentration; volume of distribution is 0.4 to 0.9 L/kg; elimination half-life is 8 to 15 h; minimal hepatic metabolism is followed with 48% to 100% excreted unchanged in the urine and 9% in the feces. Adverse effects include leukopenia, thrombocytopenia, anemia, pancytopenia, vasculitis, neurotoxicity, headache, fever, paraplegia, cerebellar dysfunction, cranial nerve palsies, seizures, dementia, ataxia, drowsiness, paresis, colitis, toxic megacolon, gingivitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal bleeding, stomatitis, pseudomembranous colitis, nephrotoxicity, cystitis, menstrual dysfunction, oligospermia, infertility, hepatotoxicity, conjunctivitis, blurred vision, interstitial pneumonitis, alopecia, rash, toxic epidermal necrolysis, phototoxicity, systemic lupus erythematosus, and hypersensitivity with anaphylaxis. In addition, MTX has been associated with tumor lysis syndrome and potentially life-threatening or fatal opportunistic infections. MTX is an effective antineoplastic agent against a variety of cancers, such as breast cancer, acute lymphoblastic leukemia, osteogenic sarcoma, head and neck cancer, ovarian cancer, non-Hodgkin's lymphoma, colorectal carcinoma, and Hodgkin's lymphoma. In addition, the drug is used extensively for severe cases of recalcitrant psoriasis, severe rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease; however, due to potential toxicity, it should be used with caution in these patients.


1.2.2 Cytarabine (Ara-C) Ara-C is a synthetic antimetabolite that is cell-cycle specific. Ara-C is cytotoxic primarily to cells in the S-phase. High-dose therapy consists of 1-3 gr/m2 every 12 hours. Following IV administration, Ara-C is widely distributed to areas including the CNS and tears. Ara-C is metabolized in the liver to an inactive metabolite; both Ara-C and its metabolite are excreted in the urine. The elimination half-life is between 1 and 3 hours. The major toxic effect of Ara-C is myelosuppression resulting in megaloblastic changes in erythropoiesis and reticulocytopenia. Other adverse effects include neuropathies, GI distress, hepatic toxicity, and hypersensitivity. Ara-C is useful in various neoplastic disorders including chronic myelocytic leukemia, lymphoblastic leukemia, acute lymphocytic leukemia, acute non-lymphocytic leukemia, meningeal leukemia, and non-Hodgkin’s lymphomas. Other disease states in which Ara-C has been used include herpes virus infections and psoriasis. AraC has been used in different combinations with HD-MTX in the treatment of PCNSL, mostly encouraging results. The clinical benefit of the addition of HD-araC to HD-MTX has been suggested by a large retrospective series7 and a meta-analysis of 19 prospective trials27 and was recently confirmed by the first worldwide randomized trial with complete accrual in PCNSL16. As main conclusion from that trial, the combination of HD-MTX and HD-araC could be used as control arm for future randomized trials assessing new chemotherapy combinations for newly diagnosed PCNSL. 1.2.3 Rituximab Rituximab is a chimeric monoclonal antibody directed against the B-lymphocyte antigen CD20. This antibody has been largely used in the treatment of B-cell lymphomas with excellent results. In particular, the addition of rituximab to CHOP chemotherapy regimen has been associated with a significantly improvement in outcome in patients with diffuse large B-cell lymphomas17. This is a relevant aspect considering that this lymphoma category constitutes the most common histological form of PCNSL6. Nevertheless, rituximab has been only anecdotally used in PCNSL patients considering that there are many doubts about its capability to cross the BBB. Feasibility of a combination of HD-MTX and rituximab has been demonstrated in a prospective series19, but its real contribution in the management of PCNSL remains to be defined. Rituximab is usually a well tolerated agent, with some forms of infusion-related reactivons (rush, broncospasm, allergic processes, fever, hypotension). Severe events are rare and could be related to a high tumor burden, and, with the single exception of intravascular large B-cell lymphoma28, they have not been reported in lymphoma patients with CNS involvement. 1.2.4 Thiotepa Thiotepa is a cytotoxic agent of the polyfunctional alkylating type (more than one reactive ethylenimine group), related chemically and pharmacologically to nitrogen mustard. Its radiomimetic action is believed to occur through the release of ethylenimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines. Thiotepa has been tried with varying results in the palliation of a wide variety of neoplastic diseases. However, the most consistent results have been seen in the following tumors: adenocarcinoma of the breast and ovary; for controlling intracavitary effusions secondary to neoplastic diseases of various serosal cavities; for the treatment of superficial papillary carcinoma of the urinary bladder. Some efficacy has been proved for Hodgkin’s disease and other lymphomas. Thiotepa is highly toxic to the hematopoietic system, and bone-marrow depression has to be expected. Weekly blood and platelet counts are recommended during therapy and for at least 3 weeks after therapy has been discontinued. Other adverse effects include: fatigue, weakness, allergic reactions, nausea, vomiting, abdominal pain, anorexia, dysuria, urinary retention, dizziness, headache, blurred vision, dermatitis, alopecia, amenorrhea, interference with spermatogenesis. Thiotepa is capable of cross-linking the DNA within a cell and changing its nature. The replication of the cell is, therefore, altered, and thiotepa may be described as mutagenic. Effective contraception should be used during thiotepa therapy if either the patient or the partner is of childbearing potential. In patients treated with thiotepa, cases of myelodysplastic syndromes and acute nonlymphocytic leukemia have been reported. There is no known antidote for overdosage with thiotepa. A single-arm phase II trail assessing the chemotherapy combination named “MATILDE” included thiotepa29. This combination has been associated with an ORR of 72% and a CRR of 46%, with a 5-yr OS of 42% and a persistent plateau in the survival curve. Thiotepa has been used in combination with other alkylating agents as conditioning regimens for ASCT in patients with PCNSL, both at diagnosis or relapse21-23.


1.2.5 Carmustine (BCNU) Carmustine is an alkylating agent that belongs to the Nitrosoureas group. These agents act by the process of alkylation to inhibit DNA repair. The nitrosoureas can cross the blood-brain barrier and are therefore used to treat brain tumors. BCNU is also effective as a single agent against lymphomas and Hodgkin’s disease. Bone marrow suppression, notably thrombocytopenia and leukopenia, is the most common and severe toxic effect of BCNU. Myelosuppression appears later (14-28 days) and last longer (up to 6-8 weeks) than most other cytotoxic drugs. Other less frequent adverse side-effects are nausea, vomiting, diarrhea, pulmonary fibrosis, skin flashing, amenorrhea and interference with spermatogenesis. Secondary carcinogenesis has occasionally been reported, as well as secondary acute myeloid leukemias. This drug has been largely used in primary brain tumors, and, importantly, in PCNSL, both at conventional doses30 and as part of conditioning regimens before ASCT22,23. 1.3 RATIONALE Primary chemotherapy constitutes the main unsolved problem in PCNSL management. Systemic HD-MTX (MTX ≥ 1 g/m2) seems to be the most effective drug in PCNSL6. However, this drug produces comprehensively a 5-yr survival of <25% in PCNSL patients. Recently a randomized trial documented a clear advantage in response rate and overall survival with the association of HD-MTX and HD-Ara-C16. Therefore, this HD-MTX + HD-Ara-C combination followed by consolidation WBRT should be consider as the control arm for future randomized trials on newly diagnosed PCNSL. Because of the intense myelotoxicity a pilot trial with lower Ara-C dose (from 2 to 1g/m2) was conducted at the S. Raffaele Hospital in Milan, but it showed a significantly inferior activity (Andrés Ferreri, unpublished results). The use of thiotepa seems justified by its activity in systemic aggressive lymphomas and in recently reported trials on PCNSL29,31, by its different antineoplastic mechanism if compared with MTX and Ara-C and, finally, by its radiomimetic activity. Added toxicity, mainly haematological and mainly due to cytarabine has to be taken into account. The addition of rituximab, even if with some doubts about the capability of this drug to cross the BBB, could result in an increased disease control since its activity against diffuse large B-cell lymphomas. This could be more evident in the first treatment courses, when the BBB is evidently altered by the presence of infiltrating lymphoma. Thus, the addition of rituximab as upfront strategy and its use in combination with other cytostatics deserves to be addressed in a randomized trial in comparison with HD-MTX-HD-araC conventional combination. The efficacy of WBRT, a well established consolidation therapy considered to be the up-to-date standard, deserves to be compared with more aggressive strategies, including HD-chemotherapy with ablative intention (BCNU + Thiotepa) and ASCT rescue, in order to obtain an improved overall survival and an ameliorated progression free survival (2-yr follow-up). Moreover, the replacement of WBRT with HD-chemotherapy supported by ASCT as consolidation treatment after primary HD-MTX-based chemotherapy could result in significant reduction of iatrogenic neurotoxicity, with the preservation of a valid strategy, like WBRT, as salvage therapy in the case of disease relapse.


2. OBJECTIVES OF THE TRIAL 2.1. GENERAL OBJECTIVES The primary endpoint of the study at first randomization is to establish in a prospective, randomized phase II trial, the activity of three different chemotherapy combinations with high-dose methotrexate (HD-MTX) + high-dose cytarabine (HD-araC), HD-MTX + HD-araC + rituximab and HD-MTX + HD-araC + rituximab + thiotepa in patients with newly diagnosed PCNSL. The primary endpoint of the study at second randomization is to establish in a prospective, randomized phase II trial, the efficacy of two consolidation strategies: conventional whole-brain radiotherapy (WBRT) vs. high-dose chemotherapy supported by autologous stem cell transplantation (HDC + ASCT) in patients with newly diagnosed PCNSL. 2.2. END POINTS 2.2.1 Primary endpoint at first randomization The primary endpoint is the complete remission (CR) rate after primary chemotherapy. 2.2.2 Primary endpoint at second randomization The primary endpoint is the 2-year failure-free survival (2-yr FFS). 2.2.3 Secondary endpoints • Toxicity • Overall survival • Relapse rates and patterns • Early and late neurotoxicity


3 TRIAL DESIGN 3.1 STUDY FLOWCHART

This is a multicenter open label randomized phase II trial. Enrolled PCNSL patients will be stratified according to the IELSG score and randomized to receive MTX + Ara-C (Arm A) or MTX + Ara-C + rituximab (Arm B) or MTX + Ara-C + rituximab + thiotepa (Arm C) as primary chemotherapy. Chemotherapy will be administered every three weeks. The maximum number of chemotherapy induction courses will be 4. Patients in SD or better after two courses will receive two more courses of the same primary chemotherapy regimen. Stem-cells harvest will be performed in the three arms after the second course. After 4 courses response assessment will be performed32. Patients who will not achieve SD or better after the 4th course, as well as those who will experience progressive disease (PD) at any time and those who will not achieve a sufficient stem cell harvest, will receive WBRT 36-40 Gy +/- tumor bed boost of 9 Gy. Patients who will achieve SD or better after the 4th course will be stratified according to objective response to primary chemotherapy (CR vs. PR+SD) and to primary chemotherapy regimen (A vs. B vs. C) and randomly allocated to receive WBRT 36 Gy +/- boost 9 Gy (Arm D) or BCNU + Thiotepa + APBSCT (Arm E) as a consolidation therapy.

PCNSL [≤ 65 ys. + PS 0-3] or [66-70 ys. + PS ≤2]

®

®

WBRT 36 Gy ± boost 9 Gy

BCNU 400 mg/m2 d.1 Thiotepa 5 mg/Kg x 2/d; d.2-3

+ APBSCT

4 c. MTX 3.5 g/m2 d.1 araC 2 g/m2 x 2/d, d. 2-3 every 3 weeks

4 c. rituximab 375 mg/m2 d-5 & 0 MTX 3.5 g/m2 d.1 araC 2 g/m2 x 2/d, d. 2-3 every 3 weeks

4 c. rituximab 375 mg/m2 d-5 & 0 MTX 3.5 g/m2 d.1 araC 2 g/m2 x 2/d, d. 2-3 Thiotepa 30 mg/m2 d.4 every 3 weeks

RESPONSE ASSESSMENT

CR - PR - SD PD – tox insufficient SC

harvest

WBRT 36-40 Gy

± boost 9 Gy


Patients in CR after WBRT or APBSCT will remain in follow-up. Patients who will not achieve a CR after WBRT will be managed according to physician’s preferences. Patients who will not achieve a CR after APBSCT will be referred to WBRT. At the end of the study a Monitoring Committee will review the data concerning the CR rate and the safety profile and will take the decision whether to continue with a phase III trial. In this case, the patients enrolled in the phase II study will be included in the phase III analysis. 3.2 DURATION OF THE STUDY The registration of the patients will last 3 years, with a minimum follow-up period for the last registered patient of two years. 4 PATIENT SELECTION CRITERIA 4.1 TARGET POPULATION Immunocompetent patients with newly diagnosed primary CNS lymphomas of any histological category eligible for high-dose chemotherapy supported by autologous stem cell transplantion. 4.2 INCLUSION CRITERIA To be eligible for inclusion in this trial, patients must fulfill all the following criteria: • Histological or cytological assessed diagnosis of non-Hodgkin's lymphoma. • Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy. • Disease exclusively localized into the central nervous system, CSF, cranial nerves or eyes. • At least one measurable lesion. • Previously untreated patients (previous or ongoing steroid therapy admitted). • Age 18-65 years (with ECOG Performance Status 0-3) or 66-70 (with ECOG Performance Status 0-2). • Adequate bone marrow (PLT ≥ 100000 mm3, Hb ≥ 9 g/dl, ANC ≥ 2.000 mm3), renal (creatinine

clearance ≥ 60 ml/min), cardiac (VEF ≥ 50%), and hepatic function (total serum bilirubin ≤ 3 mg/dL, AST/ALT and γGT ≤ 2 per upper normal limit value).

• Sexually active patients of childbearing potential agreeing in implementing adequate contraceptive measures during study participation.

• Absence of any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

• Patient-signed informed consent obtained before registration.


4.3 EXCLUSION CRITERIA • Patients with lymphomatous lesions outside the CNS. • Patients with a previous non-Hodgkin lymphoma at any time. • Previous or concurrent malignancies with the exception of surgically cured carcinoma in-situ of the

cervix, carcinoma of the skin or other cancers without evidence of disease at least from 5 years. • HBsAg and HCV positivity. • HIV infection, previous organ transplantation or other clinically evident form of immunodeficiency. • Concurrent treatment with other experimental drugs. • Concurrent Pregnancy or lactation. • Patients not agreeing to take adequate contraceptive measures during the study. • Symptomatic coronary artery disease, cardiac arrhythmias uncontrolled with medication or myocardial

infarction within the last 6 months (New York Heart Association Class III or IV heart disease).

5 STAGING WORK-UP AND PRE-TREATMENT TEST Baseline laboratory and imaging evaluations are to be conducted within 2 weeks prior to the administration of a study agent. In the event that the patient’s condition begins to deteriorate, laboratory evaluations should be repeated within 48 hours prior to the initiation of the next therapy cycle. The following examinations must be performed before registration and randomization: • Physical & Neurological examination with ECOG performance status (Appendix A) • Biochemical serum profile (including creatinine clearance and LDH) • HIV, HBV and HCV evaluation • CMV, HHV6-8 and parvovirus markers • Echocardiography with determination of LVEF in % • Respiratory volumes assessment • Thorax and abdomen CT scan • Bone marrow aspirate and biopsy • Whole-brain MRI. • CSF cytology examination (cell count) and physicochemical characterization (including protein

concentration) • Ophthalmologic evaluation (including slit-lamp examination) • 18FDG-PET (optional)


6 REGISTRATION AND RANDOMIZATION PROCEDURE Patients will be centrally registered and simultaneously randomized at the IELSG Coordination and Data Management Office after the verification of the inclusion criteria and prior to the start of treatment. A filled registration/randomization form (see CRFs) should be submitted by fax (or e-mail) on working days to: IELSG Study Coordination and Data Management Office Fax: +41 91 811 91 82 E-mail: [email protected] Patients fulfilling the eligibility criteria will then be randomized and a notification of the allocation arm will be sent back within 24 hours to the investigator. Treatment should start within 15 days from randomization. 6.1 First randomization and stratification The first randomization will be done simultaneously with registration. A stratified randomization will be performed in order to balance the randomization according to the following factors (IELSG score33): Variable Favorable feature

(value 0) Unfavorable feature

(value 1) Age ≤60 years old >60 years old Performance status (ECOG) 0 - 1 2 - 3 LDH serum level Normal increased CSF protein concentration Normal increased Infiltration of deep regions* No yes Risk unfavorable features Low 0 - 1 Intermediate 2 - 3 High 4 - 5 *deep regions of the brain: periventricular area, basal ganglia, brainstem, and/or cerebellum The formal contraindication to perform a diagnostic lumbar puncture and to obtain CSF protein concentration will be considered an unfavorable feature. This score identifies three risk groups according to the presence of 0-1, 2-3 or 4-5 unfavorable prognostic features. Patients will be randomized within these three risk groups. 6.2 Second randomization and stratification The second randomization will be done after 4 courses of chemotherapy and response assessment. Stratification criteria will be the objective response to primary chemotherapy (CR vs. PR or SD) and primary chemotherapy regimen (A arm vs. B arm vs. C arm).


7 PRIMARY CHEMOTHERAPY 7.1 CHEMOTHERAPY REGIMENS (First randomization) Patients registered according to inclusion criteria will be randomized for primary chemotherapy between: Arm A Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3 Arm B Rituximab 375 mg/m2 conventional infusion d -5 & 0 Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3 Arm C Rituximab 375 mg/m2 conventional infusion d -5 & 0 Methotrexate 3.5 g/m2 0.5 g/m2 in 15 min. + 3 g/m2 in 3-hr infusion d 1 Cytarabine 2 g/m2 1 hr infusion, twice a day (every 12 hs.) d 2 - 3 Thiotepa 30 mg/m2 30 min. Infusion d 4 Corticosteroids during treatment and their definitive interruption will depend on clinical requirements. Routine use of G-CSF is recommended. The schedule of drug delivery, all measures of support and the plan of biochemical controls during treatment are explained in Appendix B. 7.2 LEUKAPHERESIS AND CRYOPRESERVATION From day 10 of the second chemotherapy course in all the three arms, absolute CD34+ cell count per µL of blood will be determined every day. The objective is to harvest a minimum of 5 x 106 CD34+ cells/kg of body weight with as few as possible leukapheresis sessions during consecutive days. CD34+ cells will be collected, processed and stored according to conventional guidelines. 7.2.1 Patients with insufficient stem cell harvest Patient with insufficient stem cell harvest will be excluded from the second randomization. They will be treated with RT and considered evaluable for the first randomization endpoints. 7.3 DRUG SUPPLY Methotrexate, cytarabine, rituximab, thiotepa, and BCNU are considered standard treatment; they are commercially available worldwide and will be provided by each participating institute.


8 CONSOLIDATION THERAPY (Second randomization) Patients responsive (CR or PR) or with SD after primary chemotherapy (patient treated either with arm A, B or C according to this protocol) will be randomly assigned to receive: Arm D WBRT with 36 Gy in the case of CR to primary chemotherapy or the same WBRT dose followed by a tumor-bed boost of 9 Gy with 1-2 cm of margin surrounding enhanced residual lesion (total tumor-bed dose 45 Gy) in patients who achieved a PR or SD after primary chemotherapy. Photons of 4-10 Mev, 180 cGy per day, 5 weekly fractions. Whole-brain will be irradiated by two opposite lateral fields including the first two cervical vertebras and the posterior two thirds of the orbits, which must be shielded after 30 Gy (after 36 Gy in the case of evident intraocular disease at diagnosis). Tumor-bed (boost or partial-brain RT) will be irradiated by 2 to 4 isocentric treatment fields based on tumor location, with all portals treated per each RT session. Arm E (Appendix B) BCNU 400 mg/m2 in 500 ml saline sol 1-hr inf. day -6 Thiotepa 5 mg/kg in 250 ml saline sol 2-hr inf. every 12 hrs days -5 & -4 Reinfusion of PBSC ≥5 x 106 CD34+ cells/kg day 0

9 TOXICITY 9.1 EVALUATION OF TOXICITY Treatment side effects will be assessed separately for each course of chemotherapy, and for every consolidation arm. Acute side effects will be graded according to the “Common Toxicity Criteria” defined by the NCI (US) extended by the NCIC (Canada) (See Appendix C). 9.2 EXPECTED TOXICITY 9.2.1 Expected adverse events with methotrexate

The most frequently reported adverse reactions of high dose methotrexate include ulcerative stomatitis, myelosuppression, nausea and vomiting. Acute encephalopathy and toxic nephropathy have been reported, too. 9.2.2 Expected adverse events with cytarabine

The most frequently reported adverse reactions of cytarabine include myelosuppression, febrile neutropenia, thrombocytopenia, bleeding, nausea and vomiting, stomatitis. Cerebellar toxicity has been reported in association with high dose therapy. Conjunctivitis, skin reactions (rash), liver toxicity can occur, too. 9.2.3 Expected adverse events with thiotepa The most frequently reported adverse reactions of thiotepa include myelosuppression, nausea and vomiting. Amenorrhea and interference with spermatogenesis are expected.


9.2.4 Expected adverse events with carmustine (BCNU) The most frequently reported adverse reaction of BCNU include myelosuppression (appears later and lasts longer than most other cytotoxic drugs), thrombocytopenia, fevrile neutropenia, nausea, vomiting, diarrhoea, stomatitis, mucositis, neurological symptoms. Lung fibrosis appears in about 1/3 of patients treated with very high dose of BCNU. Amenorrhea is frequent and interference with spermatogenesis is more than occasional. 9.2.5 Expected adverse events with Thiotepa The most frequently reported adverse reactions of thiotepa include myelosuppression, thrombocytopenia, febrile neutropenia, nausea and vomiting. Amenorrhea and interference with spermatogenesis are expected. 9.3 DOSE MODIFICATIONS OF PRIMARY CHEMOTHERAPY ACCORDING TO

HEMATOLOGIC TOXICITY In case of inadequate bone marrow recovery, that is ANC <1.500/mmc (<1.200/mmc in arm “A”) and <90.000 platelets /mmc, on the intended day of re-treatment, the start of the next cycle could be delayed for a maximum of 2 weeks. Thereafter, chemotherapy has to be discontinued, and patient referred to WBRT 40 Gy plus boost 9 Gy. The dose of cytostatics will be determined according to the nadir neutrophil or platelet counts of the previous course as follows:

Nadir neutrophils/mm3

Arm A dose modifications

Arms B & C dose modifications

Nadir platelets/mm3


Arms B & C dose modifications

> 2.000 Unchanged Unchanged > 125.000 Unchanged Unchanged

1.500-1.599 Unchanged Unchanged 75.000-124.999

Unchanged Unchanged

1.000-1.499 Unchanged Unchanged 50.000-74.999 Unchanged Unchanged

500-999 Unchanged Unchanged 25.000-49.999 Unchanged Unchanged

< 500 25% decrease of Ara-C dose

25% decrease of Ara-C dose

< 25.000 25% decrease of Ara-C dose

25% decrease of Ara-C & thiotepa

doses

Ara-C dose reduction consists of the omission of the 4th dose of the drug (2nd dose of the day 3).


9.4 DOSE MODIFICATIONS ACCORDING TO NON-HEMATOLOGIC TOXICITY For CTC grade 2 or less non-hematological toxicity, no dose reductions will be required. For CTC grade 3-4 non-hematological toxicity, the total dose of drugs to be administered for the next course will be reduced as follows:

Grade 3 Grade 4 Toxicity


Arm B & C dose modifications


Arm B & C dose modifications

Cardiovascular Interruption Interruption Interruption Interruption

Coagulation Unchanged Unchanged 25% decrease for both drugs

25% decrease for MTX, araC & thiotepa

Gastrointestinal Unchanged Unchanged 25% decrease for both drugs


Renal 25% decrease for both drugs


25% decrease for both drugs


Hepatic 25% decrease for both drugs


25% decrease for both drugs


Pulmonary Unchanged Unchanged 25% decrease for both drugs


Rituximab infusion reactions will be managed according to international guidelines. 9.5 TREATMENT-RELATED NEUROTOXICITY Patients will undergo neuropsychological evaluation with Mini Mental Status Examination (Appendix D) and IPCG neuropsychological tests battery 34 with the addition of two tests assessing the language function and pre-morbid intelligence (Appendix E). Neuropsychological evaluation will be performed immediately before to start primary chemotherapy, 30 days after WBRT conclusion (arm D) and autologous transplant (arm E), every six months for the first two years of follow-up, and yearly from the 3rd to the 10th year of follow-up. Neuropsychological scores will be compared to basal scores obtained before to start the treatment. 9.6 SERIOUS ADVERSE EVENTS (SAE) One of the main aims of this trial is to assess the safety and tolerability of the experimental treatments. It is the investigator’s responsibility to record and report all adverse events observed during and after treatment. 9.6.1 Definition of adverse event Patients will be instructed by the investigator to report the occurrence of any adverse event. An adverse event is any undesirable event occurring during the trial, whether or not considered drug related, and includes any side effect, injury, toxicity, or sensitivity reactions. It also includes any undesirable clinical or laboratory change, which does not commonly occur in the patient. An adverse event may occur under therapy and follow-up.


9.6.2 Definition of serious adverse event A serious adverse event includes any event that is: • Fatal: includes all deaths up to 30 days after cessation of treatment. Deaths occurring later are only to

be considered as SAE if they are not related to the tumor. • Life-threatening: means that the patient was at immediate risk of death from the event as it

occurred. It does not include an event that, had it occurred in a more serious form, might have caused death.

• Disabling: includes persistent or relevant disability or incapacity occurring during or after treatment. • Requires inpatient hospitalization: defined as hospital admission required for treatment of the

adverse event. Hospital admission for scheduled elective surgery would not be a serious adverse event.

• Prolonged hospitalization: due to a serious disease not necessarily related to the tumor is also considered as SAE.

• Cancer: any new malignancy other than a relapse of the current tumor. • Congenital anomaly • Important medical events: are those which may not be immediately life-threatening, but are clearly

of major clinical significance. • Grade 4 toxicity except for: hematological toxicity, alopecia and mucositis 9.7 REPORTING OF SERIOUS ADVERSE EVENTS Any SAE must be reported within 24 hours (working days) by completing the SAE “Report form” (see CRFs) and sending it by fax to IELSG Study Coordinating Center (++4191 811 91 82). The SAE outcome must be reported within 2 weeks after definitive assessment by completing the SAE “Follow-up form” (see CRFs) and sending it by fax to IELSG Coordinating Center (++4191 811 91 82). The investigator according to local regulations will inform local authorities (ethics committees). The physician responsible for patient care should organize any supplementary investigation of serious adverse events based on the clinical judgement on the likely causing factors. These means include seeking a further opinion from a specialist in the field of the adverse event. If a patient dies, any post mortem finding including histopathology must be provided.

10 CRITERIA OF EVALUATION 10.1 ASSESSMENT OF RESPONSE 10.1.1 General method Response to treatment has to be assessed on the basis of a maximum of three ‘target lesions’ selected before the start of the treatment. Whole brain MRI will be used as measurable disease parameter to evaluate the tumor response. Baseline radiograms will be performed at least 2 weeks after start of corticosteroids assumption and primary chemotherapy will start within 7 days from scans. Tumor size will be calculated by multiplying the largest cross-sectional diameter by its largest perpendicular diameter in the enhancing mass on MRI (T1 weighted, post-gadolinium).


All radiograms regarding target lesions used to assess the response will be centrally reviewed by: Dr. Andrea Falini Division of Neuroradiology, San Raffaele Scientific Institute Via Olgettina 60, 20132 Milan, Italy Phone: 0039 02 2643 2213 – e-mail: [email protected] All available radiographs per each patients (baseline radiograms included) must be submitted for response definition after the 2nd and the 4th course of chemotherapy and after WBRT or autotransplant. 10.1.2 Whole-brain MRI protocol Proton Density, T1W SE and T2 Weighted (W) Spin-Echo (SE) and FLAIR (Fluid Attenuated Inversion Recovery) sequences with 5 mm-thick slices oriented along the orbito-meatal axis. Diffusion (if available) oriented on the axial plane with 5 mm-thick slices and “b factor” = 0 and 1000. Isotropic (Trace) images and ADC maps have to be provided. After intra-venous administration of 0.2 ml/kg of paramagnetic contrast agent: T1W SE oriented on the axial plane with 5mm-thick slices; T1W SE oriented on the sagittal or coronal plane with 3 mm-thick slices. Maximum lesion size in two dimensions from images obtained after gadolinium injection, have to be provided. 10.1.3 Schedule of response evaluation Although response definition during primary chemotherapy will be performed after the 2nd and the 4th course, response assessment before to start every chemotherapy course is strongly recommended. Response assessment following 2nd randomization will be performed at 45 days from radiation conclusion and at 30 days and 90 days from autologous transplant. After conclusion of treatment, the disease will be assessed every three months. Patients discontinuing therapy in the absence of progression should not receive any other cancer treatment before their disease progresses, unless this is clearly not in the interest of the patient. 10.2 RESPONSE DEFINITION Response assessment will be based on measurable change in tumor size, taking into account corticosteroid requirements. Response criteria are defined according to the IPCG response criteria32. For more details see Appendix F. The best response recorded from the start of the treatment until disease progression will be considered. In the cases with concomitant positive CSF, cytology examination will be performed after the 2nd and the 4th course of chemotherapy and after WBRT or transplantation. A reduction of more than 50% of cell number will be considered PR, while a reduction lower than this will be considered SD. The duration of response will be measured from the date of start of treatment to the date of objective progression. For complete responders, the duration of response will be measured from the date of documentation of CR. 10.2.1 Patients for whom response has not been assessed All eligible patients will be considered for response evaluation. • Patients who die before response assessment will be considered as ‘early deaths’ and classified

according to the cause of death: progression, toxicity or disease and drug unrelated. • Patients who discontinue treatment before response assessment will be considered as ‘early

discontinuation’ due to progression, toxicity or disease and drug unrelated. • Patients stopping treatment with an unconfirmed response or a too short stabilization will be considered

as ‘early discontinuation’, unless the response or stabilization is further confirmed in the absence of any treatment.

• Patients not evaluated for any reason (lost to follow-up, refusal…) will be considered as ‘not assessed’.


11 LABORATORY TEST AND FOLLOW-UP 11.1 DURING TREATMENT A clinical examination and neurological evaluation should be performed immediately before the administration of the next chemotherapy course. Haemogram and biochemical blood profile will be performed before every chemotherapy course, and according to clinical requirements between 7th and 21st day of each course. CMV reactivation should be monitored once a week during the interval among chemotherapy courses with the most reliable method according to the Institutional Guidelines. All adverse events that have occurred during the previous cycle of therapy should be assessed. Whole brain MRI should be repeated before the start of every course of primary chemotherapy and at the end of WBRT or transplantation. All the lesions chosen as target during the initial assessment must be measured by the same method and by the same person. 11.2 AFTER THE END OF TREATMENT If the patient has not progressed, the disease should be assessed every three months following the same procedure as during treatment. Brain MRI will be repeated every 3 months for 2 years than every 6 months for 3 years and yearly thereafter. This will be used to evaluate the duration of response and/or stabilization of the disease. A clinical examination should be simultaneously performed. A whole body CT scan should be performed in case of clinical suspicion of systemic dissemination. 11.3 AFTER PROGRESSION OF THE DISEASE The patient should be followed every three months for survival. 11.4 SUMMARY TABLE

Before treatment

During Treatment After treatment

Within 14 days prior treatment

Days 1- 21

Start of each cycle

Every 3

months

Every 12

months

At relapse

Medical history X Clinical examination X X X X Neurological evaluation X X X X Performance status X X X X Haemogram * X *** X X X Serum Chemistry^ X *** X X X Creatinine clearance X X CSF cytology exam.** X X Slit lamp examination** X X 18FDG-PET** X X Brain MRI X X X° X Assessment target lesion X X X Bone marrow biopsy X X Whole body CT scan X X X

* Hematology includes white blood cells, neutrophils, platelets and hemoglobin counts ^ Serum chemistry includes creatinine, bilirubin, alkaline phosphatase, LDH, AST, ALT ** These procedures will be performed after the conclusion of CT when positive at diagnosis. *** These tests will be performed according to clinical requirements. ° Brain MRI will be repeated every 3 months for 2 years than every 6 months for 3 years and annually thereafter.


12 CONCOMITANT TREATMENTS - ANTIMICROBIAL PROPHYLAXIS

The following drugs can be delivered: antiemetics, analgesics, antibiotics, anticonvulsants, sedatives, anti-hyperuricemic agents as well as other therapies to control metabolic and malnutrition disturbances. Additional cytotoxic therapy, biological responsive modifiers and drugs possibly interfering in the action or pharmacokinetics of MTX, Ara-C, rituximab, BCNU or thiotepa must be avoided. The type and doses of anticonvulsants and corticosteroids has to be accurately registered. Antimicrobial prophylaxis should follow Institutional guidelines since the variability in endemic or epidemic distribution of infectious agents. However, oral antiviral (Acyclovir 400 mg x 2/d), antifungine (Fluconazole 400 mg/d per os once weekly), antipneumocystic (Trimethoprim 160 mg and sulfamethoxazole 800 mg; three times per week) are suggested. Conventional doses of rHuG-CSF from day 7th - 14th of every course associated with antibiotic prophylaxis with Levofloxacin 500 mg/day (same period) is strongly suggested. Antimicrobial drugs should be interrupted during chemotherapy administration to avoid potential negative pharmacological interactions.

13 SALVAGE THERAPY AFTER CHEMOTHERAPY Since neurological deterioration induced by treatment-related vascular injury is frequent, exclusive neurological impairment should be considered insufficient to indicate a second-line treatment. Only patients with radiologically or cyto-histologically proven relapse will be submitted to salvage therapy. Salvage therapy will start anytime during primary chemotherapy at the documentation of progressive disease, provided haematological toxicity from last chemotherapy has been recovered. The treatment of relapsed patients is suggested considering that salvage therapy seems to prolong survival and improve quality of life35. Second-line treatment for patients with a progressive disease after primary chemotherapy consists of WBRT ≥40 Gy followed by a tumor-bed boost of 9 Gy with photons of 4-10 MeV, 180 cGy per day, 5 weekly fractions. Patients, who will experience relapse or progression after the completion of chemotherapy and WBRT will be referred to salvage therapy according to Institutional guide Lines or Physician’s preferences.

14 PREMATURE TREATMENT WITHDRAWAL Patients who will experience progressive disease (see point 8) at any time, life-threatening toxicity or unsatisfactory stem-cell harvest will be excluded from second randomization and treated with WBRT (40 Gy +/- boost 9 Gy). In any of these cases the patient will be considered as having had treatment failure from the moment of the withdrawal. In the case of patient’s choice to withdraw, it will be censored but not regarded as an event (i.e. not treatment failure). As a general guideline, patients should be considered as "off protocol therapy" if:

• All treatments prescribed by the protocol are discontinued • One of the components of the protocol therapy is stopped, and modifications not prescribed by the

protocol are also brought to any of the other components (dose increase, schedule modifications) • An anticancer agent (or treatment modality) is added to the protocol therapy


15 PATHOLOGY REVIEW The local pathologist of each center participating in this trial has to be informed by the local investigator about the trial protocol, particularly about data and sample processing. After examination, available pathological material must be sent for central pathology review to the IELSG Coordinating Center (IOSI, Ospedale San Giovanni, CH 6500 Bellinzona, Switzerland - [email protected] - phone +41 91 811 9040), together with the filled Shipment form (see 21.2 page 25) and a copy of the original pathology report(s) including diagnosis, classification and immunophenotyping result. A IELSG panel of expert pathologists will review all cases under the supervision of: • Dr. Maurilio Ponzoni (Unit of Lymphoid Malignancies, Pathology Unit, San Raffaele H, Milan, Italy) • Dr. Martina Deckert (Department of Neuropathology, University of Cologne, Germany) In case of doubt the paraffin embedded material to complement the analysis may be requested.

16 STATISTICAL CONSIDERATIONS 16.1 STATISTICAL DESIGN AND SAMPLE SIZE The Fleming design will be used. For the first part of the trial (first randomization), the maximum CR rate considered of low interest is 45% (P0) and the minimum CR rate considered of interest is 65% (P1). In order to detect such a difference, a total number of 42 patients per arm is required (two-sided test, type I error 5% and power 80%). If at least 25 CR will be observed among the 42 patients, the combination will be considered active. For the second part of the trial (second randomization), the maximum 2-yr FFS rate considered of low interest is 65% (P0) and the minimum 2-yr FFS rate considered of interest is 85% (P1). In order to detect such a difference a total number of 31 patients per arm is required (two-sided test, type I error 5% and power 80%). If at least 25 patients will be progression-free at 2 years the combination will be considered active. All primary analyses are based on intention to treat, where all randomized patients are included with the exception of patients who post-hoc objectively do not meet the eligibility criteria at the time of the randomization. 16.2 ANALYSIS OF OUTCOME Differences in response rate will be tested using the test chi-square. Efficacy analysis will be done on an intent-to-treat basis. Survival curves will be estimated using the Kaplan-Meier method and the Log rank test will be used to compare outcome of the different treatment arms. Independent association between studied variables and survival will be tested using the Cox proportional hazard model. 16.3 DEFINITION OF SURVIVAL ENDPOINTS • Event-free survival (EFS) for all patients, is defined as the interval between the time of entry onto

trial and failure or death from any cause. • Overall survival (OS) for all patients, is measured from entry onto trial until death from any cause. • Failure-free interval (FFS) for all patients, is taken from the time of entry onto study until disease

progression or death from any cause. • Duration of response for patients who achieved complete or partial response, is measured from the

first assessment that documents the response to the date of relapse.


16.4 PRELIMINARY SAFETY ANALYSIS A preliminary safety analysis will be performed after recruitment of the first 15 patients (5 patients per arm at the first randomization) to address feasibility and introduce timely changes in therapeutic arms schedules. This analysis will be performed by an Independent Data and Safety Monitoring Board whose responsibility is to establish the early stopping rule to be used and the frequency and timing of further safety analyses.

17 ETHICAL CONSIDERATIONS 17.1 PATIENT PROTECTION This study is conducted in agreement with the declaration of Helsinki. The protocol has been written and the study will be conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice. This protocol has been approved by the Local Ethics Committees. 17.2 SUBJECT IDENTIFICATION A sequential identification number will be automatically attributed to each participating institution and to each patient registered in the trial. These numbers will identify the patient and must be included on all case report forms. In order to avoid identification errors, patient's initials and date of birth will also be reported on the case report forms. 17.3 INFORMED CONSENT All patients will be informed of the aims of the study, the possible adverse events, the procedures and the possible hazards to which they will be exposed. They will be informed that authorized individuals other than their treating physician may review their medical records for trial purposes. It will be emphasized 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 according to local Ethics Committee Guidelines must be obtained for all patients included in this study before they are registered. 17.4 CONDITIONS FOR MODIFYING AND TERMINATING THE STUDY Protocol modifications to ongoing study, which alter the aim of the investigation, experimental design, duration of therapy, patient selection criteria, must be made only after appropriate consultation with the study coordinators. Patient will be considered off study in case of evident progression or severe treatment-related toxicity and, consequently, candidate to salvage therapy. However, neurological deterioration without radiological assessment may not be considered a sufficient reason to stop treatment.


18 INSURANCE Patients from Switzerland, Italy, United Kingdom, France, and Germany enrolled in this trial are covered by a clinical trial liability insurance, which applies exclusively to this clinical trial.

19 PUBLICATION POLICY The study chairman on the basis of the statistical analysis will write the final publication of the trial results. A draft manuscript will be written at 24 months after the last patient has discontinued therapy. After revision by the co-authors, this manuscript will be sent to a major scientific journal. Authors of the manuscript will include at least the Study Chairmen and the investigators who have included more than 5% of the eligible patients in the trial (by order of inclusion). Participating investigators can not report the own experience on patients registered in this trial at scientific meetings or journals without a written assent from study coordinators. Case reports on therapeutic features involving patients registered in this trial are strongly discouraged.


20 STUDY ACKNOWLEDGEMENT

PROTOCOL IELSG 32 RANDOMIZED PHASE II TRIAL ON PRIMARY CHEMOTHERAPY WITH HIGH-DOSE METHOTREXATE AND HIGH-DOSE CYTARABINE WITH OR WITHOUT THIOTEPA, AND WITH OR WITHOUT RITUXIMAB, FOLLOWED BY BRAIN IRRADIATION vs. HIGH-DOSE CHEMOTHERAPY SUPPORTED BY AUTOLOGOUS STEM CELLS TRANSPLANTATION FOR IMMUNOCOMPETENT PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA As investigator for this study, I understand that this protocol contains information that is confidential and proprietary to IELSG. I have received and read the above mentioned protocol and agree that it contains all necessary details for carrying out the study as described; I will conduct this protocol as outlined therein.

I will provide copies of this protocol and access to all information furnished by IELSG to study personnel under my supervision. I will discuss this material with them to ensure that they are fully informed about the investigational product and the study. I agree to keep accurate records on all patients information (CRFs and Patients’s informed consent statement) and all other information collected during the study for a minimum period of 10 years.

I agree not to publish all or any part of the results of the study carried out under this protocol, without the prior written consent of IELSG.

All parties agree to ensure direct access to examine, analyze, verify and reproduce source data / documents, and reports from all trial related sites for the purpose of monitoring and auditing, and inspection by domestic and foreign regulatory authorities. ............................................................................... ............................................................. Investigator (printed name) Signature Date

Prof. Dr. med. Franco Cavalli

............................................................................... ............................................................. IELSG Representative Signature Date: 26.05.2009


21 FORMS AND PROCEDURES FOR COLLECTING DATA 21.1 CASE REPORT FORMS AND SCHEDULE FOR COMPLETION Data will be reported on the enclosed forms and sent to: INTERNATIONAL EXTRANODAL LYMPHOMA STUDY GROUP (IELSG) - Studies Coordination Oncology Institute of Southern Switzerland (IOSI) - Ospedale San Giovanni CH-6500 Bellinzona SWITZERLAND Phone ++41 91 811 90 40 - 811 91 11 - Fax ++41 91 811 91 82 - E-mail <[email protected]> Case reports forms must be completed according to the following schedule: After diagnosis, before the treatment starts • Registration – first randomization form After first randomization • On study form 1 At the end of treatment (arm A, B or C) • Therapy form – Part 1 • Second randomization form After second randomization • On study form 2 At the end of PBSC collection (cycle 2) • Leukapheresis form At the end of treatment (arm D or E) • Therapy form – Part 2 • Central radiology review After conclusion of treatment (arm D or E) • Follow-up form (every 3 months for 2 years, than every 6 months for 3 years, than yearly) In case of relapse after the treatment • Relapse form

In case of patient refusal or in case of death for any cause • Withdrawal form Within 24 hours after a serious adverse event • Serious adverse event “Report form” Within 2 weeks after definitive assessment of the serious adverse event • Serious adverse event “Follow-up form” All forms must be dated and signed by the responsible investigator or one of her/his authorized staff members. In all cases it remains the responsibility of the investigator to check that original case report forms are completely and correctly filled out and that they are sent to the data center. 21.2 SHIPMENT FORM FOR PATHOLOGY REVIEW A Shipment form to be used for sending to the IELSG Coordinating Center the material required for pathology review is also enclosed. It will contain the address to whom the material will be returned after the review.


22 REFERENCES

1. Reni M, Ferreri AJ, Garancini MP, Villa E. Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Ann Oncol 1997;8:227-34.

2. Nelson DF. Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neurooncol 1999;43:241-7.

3. DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992;10:635-43.

4. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ, Radiation Therapy Oncology Group Study 93-10. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 2002;20:4643-8.

5. Ferreri AJ, Reni M, Villa E. Therapeutic management of primary central nervous system lymphoma: lessons from prospective trials. Ann Oncol 2000;11:927-37.

6. Ferreri AJ, Abrey LE, Blay JY, et al. Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002. J Clin Oncol 2003;21:2407-14.

7. Ferreri AJ, Reni M, Pasini F, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology 2002;58:1513-20.

8. Bataille B, Delwail V, Menet E, et al. Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg 2000;92:261-6.

9. Hayabuchi N, Shibamoto Y, Onizuka Y. Primary central nervous system lymphoma in Japan: a nationwide survey. Int J Radiat Oncol Biol Phys 1999;44:265-72.

10. Ferreri AJ, Reni M. Primary central nervous system lymphoma. Crit Rev Oncol Hematol 2007;63:257-68.

11. Mead GM, Bleehen NM, Gregor A, et al. A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. Cancer 2000;89:1359-70.

12. Schultz C, Scott C, Sherman W, et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 1996;14:556-64.

13. O'Neill BP, Wang CH, O'Fallon JR, et al. Primary central nervous system non-Hodgkin's lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52. Int J Radiat Oncol Biol Phys 1999;43:559-63.

14. Bessell EM, Graus F, Punt JA, et al. Primary non-Hodgkin's lymphoma of the CNS treated with BVAM or CHOD/BVAM chemotherapy before radiotherapy. J Clin Oncol 1996;14:945-54.

15. Glass J, Shustik C, Hochberg FH, Cher L, Gruber ML. Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). J Neurooncol 1996;30:257-65.

16. Ferreri AJ, Foppoli M, Martelli M, et al. Randomized phase II trial on primary chemotherapy with high-dose methotrexate alone or associated with high-dose cytarabine for patients with primary CNS lymphoma (IELSG #20 trial): survival analysis. Haematologica 2008;93:abstract #397.

17. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-42.


18. Feugier P, Virion JM, Tilly H, et al. Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol 2004;15:129-33.

19. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007;25:4730-5.

20. Ferreri AJ, Blay JY, Reni M, et al. Relevance of intraocular involvement in the management of primary central nervous system lymphomas. Ann Oncol 2002;13:531-8.

21. Soussain C, Hoang-Xuan K, Taillander L, et al. Intensive Chemotherapy Followed by Hematopoietic Stem Cell Rescue for Refractory or Recurrent Primary Central Nervous System (PCNSL) or Intra Ocular Lymphoma (IOL). Results of a Multicentric Phase II Study. Blood 2006;108:abstract #402.

22. Illerhaus G, Marks R, Ihorst G, et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 2006;24:3865-70.

23. Illerhaus G, Muller F, Feuerhake F, Schafer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica 2008;93:147-8.

24. Montemurro M, Kiefer T, Schuler F, et al. Primary CNS Lymphoma Treated with HD-Methotrexate, HD-Busulfan/Thiotepa, Autologous Stem Cell Transplantation and Response-Adapted Whole-Brain Radiotherapy: Results of the Multicenter OSHO-53 Phase II. Blood 2005;106:abstract #3342.

25. Glass J, Gruber ML, Cher L, Hochberg FH. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 1994;81:188-95.

26. Hiraga S, Arita N, Ohnishi T, et al. Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. J Neurosurg 1999;91:221-30.

27. Reni M, Ferreri AJ, Guha-Thakurta N, et al. Clinical relevance of consolidation radiotherapy and other main therapeutic issues in primary central nervous system lymphomas treated with upfront high-dose methotrexate. Int J Radiat Oncol Biol Phys 2001;51:419-25.

28. Ferreri AJ, Dognini GP, Govi S, et al. Can rituximab change the usually dismal prognosis of patients with intravascular large B-cell lymphoma? J Clin Oncol 2008;26:5134,6; author reply 5136-7.

29. Ferreri AJ, Dell'Oro S, Foppoli M, et al. MATILDE regimen followed by radiotherapy is an active strategy against primary CNS lymphomas. Neurology 2006;66:1435-8.

30. Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol 2003;21:4483-8.

31. Illerhaus G, Marks R, Muller F, et al. High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study. Ann Oncol 2008;.

32. Abrey LE, Batchelor TT, Ferreri AJ, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005;23:5034-43.

33. Ferreri AJ, Blay JY, Reni M, et al. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 2003;21:266-72.

34. Correa D, Maron L, Harder H, et al. Cognitive functions in primary central nervous system lymphoma: literature review and assessment guidelines. Ann Oncol 2007;.

35. Reni M, Ferreri AJ. Therapeutic management of refractory or relapsed primary central nervous system lymphomas. Ann Hematol 2001;80 Suppl 3:B113-7.


APPENDIX A

ECOG PERFORMANCE STATUS

0 Asymptomatic, fully active, and able to carry on all predisease performance without restrictions.

1 Symptomatic, fully ambulatory but restricted in physically strenuous activity and able to carry out

performance of a light or sedentary nature, e.g., light housework, office work.

2 Symptomatic, ambulatory and capable of all self-care but unable to carry out any work activities. Up and

about more than 50 % of waking hours: in bed less than 50 % of day.

3 Symptomatic, capable of only limited self-care, confined to bed or chair more than 50 % of waking

hours, but not bedridden.

4 Completely disabled. Cannot carry on any self-care. Totally bedridden.

5 Dead.


APPENDIX B

STUDY DRUG ADMINISTRATION

• MTX ADMINISTRATION SCHEDULE OF DRUG DELIVERY hour 0: HCO3

- 1 mEq/mL (2-4 mL/Kg of body weight) + KCl 20 mEq + Alizapride 100 mg or similar + dexamethasone 8 mg hour 2: Lactate Ringer 500 mL hour 3: MTX 0.5 g/m2 in 15 min., followed by MTX 3 g/m2 in 1000 mL of 5 % glucose sol. in 3-hour infusion hour 7: 0.9 g/L saline sol. 500 mL + dexamethasone 8 mg + Alizapride 100 mg + furosemide 25 mg hour 9: HCO3

- 1 mEq/mL (2-4 mL/Kg of body weight) + KCl 20 mEq + 0.9 g/L saline sol. 1500 mL PRE-MTX HYDRATION HD-MTX administration requires an urinary pH > 8 and a diuresis > 100 mL/h. Thus, 24 hours before MTX administration patients will be hydrated with 1500 mL of 0.9 g/L saline solution, 1500 mL of 5 % glucose solution, 20 mEq KCl and 100 mEq HCO3

-. In some cases, such as resected or diabetic patients, hydration will be modified according to clinical requirements. LEUCOVORIN RESCUE AND POST-MTX HYDRATION Folinic (THF) rescue starts 24 hours after the start of MTX infusion. Levo-folinic acid will be administered at a dose of 15 mg/m2/dose intravenous push every six hours for 12 times. The post MTX hydration (including the solutions used to administrate Ara-C, antiemetics and other drugs) should reach a total volume of 2000 ml. MTX SERUM LEVEL DETERMINATION MTX serum level determination will start immediately after the end of drug infusion, and it will be repeated every 24 hours until to obtain a concentration lower than 5 x 10-8M/L. In the case high MTX serum levels persist after 48 hours after the end of infusion, leucovorin rescue will be modified according to MTX levels as follows: if MTX < 5 x 10-7 M/L THF 15 mg/m2/6 hours if MTX < 1 x 10-6 M/L THF 50 mg/m2/6 hours if MTX > 1 x 10-6 M/L THF 100 mg/m2/6 hours The registration of daily MTX serum levels (Therapy forms) will be of major interest to study the predictive role of area-under-curve of this drug in the treated patients. BIOCHEMICAL CONTROLS Urinary pH will be determined every 8 hours after MTX infusion. Value must be ever > 8. Otherwise, HCO3

- 100 mEq will be administered and parenteral hydration will be accelerated. Diuresis must be ever > 100 mL/h. High hydration and furosemide will be used in case of diuresis

• Ara-C ADMINISTRATION SCHEDULE OF DRUG DELIVERY (days 2 and 3 of every course) hour 0: Antiemetic + dexamethasone 8 mg hour 1: Ara-C 2 g/m2 in 250 mL of 0.9 g/L saline solution in 1-hour infusion hour 12: Antiemetic + dexamethasone 8 mg hour 13: Ara-C 2 g/m2 in 250 mL of 0.9 g/L saline solution in 1-hour infusion


• Thiotepa and BCNU ADMINISTRATION

day -6 hour 0: Antiemetic + dexamethasone 8 mg hour 1: BCNU 400 mg/m2 in 500 ml saline sol in 1-hr infusion hour 2: 2000 mL of 0.9 g/L saline solution in 24-hour infusion days -5 & -4 hour 0: Antiemetic + dexamethasone 8 mg hour 1: Thiotepa 5 mg/kg in 250 ml saline solution in 2-hr infusion hour 2: 3000 mL of 0.9 g/L saline solution in 24-hour infusion hour 12: Thiotepa 5 mg/kg in 250 ml saline solution in 2-hr infusion

APPENDIX C

TOXICITY CRITERIA

In the present study, toxicities will be recorded according to the International Common Toxicity Criteria (CTC), version 3.0. At the time this protocol was issued, the full CTC document was available on the NIH web site, at the following address: http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf


APPENDIX D

MINI MENTAL STATUS EXAMINATION (MMSE)

INSTRUCTIONS: In general, speak slowly and clearly. If necessary repeat the question (except for question no. 7). Tick and sum each correct answer.

Date of assessment (dd/mm/yyyy) __ / __ / ____

ORIENTATION 1. What is the year? 1 Season? 1 Date? 1 Day? 1 Month? 1 2. Can you tell me where we are: in which state or country? 1 Country? 1 Town or city? 1 Address or name of hospital/ building? 1 Floor? 1 REGISTRATION Name 3 objects (book, plant, mill), taking 1 second to say each. Then ask the patient to tell you all 3 (score 1 point for each correct answer). Repeat naming the objects until the patients has learned all 3. 3. I’m going to name three objects, can you repeat all three after I’ve finished? 3 ATTENTION AND CALCULATION Serial 7s (100-7). One point for each correct answer, also for a correct answer after a false response (subtracting more or less than 7). Stop after 5 correct answers. If the patient has great difficulty with numbers (e.g. acalculie) use the alternative: spelling “WORLD” backwards. 4. Could you subtract 7 from 100, then substract 7 from that number and so on? 5 RECALL Ask for the names of three objects learned in question no. 3. Give 1 point for each correct answer. 5. Can you name the three objects again? 3 LANGUAGE Point to a pencil and watch, and have the patient name them as you point. 6. What is the name of this object? 2 Have the patient repeat the sentence “no ifs, and, or buts”. Read the sentence only once.


7. Can you repeat the next sentence “no ifs, and, or buts”. 1 Have the patient follow a three-stage command. Don’t repeat the instruction. Give 1 point for each correct step, carried out in the right order. 8. Can you take this paper in your right hand. Fold the paper in half. Put the paper on the floor/table? 3 Have the patient read and obey the following: “CLOSE YOUR EYES”. Write it in large letters. The patient doesn’t have to read aloud. If the patient is only reading the sentence, ask him to carry out the sentence. 9. Can you read this sentence and carry it out? 1 Have the patient write a sentence of his or her choice. The sentence should contain a subject and an object and make sense. Ignore spelling or grammar errors. 10. Can you write a sentence on this paper? 1 GRAPHIC CONSTRUCTION Enlarge the design printed below to 2 cm per side and have the patient copy it. There is no time limit (give one point if all the sides and angles are preserved and the intersecting sides form a hexagonal). Can you copy this figure? 1

TOTAL SCORE /30


APPENDIX E IPCG NEUROPSYCHOLOGICAL TESTS (modified from ref 34)

Cognitive domain

Test References

Attention/executive funtions Digit forward Digit backward

WAIS III

Trail Making Test Brief Test of Attention WCST – Brief form

Reitan 1958 Schretlen 1997 Nelson 1976

Memory Hopkins Verbal Learning-Revised Rey Auditory Verbal Learning Test Rey complex figure delayed

Brandt 1991 Rey, 1964 Taylor, 1959 Rey 1968

Language Token Test Phonetic Verbal Fluency Semantic Verbal Fluency

De Renzi, Vignolo 1962; Spinnler e Tognoni 1987 Novelli 1986

Pre-morbid IQ estimation

NART Barona index

Nelson 1982 Barona 1984; 1996

Quality of Life EORTC- QLQ Fayers 1998

BCM 20 Osoba 1996

Motor Grooved pegboard Test Heaton et al., 1991


APPENDIX F

IPCG RESPONSE CRITERIA32

Brain Imaging Steroid Dose Eye Exam CSF Cytology

CR No contrast enhancement None Normal Negative

Cru No contrast enhancement Any Normal Negative

Minimal abnormality Any Minor RPE abnormality Negative PR 50% decrease in enhancing tumor Irrelevant Minor RPE abnormality

or normal Negative

No contrast enhancement Irrelevant Decrease in vitreous cells or retinal infiltrate

Persistent or suspicious

PD 25% increase in lesion Irrelevant Recurrent or new ocular disease Recurrent or

positive Any new site of disease:

CNS or systemic

randomized phase ii trial on primary chemotherapy … · ielsg 32 protocol – version 1.2 – may...

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