HOVON 69 T-NHL Version: July 27, 2005 PROTOCOL

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1 A phase II study of anti-cd52 monoclonal antibody (Alemtuzumab, MabCampath ) with 2-weekly CHOP chemotherapy (Camp-CHOP 14) in patients with mature T-cell non-hodgkin s lymphoma PROTOCOL Study Coordinators : J.C. Kluin-Nelemans G.W. van Imhoff Statistician : W.N. van Wieringen Datamanager : C.M.C. van Hooije Registration : HOVON Data Center Erasmus MC-Daniel den Hoed P.O.Box AE ROTTERDAM The Netherlands tel fax EudraCT number : First version : 15 November 2004 Final version : 27 July 2005 Date of activation : 16 November 2005 Approved : CKTO, 4 November 2005 METC UMCG , 11 August 2005 Page 1 of 48

2 1 Scheme of study T-NHL (T lymphoblastic lymphoma and ALCL excluded) Age years Induction I-III 3 cycles Camp-CHOP 14 + G-CSF At least PR Less than PR: SD or progression Induction IV-VIII 5 cycles Camp-CHOP 14 + G-CSF Off protocol treatment Follow up Page 2 of 48

3 2 Table of contents Page 1 Scheme of study Table of contents Synopsis Investigators and study administrative structure Pathology review Introduction Study objectives Study design Remission induction Study population Eligibility for registration Inclusion criteria Exclusion criteria Treatments Remission induction treatment Dose modifications of CHOP Special management of alemtuzumab administration Product information of MabCampath (Alemtuzumab) Administration of alemtuzumab Prophylactic measures Measurements to monitor and treat CMV (re)activation Concomitant medication and treatment End of protocol treatment Required clinical evaluation Observations prior to start of treatment Observations after each cycle of Camp-CHOP in relation to alemtuzumab toxicity Observations after 3 and 8 cycles of Camp-CHOP Response assessment after cycle 3 and cycle 8 of Camp-CHOP Observations during follow up Toxicities Reporting serious adverse events Endpoints Procedures for collecting data Registration Statistical considerations Page 3 of 48

4 17.1 Patient number and power considerations Statistical analysis Efficacy analysis Interim analysis and stopping rules Ethics Independent ethics committee or Institutional review board Ethical conduct of the study Patient information and consent Trial insurance Publication policy Glossary of abbreviations References Appendices A. NHL WHO classification, T cell part only...31 B. HOVON Staging and Response Criteria for Non Hodgkin s Lymphomas...32 C. Ann Arbor staging classification...37 D. Common Terminology Criteria for Adverse Events...38 E. ZUBROD-ECOG-WHO Performance Status Scale...39 F. NYHA* scoring list...40 G. International Prognostic Index...41 H. Patiënteninformatie...42 Page 4 of 48

5 3 Synopsis Study phase Study objectives Patient population Study design Duration of treatment Number of patients Adverse events Planned start and end of recruitment Phase II Evaluation of the efficacy and toxicity of anti-cd52 (Alemtuzumab, MabCampath ) combined with 2-weekly CHOP + G-CSF Patients with extranodal NK/T cell lymphoma nasal type, enteropathy-associated T-NHL (EATL), panniculitis-like T-NHL, angioimmunoblastic T-NHL (AITL), peripheral T-NHL, unspecified( T-NHL NOS), all previously untreated, age years, stages II-IV and with good WHO performance status (WHO 0, 1 or 2) Prospective, multicenter, phase II Expected duration of treatment is 16 weeks 20 patients Adverse events will be documented if observed, mentioned during open questioning, or when spontaneously reported Start of recruitment: III 2005 End of recruitment: IV 2007 Page 5 of 48

6 4 Investigators and study administrative structure Responsibility Name Affiliation/Address Study Coordinators J.C. Kluin-Nelemans University Medical Center Groningen G.W. van Imhoff Writing Committee J.W. Baars A. van Leeuwenhoek Hospital, Amsterdam D.H. Biesma St. Antonius Hospital, Nieuwegein P.J. Lugtenburg Erasmus MC, Rotterdam G. Ossenkoppele VU University Medical Center, Amsterdam M.H.H. Kramer Meander MC, Amersfoort M. van Marwijk-Kooy Isala Clinic, Zwolle M.J. Kersten Academic Medical Center, Amsterdam M.R. Schaafsma Medical Spectrum Twente, Enschede M. van Gelder University Hospital Maastricht M.B. van t Veer Erasmus MC, Rotterdam L.F. Verdonck University Medical Center Utrecht P.W. Wijermans Leyenburg Hospital, The Hague R. Barge LUMC, Leiden Pathology review L.M. Budel J.J. Oudejans Meander MC, Amersfoort VU University Medical Center, Amsterdam Statistician W.N. van Wieringen HOVON Data Center, Rotterdam Datamanagement C.M.C. van Hooije HOVON Data Center, Rotterdam Serious Adverse Events (SAE s) notification HOVON Data Center fax: Pathology review A central review of the diagnosis is performed for each case by L.M. Budel and J.J. Oudejans, to confirm the diagnosis of T-cell lymphoma, to assess CD52 positivity (mandatory!), and to define the subtype according to the WHO lymphoma classification. Classification of these lymphomas includes immunophenotypical characterization by a standard panel of markers including CD2, CD3, CD4, CD8, CD21, ALK1, CD30, CD56, TdT, TIA-1 and granzyme B. The presence of Epstein Barr virus (EBV) in the neoplastic cells is important in sub -classification and will be determined in all cases by EBER RNA in situ hybridization. If a definite diagnosis cannot be attained based on histological and immuno-histochemical findings alone, additional TCR rearrangement studies will be performed (department of pathology of the VU medical center) by multiplex PCR analysis using the Biomed-2 concerted action primers (Droese J et al. Leukemia 2004;18:1531). However, the definition of T-cell lymphomas based on morphological, immunophenotypic and genetic features is frequently imprecise. Therefore, clinical features play an important part in final classification of Page 6 of 48

7 these lymphomas. A review by a second/third hematopathologist will be performed in case of discrepancy with the local pathologist or when judged appropriate. Expression of CD52 will be determined on frozen tissue sections, because detection of CD52 expression proved to be impossible on paraffin-embedded tissue sections. For this reason the review pathologist will contact the local pathologist to send in frozen material (if available). If at all possible, relapse material should be sent as well to verify persistence of CD52 expression after treatment. The review analysis will be done without knowledge of patient outcome. Once a patient is registered in the study, the local pathologist as well as the central pathologist will be notified by the HOVON Data Center by . The local pathologist will be asked to send in 15 unstained slides (suitable for immunohistochemical stainings) or a paraffin embedded block of the primary biopsy (on which the T-cell lymphoma diagnosis is based) and the pathology report to the review pathologist. If the CD52-expression assessment will prove to be impossible on formaline fixed material, the review pathologist will ask the local pathologist to send in frozen material (if available).after review of diagnosis, including possible additional tests necessary for diagnosis, the material will be returned to the pathologist who has sent in the material. Review material will not be used for additional studies without consent of the local pathologist. A copy of the results of the review will be sent to the local pathologist and to the HOVON Data Center. All histological materials are to be sent to: J.J. Oudejans Department of Pathology VU University Medical Center De Boelelaan HV Amsterdam The Netherlands 5 Introduction The prognosis of patients with T-NHL treated by classical CHOP chemotherapy is extremely poor with a median survival of about 6 months, the large majority (>85%) of the patients dying within 2-3 years 1,2,3. T-NHL s within the WHO classification consist of extranodal NK/T-cell lymphoma nasal type, enteropathy associated T-NHL (EATL), hepatosplenic T-NHL, panniculitis-like T-NHL, AILDlike T-NHL and T-NHL not otherwise specified (NOS) 4,5. In spite of the bad prognosis, no specific therapy for T-NHL has been designed thus far. Page 7 of 48

8 For aggressive B-NHL, the addition of an anti-b cell monoclonal antibody to classical CHOP chemotherapy resulted in an improvement of overall survival of 15%. It is attractive to consider an identical design for mature T-NHL by combining alemtuzumab (MabCampath ) with CHOP. Alemtuzumab has shown activity to T cell malignancies, especially to a variant of mature T cell leukemia (T cell prolymphocytic leukemia) 6-9 and in mycosis fungoides/sezary syndrome 10. Because malignant T cells have been reported to express high numbers of CD52 cell surface molecules 11, mature T-NHL s might be suitable candidates for therapy with alemtuzumab. We observed an impressive response after treatment with alemtuzumab monotherapy in a patient with enteropathy-associated T-NHL who showed an unusual leukemic pattern (personal communication J.C. Kluin-Nelemans). A recent pilot study of alemtuzumab for patients with relapsed or refractory peripheral T cell lymphomas showed promising results 12. Fourteen heavily pretreated patients received alemtuzumab monotherapy at a dose of 30 mg, 3 times a week for a maximum of 12 weeks. Three patients achieved a complete remission (CR) with a duration of 2, 6 and 12 months, and a further two a partial remission (PR). Toxicity was considerable, however, with CMV reactivation in six patients, pulmonary aspergillosis in two and pancytopenia in four. There are no published data on the combination of alemtuzumab with CHOP thus far. An UMCG patient with T-PLL received 8 cycles of alemtuzumab combined with CHOP-14, and did not experience any serious haematological or infectious toxicity. During the International Lymphoma Conference in Lugano (June 2005) a satellite T-NHL Workshop (sponsored by Schering Berlin) was held. Three international groups presented preliminary data on ongoing phase II studies incorporating polychemotherapy schemes combined with alemtuzumab. Interim results of a total of approximately 70 patients with T-NHL were reported. Alemtuzumab was combined with CHOP- (like) therapy or administered after at least partial response on chemotherapy. Weekly dose as well as cumulative dose of alemtuzumab differed. Although the number of patients with CMV reactivation was substantial, no obvious relation between alemtuzumab dosing schedule or cumulative dose and infectious SAE were reported. CHOP can be given at 3 weekly or 2 weekly intervals. The latter suggests a better outcome 13,14, which justifies this scheme for T-NHL patients. The combination of monoclonal antibodies with polychemotherapy requires adaptation. Compared to the monotherapy of rituximab for follicular lymphoma (4 weekly gifts only), the CHOP-rituximab combination consists of rituximab at day 1 only, given at a 3 weekly interval in parallel with day 1 of CHOP. For comparison, alemtuzumab given for CLL is dosed at 30 mg gifts, 3 times a week for at least 12 weeks. To avoid later criticism of underdosing MabCampath, we decided to use (after a first stepping up of 3 mg and 10 mg) 3 gifts of 30 mg up to a total dose of 90 mg subcutaneously per CHOP cycle. Whereas the intravenously given alemtuzumab is accompanied by severe adverse reactions related to the infusion, subcutaneously given alemtuzumab is much better Page 8 of 48

9 tolerated and equally effective 15,16. The choice of T-NHL categories for this study is disputable. The results obtained should be exemplary for other patients, which means that too rare malignancies should not be selected. Moreover, several of the T-NHL s lack measurable disease as these present mainly with hepatosplenomegaly and/or bone marrow involvement only. Finally, patients with EATL can be severely ill, especially if the T-NHL evolves from refractory celiac disease. Therefore, not all categories will be submitted to this phase II trial. Most patients with T-NHL are already immunocompromised. Therefore, the addition of the immunosuppressive alemtuzumab will hopefully not be a serious problem, because prophylactic antibiotics (linked to the MabCampath ) have to be given anyway. Specific care will be needed for monitoring of CMV reactivation. Moreover, since recently unexplained cardiotoxicity has been described 17, monitoring of cardiac function will be additionally required. Recently presented data (see above) suggest that the combination of alemtuzumab with intensive polychemotherapy for newly diagnosed T-NHL patients harbours an acceptable safety profile, justifying the hereby presented study proposal for a NHL subset with an often dismal outcome. 6 Study objectives To assess the efficacy of alemtuzumab combined with 2-weekly CHOP + G-CSF on complete remission rate, the event-free survival of mature T-cell lymphoma patients treated with alemtuzumab with 2-weekly CHOP + G-CSF, the disease free survival of mature T cell lymphoma patients treated with alemtuzumab with 2-weekly CHOP + G-CSF, the overall survival of patients with mature T cell lymphoma To evaluate the toxicity of alemtuzumab combined with 2-weekly CHOP + G-CSF. 7 Study design Details of all treatments (dose and schedule) are given in Remission induction Patients with T- NHL meeting all eligibility criteria (see 8.1) will be registered and treated with: 8 cycles of CHOP q 2 weeks plus G-CSF (Pegfilgrastim), combined with 24 administrations of alemtuzumab (MabCampath ) Page 9 of 48

10 Patients will be evaluated for response after 3 cycles of Camp-CHOP (all patients) and after 8 cycles of Camp-CHOP (if applicable, otherwise after last cycle administered). All patients, who have not attained at least a PR after 3 cycles of Camp-CHOP, will go off protocol treatment. 8 Study population 8.1 Eligibility for registration All eligible patients have to be registered before start of treatment (see paragraph 16) Inclusion criteria Patients with a confirmed histologic diagnosis of T-NHL according to the WHO classification (Appendix A):! Extranodal NK/T cell lymphoma, nasal type! Enteropathy-type T-cell lymphoma (EATL), if measurable disease! Subcutaneous panniculitis-like T-NHL! Angioimmunoblastic T-cell lymphoma! Peripheral T-cell lymphoma, unspecified (T-NHL NOS) Age years inclusive Stage II or more WHO performance status 0, 1 or 2 (see appendix E) Measurable disease (see appendix B) Written informed consent Exclusion criteria Patients with NK/T-NHL of the following type:! Precursor T cell lymphoblastic lymphoma/leukemia! All mature T cell leukemias (T-PLL, ATLL, NK cell leukemia, T-LGL)! Anaplastic large cell lymphoma! Hepatosplenic T cell lymphoma! Enteropathy-type T cell lymphoma without measurable disease! Blastic NK cell lymphoma Intolerance of exogenous protein administration Severe cardiac dysfunction (NYHA classification II-IV, appendix F) or LVEF < 45 % Page 10 of 48

11 Significant renal dysfunction (serum creatinine 150 µmol/l), unless related to NHL Significant hepatic dysfunction (total bilirubin 30 µmol/l or transaminases 2.5 times normal level), unless related to NHL Suspected or documented Central Nervous System involvement by NHL Patients known to be HIV-positive Patients with active, uncontrolled infections Patients with uncontrolled asthma or allergy, requiring steroid treatment Prior treatment with chemotherapy, radiotherapy or immunotherapy for this lymphoma, except local radiotherapy in case of (potential) organ dysfunction by localized lymphoma mass or infiltration History of active cancer during the past 5 years, except basal carcinoma of the skin or stage 0 cervical carcinoma 9 Treatments 9.1 Remission induction treatment CHOP chemotherapy + G-CSF Agent Dose/day Route Days Cyclophosphamide 750 mg/m 2 i.v. 1 Doxorubicin 50 mg/m 2 i.v. 1 Vincristine 1.4 mg/m 2, with a maximum of 2 mg i.v. 1 Prednisone/Prednisolone 100 mg p.o. 1, 2, 3, 4, 5 G-CSF(Pegfilgrastim) 6 mg s.c. 2 (before bedtime) Patients will be treated with 8 cycles of Camp-CHOP, every 2 weeks. In addition, they will receive pegylated G-CSF at day 2 during each cycle of Camp-CHOP. Alemtuzumab will be given subcutaneously 3 times per CHOP cycle. The easiest way is to inject at day 1, 5 and day 10 of each CHOP-14 schedule. The first gift will be 3 mg, the next 10 mg, followed by 30 mg. If the first day starts at Monday the weekend-days can be easily skipped. All patients need prophylactic medication to avoid first-dose reactions and reactivation of severe infections. See paragraph 9.3 for special management of alemtuzumab administration. Page 11 of 48

12 Agent Dose/day Route Day Alemtuzumab (MabCampath ) 3 mg 10 mg 30 mg s.c. s.c. s.c. Cycle 1: day 1 Cycle 1: day 5 Cycle 1: day mg s.c. Cycle 2-8: day 1, 5 and 10 If day 1 = Monday, then day 5 = Friday and day 10 is Wednesday Assessment of response after 3 cycles is described in Patients who have not achieved at least PR will go off protocol treatment. Patients in PR or CR after cycle 3 will receive another 5 cycles of Camp-CHOP, every 2 weeks. 9.2 Dose modifications of CHOP Dose modifications will not be made in the first course. During the next courses modifications of the treatment schedule will only be made in case of: a) Myelosuppression If leukocytes are < 3 x 10 9 /l and/or platelets < 100 x 10 9 /l: delay course for one week. If leukocytes or platelets remain below these values, the doses of doxorubicin and cyclophosphamide have to be reduced (only once) following the scheme below. The next course(s) should again be dosed at 100% level. Leucocytes x 10 9 /l Platelets x 10 9 /l Cyclophosphamide Doxorubicin Vincristine Prednison > 3 and > % 100% 100% 100% 2-3 and > % 75% 100% 100% 1-2 or > 50 < % 50% 100% 100% <1 or < 50 0% 0% 100% 100% b) Neurotoxicity Dose modifications of vincristine are made at the discretion of the medical attendant. c) Cardiotoxicity In case of documented cardiomyopathy that developed during treatment, LVEF should be repeated and alemtuzumab interrupted. In case of a reduction of LVEF by >15% (absolute values, e.g. from 60% to < 45%) the patient goes off protocol treatment, but less reduction (10%) might be as important in case of lower (<60%) starting values of the LVEF. Any symptomatic patient requiring Page 12 of 48

13 therapy and diagnosed with serious cardiomyopathy should go off protocol treatment during a decline of the LVEF or if NYHA grade 3 or 4 develops. 9.3 Special management of alemtuzumab administration Product information of MabCampath (Alemtuzumab) MabCampath is a genetically modified humanized monoclonal antibody (IgG1-kappa) and is provided as a sterile, clear, colourless, isotonic solution for injection. For subcutaneous injection specific vials have been developed containing higher concentrations than the ampoules used for intravenous therapy. Thus, each single-use 1-ml vial of MabCampath contains 30 mg alemtuzumab, 2.7 mg sodium chloride, 0.07 mg potassium chloride, 0.07 mg monobasic potassium phosphate, 0.38 mg dibasic sodium phosphate, mg disodium edetate, and mg polysorbate 80. No preservatives are added. For a 3 mg dose, 0.1 ml is to be used; for a 10 mg dose 0.35 ml, and for the final 30 mg dose 1 ml. Packaging, labelling and storage: Store at 2 to 8 C (36 to 46 F). Do not freeze. Discard vial if it has been frozen. Do not use beyond expiration date. Protect from direct sunlight. Unused diluted solutions should be discarded after 8 hours Administration of alemtuzumab Alemtuzumab will always be given after the CHOP chemotherapy. To reduce toxicity, alemtuzumab will be injected subcutaneously in the thighs using vials of the higher concentration at 30 mg/ml 15,16. Even using this route, side effects will occur. Intravenous alemtuzumab is frequently followed by rigors, fever and hypotension. Also dyspnea and urticaria with bronchospasm can occur. After subcutaneous injection, in >90% of the patients local injection site reactions will be seen, especially during the first 2 weeks. These may consist of erythema/edema (Grade I) or be accompanied by pruritus and slight pain (grade II). The erythema can measure up to 30 cm in diameter in some patients, but will always disappear before the next injection. Generally, side effects will decrease within 2 weeks. The majority of patients will experience fever, a minority rigors, all grade I-II, and all will show diminishment of these symptoms within 2 weeks during continuation of alemtuzumab. During the first injection of 3 mg (0.1 ml) the patient needs to be observed with an IV line that should be kept open for medications. Vital signs (blood pressure, pulse, respiration, and temperature) should be monitored every 15 minutes during the first hour or until stable and then for another hour. Premedication with paracetamol (1000 mg) and an antihistaminic (e.g. clemastine 2 Page 13 of 48

14 mg) is mandatory. Moreover, alemtuzumab should be given after the CHOP including oral prednisolone and/or intravenous anti-emetic dexamethason. If one of the following symptoms occurs: 1) mild/moderate rigors; 2) mild/moderate mucosal congestion or edema; 3) drop in systolic blood pressure >30 mm Hg, the next planned gift should be given at the same low dose of 3 mg under monitoring with an open IV line available. If the first dose is well tolerated, the next dose should be 10 mg (0.35 ml), followed by the final aimed dose of 30 mg (1 ml). All doses can subsequently be given at home by self-injection. If complications occur after injection, the patient should be observed for two hours after the completion of the injection. In the rare event of grade 3 or 4 toxicity, 200 mg hydrocortison can be given one hour prior to alemtuzumab injection Prophylactic measures Prophylaxis is required against so-called first-dose allergic reactions, against tumor lysis, against infections, and against transfusion-related GvHD. Prophylaxis against first-dose reactions will include paracetamol 1 gram orally and clemastine (Tavegil) 2 mg intravenously or orally, 30 minutes before the injections. In the absence of severe side effects, both drugs can be tapered down during the following weeks. Prophylaxis against tumor lysis should consist of allopurinol, 300 mg, during the first weeks. The dose should be adapted if the creatinine clearance is decreased. Prophylaxis against infections related to T cell lymphocytopenia such as pneumocystis carinii and herpes infections should consist of o cotrimoxazol 480 mg twice a day, 3 times a week; during granulocytopenia, the dose can be increased to 960 mg, twice daily o fluconazol 100 mg once a day o valaciclovir 500 mg twice a day. All three drugs should be continued until 2 months after the last alemtuzumab gift. In addition, close CMV antigen monitoring is required, at least at the start of each Camp-CHOP cycle. Finally, all blood products need to be irradiated until 6 months after the last alemtuzumab gift. Vaccinations with live viral vaccines should be avoided until at least one year after the last alemtuzumab gift Measurements to monitor and treat CMV (re)activation CMV (re) activation should be monitored with an appropriate antigen or virus-dna detection technique according to the methods of the participating hospital at least every fortnight or more frequently if necessary based on prior results. In case of active CMV disease and/or evident Page 14 of 48

15 laboratory signs of reactivation (positive antigenaemia or rising PCR results; transient low level CMV activity should be ignored) prompt (preemptive) treatment should be instigated with oral valgancyclovir or intravenous gancyclovir according to the rules of the local hospital. During valgancyclovir/gancyclovir treatment therapy with valaciclovir should be stopped. In the case of CMV disease such as pneumonia (CTC grade 3) Alemtuzumab should be stopped, the patient will go off protocol, and should preferably continue with CHOP alone. In the case of CMV-reactivation (CTC grade 2) Camp-CHOP should be interrupted for 1-2 weeks. If the CMV antigenemia responds upon therapy, Camp-CHOP can be resumed at full dose, while valganciclovir will be continued at prophylactic doses (3 times a week 900 mg). If CMV antigenemia does not respond, Alemtuzumab will be stopped and the patient will go off protocol treatment. It is advised to continue therapy with CHOP alone. 9.4 Concomitant medication and treatment Thus far, there are no reported interactions between alemtuzumab and other drugs. a) Drugs Concomitant medication introduced in the patient since the beginning of the treatment will be recorded on the Case Report Form (CRF) in case of any adverse event of CTCAE grade 2. Patients should receive full supportive care including blood transfusions and blood products (which should always be irradiated!), antibiotics, anti-emetics etc., where applicable. It is advised to administer ondansetron (Zofran) or granisetron (Kytril) orally once or twice daily with each Camp-CHOP cycle. b) Radiotherapy Radiotherapy before start and during protocol treatment is permitted for localized problems, i.e. in case of potential or actual organ dysfunction by localized lymphoma mass or infiltration. Additional radiotherapy after completion of the protocol is only allowed in case of bulky disease (> 10 cm) at diagnosis, with residual PET positive abnormalities at the end of protocol treatment. 10 End of protocol treatment Reasons for going off protocol treatment are: 1. No response after 3 Camp-CHOP cycles 2. Progression/relapse after initial response (i.e. before completion of treatment) 3. Manifest cardiomyopathy (absolute reduction of ejection fraction >15%) Page 15 of 48

16 4. Other excessive toxicity requiring stopping of protocol treatment (including toxic death) 5. No compliance of the patient (especially refusal to continue treatment) 6. Intercurrent death 7. Major protocol violation 8. Normal completion of protocol treatment Concerning intercurrent stopping of participation as described under point 5: the patient should if responsive thus far preferably receive continuing treatment according to CHOP chemotherapy alone, thus avoiding the risk of undertreatment causing a lesser chance upon complete remission. 11 Required clinical evaluation Also see appendix B for a specification of staging and restaging evaluations Observations prior to start of treatment history (including B symptoms) physical examination (including WHO performance) laboratory tests (including Hb, WBC and differential, platelet count, sodium, potassium, calcium, creatinine, uric acid, bilirubin, glucose, alkaline phosphatase, γ-gt, ALAT, ASAT, LDH, albumin) routine urine analysis imaging (including chest X-ray, CT or MRI neck, thorax and abdomen) lymph node or tissue of biopsy of involved site for morphology and immunopathology immunophenotyping of biopsy of involved site for CD3, CD4, CD5, CD8, CD30, CD52, CD56, granzyme B/perforin, TIA-1, and if possible EBER RNA in situ hybridization if possible, cryopreservation of lymphoma involved tissue for external PA review in case T-cell receptor rearrangement analysis is required for a definite diagnosis bone marrow aspirate and biopsy (marrow fields minimal 2 cm length) peripheral blood for cytology ABO and RhD blood group, irregular antibody screening, anti Hepatitis B and C Left ventricular ejection fraction (LVEF) or cardiac ultrasound/doppler CMV Ig antibodies and CMV antigen in peripheral blood EBV-DNA (quantitative PCR peripheral blood) if NHL is EBV+ (especially angioimmunoblastic T-NHL can be EBV-positive) Page 16 of 48

17 11.2 Observations after each cycle of Camp-CHOP in relation to alemtuzumab toxicity o o CMV antigen monitoring Cardiotoxicity should be frequently monitored. The LVEF should be repeated halfway and at the end of therapy Observations after 3 and 8 cycles of Camp-CHOP history (including B symptoms) physical examination (including WHO performance) laboratory tests (including Hb, WBC and differential, platelet count, sodium, potassium, creatinine, uric acid, bilirubin, glucose, alkaline phosphatase, γ-gt, ALAT, ASAT, LDH, albumin) routine urine analysis imaging of involved areas (including chest X-ray, CT or MRI thorax and abdomen and echography of the cervical lymph node stations), PET scanning in case of residual abnormalities bone marrow aspirate and biopsy / peripheral blood (if initially positive) LVEF or cardiac ultrasound/doppler EBV-DNA if positive at start Response assessment after cycle 3 and cycle 8 of Camp-CHOP Response will be formally evaluated after Camp-CHOP cycles 3 and 8 according to the criteria of response. The response criteria are in appendix B. PET scanning or histology/cytology of the residual lesion at end of protocol is strongly advised in case of residual abnormalities. A patient with PET (or histology) negative residual abnormalities on CT may be considered as CRu. All relevant information on drug dose, measurable lesions, tumor response and treatment related toxicity will be collected Observations during follow up Follow up for patients in CR or CRu will be every 3 months during the first two years, every 6 months the next two years and annually thereafter. Patients who have not achieved CR/CRu and relapsed patients will be followed until death. Physical examination (including WHO performance) Page 17 of 48

18 Blood count, LDH Any clinically indicated examinations (appropriate scans annually for the first 2 years) Any documentation of abnormal events (e.g. serious late infections, cardiac abnormalities, secondary malignancies) Any relapse should preferably be documented by histology. Biopsy material should be sent for central pathology review to assess CD52 expression. 12 Toxicities CHOP is a commonly used chemotherapeutic regimen with well-known side effects. The most frequent side effect is myelosuppression which may hamper patient adherence to the projected schedule of CHOP. Side effects of subcutaneously administered alemtuzumab may include fever (frequent, grade I-II during the first 2 weeks), rigors (about 25%, grade I-II, during the first 2 weeks), mucosal congestion or edema (rare), and drop in systolic blood pressure (rare). Most patients will experience local reactions at injection sites varying from grade I erythema only (can measure up to 30 cm in diameter), local mild pain or local mild pruritus. Special management is provided in paragraph 9.3. Toxicities will be scored according to the NCI Common Terminology Criteria for Adverse Events, CTCAE version 3.0, published June 10, 2003 (see Appendix D). Cardiotoxicity should be carefully monitored by physical examination and LVEF monitoring (preferably after cycle 4 and 8). In case of a reduction of >15% (absolute value, corrected for the pre-lvef value) or a decline of the LVEF <45%, the patient should go off treatment. If the patient develops symptomatic cardiomyopathy, the LVEF should be repeated, and the patient should go off protocol treatment during a decline of the LVEF or if NYHA grade 3 or 4 develops. 13 Reporting serious adverse events An Adverse Event (AE) is any untoward medical occurrence or experience in a patient or clinical investigation subject which occurs during or following treatment regardless of the causal relationship. This can include any unfavorable and unintended signs (such as rash or enlarged liver), or symptoms (such as nausea or chest pain), an abnormal laboratory finding (including blood tests, x-rays or scans) or a disease temporarily associated with the treatment. Page 18 of 48

19 Serious Adverse Events (SAE) are defined as any undesirable experience occurring to a patient, whether or not considered related to the treatment. Adverse events which are considered as serious are those which result in: death a life-threatening event (i.e. the patient was at immediate risk of death at the time the reaction was observed) hospitalization or prolongation of hospitalization severe/permanent disability a congenital anomaly Note that any death, whether due to side effects of the treatment or due to progressive disease or due to other causes is considered as a serious adverse event. Unexpected Serious Adverse Events are those SAE s of which the nature or severity is not consistent with information in the relevant source documents. For a medicinal product not yet approved for marketing in a country, a company s Investigator s Brochure will serve as a source document in that country. Reporting Serious Adverse Events During protocol treatment all deaths, all SAE s that are life-threatening and any unexpected SAE must be reported to the HOVON Data Center by fax within 48 hours of the initial observation of the event. All details should be documented on the Serious Adverse Event and Death Report. In circumstances where it is not possible to submit a complete report an initial report may be made giving only the mandatory information. Initial reports must be followed-up by a complete report within a further 14 calendar days and sent to the HOVON Data Center. All SAE Reports must be dated and signed by the responsible investigator or one of his/her authorized staff members. At any time after the completion of protocol treatment, unexpected Serious Adverse Events that are considered to be possibly related to protocol treatment and ANY death (regardless the cause) must also be reported to the HOVON Data Center using the same procedure, within 48 hours after the SAE or death was known to the investigator. The investigator will decide whether the serious adverse event is related to the treatment (i.e. unrelated, unlikely, possible, probable, definitely and not assessable) and the decision will be recorded on the serious adverse event form. The assessment of causality is made by the investigator using the following : Page 19 of 48

20 RELATIONSHIP UNRELATED UNLIKELY POSSIBLE PROBABLE DEFINITELY NOT ASSESSABLE DESCRIPTION There is no evidence of any causal relationship There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the patients clinical condition, other concomitant treatments). There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the patients clinical condition, other concomitant treatments). There is evidence to suggest a causal relationship and the influence of other factors is unlikely. There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out. There is insufficient or incomplete evidence to make a clinical judgement of the causal relationship. The HOVON Data Center will forward all reports within 24 hours of receipt to the study coordinator and the study central datamanager. The report of an SAE will be the signal for the central datamanager to ask the investigator or the responsible local datamanager to complete and send as soon as possible all relevant CRF s for the involved patient with details of treatment and outcome. It is of utmost importance that all SAE s (including all deaths due to any cause) are reported in a timely fashion. Patients without a report of an SAE are implicity considered alive without SAE. This information will be used in monitoring the incidence of SAE s, the estimation of overall survival and monitoring of safety of experimental treatments. Page 20 of 48

21 14 Endpoints Primary endpoint 1. Complete response including CRu on protocol Secondary endpoints 2. Event-free survival (i.e. time from registration to induction failure (i.e. no CR, CRu or PR on induction treatment), death or relapse whichever occurs first); the time to failure of patients with induction failure is set at one day. 3. Overall survival measured from the time of registration 4. Disease-free interval (duration of the first CR/CRu) measured from the time of achievement of CR to day of relapse or death from any cause (whichever occurs first). 5. Toxicity CTCAE grade 3-4 (according to Appendix D), except nausea, vomiting, alopecia and hematological toxicity. 15 Procedures for collecting data Data will be collected on Case Report Forms (CRF) to document eligibility, safety and efficacy parameters, compliance to treatment schedules and parameters necessary to evaluate the study endpoints. Data collected on the CRF are derived from the protocol and will include at least: inclusion and exclusion criteria baseline status of patient including medical history and stage of disease timing and dosage of protocol treatment adverse events parameters for response evaluation any other parameters necessary to evaluate the study endpoints survival status of patient reason for end of protocol treatment Each CRF page will be identified by a pre-printed trial number, and a unique combination of patient study number (assigned at registration), hospital and patient name code (as documented at registration) to be filled out before completing the form. The CRF will be completed on site by the local investigator or an authorised staff member. Each page must be dated and signed by the local investigator upon completion. All CRF entries must be Page 21 of 48

22 based on source documents. The CRF, the schedule for filling out of forms, and written instructions for completing the CRF will be provided by the HOVON Data Center. Copies of the CRF will be kept on site. The original CRF pages must be sent to the HOVON Data Center at the requested timepoints. How and when to send in forms is described in detail in the CRF header and the CRF instructions. In order to be able to closely monitor the occurrence of untoward events it is of utmost importance that the CRF s regarding induction treatment, for all patients, are submitted in a timely fashion i.e. within one month of completion of the induction treatment. All data from the CRF will be entered into the study database by the HOVON Data Center. 16 Registration The patient should be registered immediately after satisfactory completion of screening tests and obtaining informed consent, and before the start of chemotherapy. Patients need to be registered at the HOVON Data Center of the Erasmus MC Daniel den Hoed by phone call: or fax Monday through Friday, from 09:00 to 17:00 or via the Internet via TOP (Trial Online Process; A logon to TOP can be requested at the HOVON Data Center for participants. The following information will be requested at registration: 1. Protocol number 2. Institution name 3. Name of caller/responsible investigator 4. Patient s initials or code 5. Patient s hospital record number 6. Sex 7. Date of birth 8. Date of diagnosis of NHL 9. WHO classification 10. PA number 11. Eligibility criteria All eligibility criteria will be checked with a checklist. Page 22 of 48

23 Each patient will be given a unique patient study number. Patient study number will be given immediately by TOP or phone and confirmed by fax or Statistical considerations 17.1 Patient number and power considerations This phase II trial follows an optimal two-stage Bryant-Day design 18. The objective of this phase II trial is to evaluate whether the treatment is worth with respect to response and toxicity further study. In addition, the design shields patients from an ineffective or toxic treatment by requiring early termination of the trial if either the initial response rate is poor or the toxicity rate is high. The sample size calculations of the design are based on the response and toxicity endpoints. The following assumptions are made: # A response rate larger than 50% is considered acceptable. # A response rate smaller than 20% is considered unacceptable. # A toxicity rate larger than 50% CTCAE grade 3-4 (except nausea, vomiting, alopecia and hematological toxicity) is considered unacceptable. # A toxicity rate smaller than 20% CTCAE grade 3-4 (except nausea, vomiting, alopecia and hematological toxicity) is considered acceptable. # The probability of accepting a treatment as worth further study, while in fact its response rate is unacceptable, is limited to 10% (α R = 0.10). # The probability of accepting a treatment as worth further study, while in fact its toxicity rate is unacceptable, is limited to 15% (α T = 0.15). # The probability of rejecting a treatment for further study, while in fact it is acceptable with respect to both reponse and toxicity, is limited to 20% (β = 0.20). These assumptions imply a sample size of 18 patients to be included in the study. To account for an unexpected loss of 10%, the total number of patients to be included in the study is set to 20. The accrual of the required 20 patients is expected to take place within two years. This is motivated as follows. Each year, there are approximately 3000 new NHL patients in the Netherlands, of which 6%, i.e., 150 are T-NHL patients. A large percentage of these 150 is assumed to be too old or too ill to receive the treatment under study. Moreover, of the remainder not all will participate. These considerations lead to the expectation of 10 to 20 patients that enter the study each year. Page 23 of 48

24 17.2 Statistical analysis Efficacy analysis The efficacy of the treatment with respect to the main end points response and toxicity will be evaluated as follows. If: # Five or less out of the 18 patients obtain a response, the treatment is rejected due to inadequate response. # Eight or more out of the 18 patients experience toxicity (grade 3-4, except nausea, vomiting, alopecia and hematological toxicity), the treatment is rejected due to excessive toxicity. If none of the above applies the treatment is considered acceptable. In addition, point estimates and corresponding confidence intervals of the response rate and toxicity rate will be estimated, With respect to the secondary endpoints, as defined in chapter 14, # The event-free survival will be analysed using an actuarial Kaplan-Meier estimate. Its median and the corresponding 95% confidence intervall will be calculated # The overall survival will be analysed using an actuarial Kaplan-Meier estimate. Its median and the corresponding 95% confidence intervall will be calculated # The disease-free interval will be analysed using an actuarial Kaplan-Meier estimate. Its median and the corresponding 95% confidence intervall will be calculated All analyses of secondary endpoints are exploratory. Hence, no conclusions will be drawn from them Interim analysis and stopping rules An interim analysis is planned when the response and toxicity data of the first consecutive nine patients are available. The trial will be terminated if, either: # Two or less out of these nine patients obtain a response. The treatment is rejected due to inadequate response. Or, # Four or more out of these nine patients experience toxicity. The treatment is rejected due to excessive toxicity. Page 24 of 48

25 These stopping rules imply that the probability of early termination (and the overall probability of not accepting the treatment for further study) in the case of: # Poor response (a true response rate smaller than 20%) and excessive toxicity (a true toxicity rate larger than 50%) is 93% (overall probability 99%). # Poor response (a true response rate smaller than 20%) and acceptable toxicity (a true toxicity rate smaller than 20%) is 76% (overall probability 91%). # Good response (a true response rate larger than 50%) and excessive toxicity (a true toxicity rate larger than 50%) is 77% (overall probability 86%). # Good response (a true response rate larger than 50%) and acceptable toxicity (a true toxicity rate smaller than 20%) is 17% (overall probability 19%). After inclusion of nine patients the response and toxicity data may not be available. The study will then be put on hold if at that time either: # Less than two response have been reported. Or, # It is still possible to have four out of these nine patients with toxicity. If neither of the above is applicable new patients may be included. 18 Ethics 18.1 Independent ethics committee or Institutional review board The study protocol and any amendment that is not solely of an administrative nature will be approved by an Independent Ethics Committee or Institutional Review Board Ethical conduct of the study The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki (Edinburgh, Scotland, 2000) and the ICH-GCP Guidelines of 17 January The local investigator is responsible for ensuring that the study will be conducted in accordance with the protocol, the ethical principles of the Declaration of Helsinki, current ICH Guidelines on Good Clinical Practice (GCP), and applicable regulatory requirements Patient information and consent Written Informed consent of patients is required before registration. The procedure and the risks and the opinions for therapy in NHL will be explained to the patient. He or she will be given one week time to decide in order to avoid too much delay before chemotherapy can be started. Each Page 25 of 48

26 center should in its local patient information form offer the possibility that an independent internist or hematologist (with name, address and phone number) is willing to give additional information. 19 Trial insurance The HOVON insurance program covers all patients from participating centers in the Netherlands according to Dutch law (WMO). The WMO insurance statement can be viewed on the HOVON Web site Individual participating centers from outside the Netherlands have to inform the HOVON about the national laws regarding the risk insurance of patients participating in a study. If necessary HOVON will extend the insurance to cover these patients. Intergroup studies. The HOVON insurance program does not cover the risk insurance of patients from centers participating within another cooperative group taking part in an intergroup study. The other participating groups will cover the insurance of patients registered/randomized through their offices. 20 Publication policy The final publication of the trial results will be written by the Study Coordinator(s) on the basis of the statistical analysis performed at the HOVON Data Center. A draft manuscript will be submitted to the Data Center and all co-authors (and the sponsor, where applicable) for review. After revision by the Data Center, the other co-authors (and the sponsor), the manuscript will be sent to a peer reviewed scientific journal. Authors of the manuscript will include the study coordinator(s), investigators who have included more than 5% of the evaluable patients in the trial (by order of inclusion), the statistician(s) and the HOVON datamanager in charge of the trial, and others who have made significant scientific contributions. Any publication, abstract or presentation based on patients included in this study must be approved by the study coordinator(s). This is applicable to any individual patient registered in the trial, or any subgroup of the trial patients. Such a publication cannot include any of the study endpoints unless the final results of the trial have already been published. Page 26 of 48

27 21 Glossary of abbreviations (in alphabetical order) AE Adverse Event ALAT Alanine Amino Transferase ASAT Aspartate Amino Transferase ATLL Adult T cell Leukemia/lymphoma BM Bone Marrow Camp-CHOP CHOP + alemtuzumab (MabCampath ) CD52 Cluster Defined number 52 CHOP Cyclophosphamide, Doxorubicin, Vincristine (Oncovin), Prednisone CHOP-14 2 weekly CHOP CMV cytomegalovirus CKTO Commissie voor Klinisch Toegepast Onderzoek CR Complete Remission/Response CRF Case Report Form CRu Complete Remission unconfirmed CR1 First Complete Remission CT Computerized Tomography CTCAE Common Terminology Criteria for Adverse Events DFS Disease Free Survival DSMB Data and Safety Monitoring Board EATL Enteropathy associated T cell Lymphoma EBER EBV encoded RNA EBV Epstein Barr Virus EFS Event Free Survival ENT Ear Nose Throat GCP Good Clinical Practice G-CSF Granulocyte Colony Stimulating Factor γgt Gamma Glutamyl Transferase GvHD Graft-versus-Host-Disease Hb Hemoglobin HOVON Dutch-Belgian Hematology-Oncology Cooperative Group HIV Human Immunodeficiency Virus ICH International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use IPI International Prognostic Index IV Intravenous LDH Lactate Dehydrogenase LVEF Left Ventricular Ejection Fraction MRI Magnetic Resonance Imaging NCI National Cancer Institute Page 27 of 48

28 NHL NOS NYHA OS PA PB PD PET PO PPD PR SAE SD SPD T-LGL T-NHL T-PLL TOP US WBC WHO WMO Non-Hodgkin s Lymphoma Not otherwise specified New York Heart Association Overall Survival Pathology Peripheral Blood Progressive Disease Positron Emission Tomography Per Os Product of the two largest Perpendicular Diameters Partial Response Serious Adverse Event Stable Disease Sum of the Products of the two largest perpendicular Diameters T cell large granular lymphocyte leukemia T cell Non-Hodgkin lymphoma T cell prolymphocytic leukemia Trial Online Process Ultrasound White Blood Count World Health Organization Wet Medisch-Wetenschappelijk Onderzoek met mensen Page 28 of 48