Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014;371: DOI: /NEJMoa

2 This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Statistical analysis plan.

3 1 Protocol Title: A PHASE 3, MULTICENTRE, RANDOMIZED, CONTROLLED STUDY TO DETERMINE THE EFFICACY AND SAFETY OF LENALIDOMIDE, MELPHALAN AND PREDNISONE (MPR) versus MELPHALAN (200 mg/m2) FOLLOWED BY STEM CELL TRANSPLANT IN NEWLY DIAGNOSED MULTIPLE MYELOMA SUBJECTS STUDY DRUG Lenalidomide (CC-5013) PROTOCOL NUMBER: RV-MM-PI-209 DATE FINAL: 13/03/2007 AMENDMENT: / CONFIDENTIAL The information contained in this document is regarded as confidential and, except to the extent necessary to obtain informed consent, may not be disclosed to another party unless such disclosure is required by law or regulations. Persons to whom the information is disclosed must be informed that the information is confidential and may not be further disclosed by them. Version 1,

4 2 PRINCIPAL INVESTIGATOR SIGNATURE PAGE Principal Investigator: DR. ANTONIO PALUMBO 13/03/2007 By my signature, I agree to personally supervise the conduct of this study and to ensure its conduct in compliance with the protocol, informed consent, IRB/EC procedures, instructions from Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices guidelines, and the applicable parts of the European Code of Regulations or local regulations governing the conduct of clinical studies. STUDY PERSONNEL Study Location: Principal Investigator: Study Coordinator: Version 1,

5 3 1 STUDY CONTACT INFORMATION Celgene Emergency Contact Information Drug Safety Contact Dr. Janine Collins or designee Celgene International Sàrl Faubourg du Lac Neuchâtel Switzerland Tel: Fax: DrugSafetyEurope@Celgene.com 24-Hour Emergency Contact Call Centre Direct Telephone: and follow the instructions in the recorded message Celgene S.r.l. Dr. Roberta Di Menno Di Bucchianico Pharmacovigilance Manager Tel: +39/02/ Mobile: +39/340/ drugsafetyitaly@celgene.com Version 1,

6 4 2.SYNOPSIS A PHASE 3, MULTICENTRE, RANDOMIZED, CONTROLLED STUDY TO DETERMINE THE EFFICACY AND SAFETY OF LENALIDOMIDE, MELPHALAN AND PREDNISONE (MPR) versus MELPHALAN (200 mg/m2) FOLLOWED BY STEM CELL TRANSPLANT IN NEWLY DIAGNOSED MULTIPLE MYELOMA SUBJECTS PROTOCOL NUMBER: RV-MM-PI-209 DATE PROTOCOL FINAL: 13/03/2007 STUDY DRUG: INDICATION: STUDY PHASE: LENALIDOMIDE (CC-5013) Multiple Myeloma III BACKGROUND AND RATIONALE High-dose chemotherapy with haemopoietic stem-cell support increases the rate of complete response and extends event-free and overall survival (1-4) in multiple myeloma (MM). In a randomized trial the combination of melphalan, prednisone and thalidomide (MPT) significantly increased response rate and event-free survival (5). In another trial MPT was superior to a reduced intensity autologous transplantation (MEL100) (6). In a recent report the combination of lenalidomide with MP (MPR) showed response rates quite similar to those achieved after standard autologous transplant (7). This study will evaluate the efficacy and safety of the association of lenalidomide, melphalan, prednisone (MPR) versus the standard autologous transplantation melphalan 200 mg/m 2 (MEL200). Study Objectives: Primary: To compare the efficacy of the combination of lenalidomide with low-dose melphalan versus highdose melphalan in newly diagnosed, symptomatic MM patients. Secondary: To evaluate whether induction treatment with lenalidomide compromises subsequent mobilization of peripheral blood stem cells (PBSC). To assess the safety of lenalidomide in combination with low-dose melphalan compared to high-dose melphalan in newly diagnosed, symptomatic MM patients. To assess the efficacy and safety of lenalidomide as maintenance treatment after the consolidation phase. Study Endpoints: Version 1,

7 5 Primary: Progression free survival (PFS) Secondary: Overall survival (OS) Time to progression (TTP) Objective overall response rate Time to response Duration of response Number of PBSC collected. Time to the next anti-myeloma therapy Incidence of Grade 3 and 4 hematological and non-hematologic adverse events (AEs) Quality of Life assessment (QoL) (European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients with Cancer [EORTC QLQ-C30] and QoL Questionnaire for Patients with Multiple Myeloma [QLQ-MY24] Exploratory assessment on prognosis and cytogenetic abnormalities STUDY DESIGN: This is a multicenter, randomized, open label study designed to compare the efficacy and safety of lenalidomide in combination with low-dose melphalan versus high-dose melphalan followed by stem cell support in newly diagnosed symptomatic MM patients who are 65 years of age or younger. Potential study subjects will sign an informed consent prior to undergoing any study related procedure. This study consists of 4 phases for each study subject: Pre-treatment, Treatment, Extension and Follow up. Pre-treatment period: patients will undergo screening for protocol eligibility within 28 days (4 weeks) of randomization as outlined in Section 3: Schedule of Study Assessments. Subjects who meet all the inclusion criteria will be randomized (1:1 ratio) twice based on a computer-generated randomization schedule prepared by the Coordinating Center. The first randomization will occur for the consolidation treatment: Arm A (MPR) or B (MEL200 and stem cell support). Within each arm patients will be then randomized for the maintenance treatment: Arms A1 (no maintenance) and A2 (maintenance with R), Arms B1 (no maintenance) and B2 (maintenance with R). Randomization will be concealed until the end of the induction period for the consolidation treatment and until the end of the consolidation treatment for the maintenance treatment. Patients will be stratified at randomization according to the International Staging System (8) and to age (< 60 years vs > 60 years). Treatment period includes induction, consolidation and maintenance. During the induction and consolidation phases, all patients will attend periodic study centre visits in order to asses the safety and efficacy of the treatment. Version 1,

8 6 Patients receiving MEL200 will require two periods of in-patient care to perform the autologous transplantation. During the maintenance period, all patients will attend study centre visits every 4 weeks, until development of confirmed Progressive Disease (PD) Induction regimen Patients will start induction treatment with lenalidomide and dexamethasone (RD) for 4 cycles every 28 days: Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15 and 22 every 28 days. After 1-2 months from the completion of the last RD cycle, i.v. cyclophosphamide (CY) will be given at the dose of 4 g/m 2 followed by G-CSF (10 ug/kg/day starting at day 5 until completion of PBSC collection) to collect an adequate number of PBSC (4 to 10 x 10 6 /kg CD 34+ cells). Patients who fail to collect the minimum of 4 x 10 6 /kg CD 34+ cells will receive a second course of CY for a second mobilization attempt. Patients who fails to collect a minimum of 4 x 10 6 /kg CD 34+ will be withdrawn from the study. Consolidation regimen: After 1-2 months from the completion of the last CY infusion ARM A Patients will start consolidation treatment with the association of lenalidomide, melphalan and prednisone (MPR) for 6 cycles every 28 days: Lenalidomide will be given orally at the dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), Melphalan will be given orally at the dose of 0.18 mg/kg for 4 days, followed by a 24 days rest period (day 5 to 28) Prednisone will be given orally at the dose of 2 mg/kg for 4 days followed by a 24 day rest period (days 5 to 28), ARM B Patients will start consolidation treatment with melphalan 200 mg/m 2 followed by stem cell support (MEL200) for 2 cycles every 4 months: Melphalan will be given iv at the dose of 200 mg/m 2 for 1 day followed by stem cell support and 120 days rest period. Maintenance regimen After 2-3 months from the completion of the last MPR or MEL200 cycle. ARM A1 and B1: No therapy. ARM A2 and B2: Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period. Each Version 1,

9 7 cycle will be repeated every 28 days, until any sign of disease progression (PD). Concomitant therapy Prevention of Pneumocystis infection is recommended. For this purpose, patients should be given Cotrimoxazole 800 mg twice daily for 2 days every week, throughout the entire treatment program (including maintenance therapy). Antiviral prophylaxis should be use in case history of HZV infection. Appropriate antibacterial, antifungal, or antiviral therapy should be used if infections occur. Oral levofloxacin or ciprofloxacin once and twice daily respectively is suggested if neutropenia or recurrent infection occurrs. Patients will receive anti-thrombotic prophylaxis according to the Substudy protocol Low molecular weight heparin (LMWH) versus aspirin (ASA) as thromboprophylaxis in myeloma patients at diagnosis treated with a lenalidomide-containing protocol as outlined in Appendix I. All subjects will be allowed to receive bisphosphonate therapy and haematopoietic growth factors. Extension phase A subject who develops PD during the Treatment Phase will decide whether or not to enter the Extension Phase within 1-2 months after the occurrence of PD. Patients who will not enter the Extension phase will be followed as during the Follow up period. It is suggested that subjects in Treatment Arms A (A, A1 and A2) who experience PD during the Treatment Phase will receive MEL200 (2 cycles) with stem cell support, while subjects in Treatment Arms B (B, B1 and B2) will receive conventional treatment at discretion of the treating physician. Study visits and serial measurements of safety and efficacy will be performed as outlined in Section 3: Schedule of Study Assessments. Subjects who are discontinued from the Extension Phase will enter the Follow up Phase and followed for survival. Follow up During the Follow up period all patients will be followed for survival every 3 months via telephone or office visit. Duration of study The duration of the induction and consolidation treatment is approximately 12 months for Arm A and Arm B. This time is required to complete the treatment, and to determine the safety profile and the response rate. The duration of the R maintenance is approximately 2 years. The median duration of remission at diagnosis is approximately 3 years, the duration of the Follow up from relapse will be approximately 2 years, the median overall survival from diagnosis approximately 5 years. The occurrence of PD will determine the duration of progression-free survival of each patient (primary endpoint). The occurrence of death will determine the duration of overall survival (secondary endpoint). Inclusion criteria: Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements. Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. Patient is 65 years old or younger at the time of signing the informed consent Version 1,

10 8 Female patient is either post-menopausal or surgically sterilized or willing to use an acceptable double method of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Negative serum β-human chorionic gonadotropin ( β-hcg) pregnancy test both 24 hours prior to beginning of therapy and then at 4 weeks intervals in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles during study treatment for subjects of childbearing potential Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) during study drug therapy (including dose interruption) and for 4 weeks after discontinuation of lenalidomide therapy. Patient was diagnosed with symptomatic multiple myeloma based on standard criteria (9), and has measurable disease, defined as follows: any quantifiable serum monoclonal protein value (generally, but not necessarily, greater than 1 g/dl of IgG M-Protein and greater than 0.5 g/dl of IgA M-Protein) and, where applicable, urine light-chain excretion of >200 mg/24 hours; measurable plasmacytoma > 2 cm as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan); bone marrow plasma cells>10%. Patient has a Karnofsky performance status 60%. Patient has a life-expectancy > 6 months Patient has not active infectious hepatitis type B or C, and has HIV negative test Patients must have an ejection fraction by ECHO or MUGA > 50% performed within 60 days prior to registration Patients must have adequate pulmonary function studies > 50% of predicted on mechanical aspects (FEV 1, FVC, etc) and diffusion capacity (DLCO) > 50% of predicted. Patients unable to complete pulmonary function tests because of myeloma-related chest pain, must have a high resolution CT scan of the chest and must also have acceptable arterial blood gases defined as P0 2 greater than 70. Patient has the following laboratory values within 14 days before Baseline (day 1 of the Cycle 1): - Platelet count 75 x 10 9 /L without transfusion support within 7 days before the test. - Absolute neutrophil count (ANC) 1.5 x 10 9 /L without the use of growth factors. - Corrected serum calcium 14 mg/dl (3.5 mmol/l). - Aspartate transaminase (AST): 2.5 x the upper limit of normal (ULN). - Alanine transaminase (ALT): 2.5 x the ULN. - Total bilirubin: 1.5 x the ULN. - Calculated or measured creatinine clearance: 20 ml/minute Patient has a baseline bone marrow sample available for cytogenetics, that will be processed and eventually centralized within each country. Version 1,

11 9 Exclusion criteria: Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid; < to the equivalent of dexamethasone 40 mg/day for 4 days). Any serious medical condition, including the presence of laboratory abnormalities, which places the subject at an unacceptable risk if he or she participates in this study or confounds the experimental ability to interpret data from the study. Pregnant or lactating females. Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for 3 years. Exceptions include the following: Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin, Carcinoma in situ of the cervix, Carcinoma in situ of the breast, Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b) Neuropathy of grade 2 severity. Patients previously diagnosed as bearing deep venous thrombosis or arterial thromboembolic event within the latest 6 months, or bearing a clear indication for anti-platelet or anticoagulant therapy or bearing a high risk of bleeding complications are ineligible for the sub-study protocol. Assessments: Efficacy The following evaluations will be conducted to assess the efficacy of the treatment regimens: Date of documentation of disease progression Myeloma protein measurements in serum and urine. Bone marrow examination Skeletal survey and other radiographs B2microglobulin, C-reactive Protein (CRP) Assessment of disease response (based on the International Response Criteria reported by Durie et al. [10]) Karnofsky performance status Safety The following evaluations will be conducted to assess the safety of the treatment regimens: Complete physical examination including vital signs. Clinical laboratory evaluations (hematology, chemistry) Serum or urine beta-human chorionic gonadotropin (ß-HCG; FCBP only) levels Electrocardiogram and Chest Radiograph Number of PBSC collected Serum TSH, Tri-iodothyronine (T3), and thyroxine (T4) levels (optional) Testosterone level (men only, optional) Version 1,

12 10 Concomitant medication and procedures Adverse events Health outcomes assessment (any extra medical appointment) Other Exploratory cytogenetic abnormalities by FISH analysis which will be eventually centralized within each country. QoL - EORTC QLQ-C30 module. Statistical methods Sample Size: The primary analysis for the study is to compare PFS between Treatment Arm A (MPR) and Treatment Arm B (MEL200). For the primary efficacy variable, PFS, a 15% improvement in median time to progression is considered clinically relevant. In the MPR arm we will theoretically expect 50% of patients progression free and alive at 2 years, while we will theoretically expect a 65% of patients receiving MEL200 progression free and alive at 2 years. The median survival in Treatment Arm A has been estimated at 48 months while that in Treatment Arm B has been estimated to be 56 months. We will enrol 170 patients for each arm to demonstrate a 15% improvement of progression-free survival (two-sides α = 0.05, significance level of the statistical test, β = 0.20 corresponding to power of 80%). Since 10% of the patient population is lost during follow-up, the properly sample size of 380 patients (each arm 190 patients) is required; it can be achieved in 2 years of enrolment. Efficacy analysis: Primary efficacy analyses will be based on the intent-to-treat principle. The primary comparison will be made between Treatment Arm A and B, and secondary comparisons will be made between Arms A1 and A2, and between Arms B1 and B2. Primary analyses for PFS, time to progression, response rate, time to response, duration of response, and time to the next anti-myeloma therapy will be performed after at least 190 subjects across all treatment arms have developed disease progression or died (i.e., PFS). Final analyses to compare OS will be performed after all subjects have completed 4 years or died/lost to follow-up before 4 years. The Kaplan- Meier product limit method will be used to estimate the survivorship functions for time-to-event endpoints (e.g., PFS, TTP, time to response, duration of response, time to the next anti-myeloma therapy, and OS). The log-rank test will be used to compare treatment arms for time-to-event variables. The Cox proportional hazards regression model will be used to assess the significance of demographic and prognostic variables on relative treatment differences. Exact tests for proportions will be used to compare objective overall response rates. Summary statistics (standard deviation, median, minimum and maximum) will be provided for relevant variables. Descriptive analyses by treatment regimen will be performed for information obtained during the Extension Phase. Safety Analysis: Data from all subjects who receive any study drug will be included in the safety analyses. The severity of the toxicities will be graded according to the NCI CTC whenever possible. In the by-subject analysis, a subject having the same event more than once will be counted only once. Adverse events will be summarized by worst NCI CTC grade. In the case that the adverse events or event frequencies are judged to be clinically important, an exact test will be used to analyze the difference between the treatment groups. Adverse events leading to death or to Version 1,

13 11 discontinuation from treatment, events classified as NCI CTC Grade 3 or Grade 4, study-drug-related events, and serious adverse events will be summarized separately. Laboratory data will be graded according to NCI CTC severity grade. Safety information obtained during the Extension Phase will be summarized by treatment regimen. Interim Analysis: Three interim analysis are planned. The first analysis to evaluate safety (mobilization of PBSC and incidence of thromboembolic events) is planned after 80 patients have completed the induction phase. The second interim analysis to evaluate efficacy will be conducted when the first 190 patients will be enrolled. The third interim analysis will be performed when all the 380 patients will be enrolled. STUDY DURATION: 4 years DOSING REGIMEN(S): Lenalidomide will be used at the dose of 25 mg/day during induction phase and at 10 mg/day during consolidation and maintenance phases TOTAL SAMPLE SIZE: 380 patients (190 in arm A and 190 in arm B ) STUDY DRUG SUPPLIES: Celgene Corporation will supply Lenalidomide as 2,5, 5, 10 and 25 mg capsules Melphalan, cyclophosphamide, dexamethasone and Prednisone are commercially available. Version 1,

14 12 3. SCHEDULE OF STUDY ASSESSMENT. Table1: Schedule of Study Assessments (Arms A) Procedure Screening Induction RD PBSC mobilization Consolidatio n MPR Maintenance R PD Extension study MEL200 Follow-up 28days from Baseline Cycles 1-4 Every Within 2 months from last RD 28 days 13 Cycl es 1-6 Day 1 Day Every days Day -2 and during treatment Informed consent Eligibility criteria Clinical history Randomization Physical examination 1, vital signs, weight Symptoms-directed physical examination X X X X X X X 9 X X X X X X X X 9 X X X X X Karnofsky performance status X X X 9 X X X X X 12-lead ECG 2 and cardiac function tests 3 Chest x-ray 2 and pulmonary function tests 2 CT or MRI if required 2 Skeletal Survey 4 X X X X Bone marrow assessment 5 X X Hematology X X X 9 X X X X X Serum chemistry X X X 9 X X X X X Urinalysis X X X Myeloma protein in serum and urine X 6 X X 9 X X X X Serum FLC X 14 β2-mg and CRP and LDH X X Thyroid function X X 12 X 12 Pregnancy test 7 X 8 X 10 Serum testosterone (men only) X X 12 X 12 QoL assessment X 6 X X X X X X CD34 number X 11 Record adverse events X X X X X X X Record concomitant therapies/procedures X X X X X X X X Study drug (dispensing) X X X X Perform drug accountability X X X X Anti-cancer treatments X Survival information X X 1. Including thrombosis and neurologic assessment Version 1,

15 13 2. At screening and during treatment if required 3. ECHO or MUGA (if not performed within 60 days) 4. At screening and then once a year 5. Bone marrow aspiration and/or biopsy for morphology, immunophenotype and cytogetic assessment, to be performed at screening, when clinically indicated or to confirm complete remission 6.Protein electrophoresis (SPEP and UPEP), quantitative serum immunoglobulin levels, immunofixation studies if no evidence of monoclonal protein by SPEP and UPEP 7. For women of childbearing potential only 8. Must occur within days and within 24 hour before the start of study drug administration 9. At day 1 and during the whole mobilization phase if required 10. Pregnancy test has to be performed every week during the first 4 weeks of R treatment and then every 4 weeks if menstrual cycles are regular or every 2 weeks if the cycles are irregular Pregnancy test has also to be performed if patient misses her period or has unusual menstrual bleeding 11. CD34 monitoring will start at approximately day 11 from the mobilization regimen, PBSC harvest will start when the CD34 count will be > 10 ul/kg 12. Optional 13. At day 14 for the first 2 cycles and then every 28 days. 14. Optional, to be performed at screening and then for scr definition if baseline values > 10 mg/l 15. Patients will be evaluated weekly during the first cycle and then every 14 days Table2: Schedule of Study Assessments (Arms B) Procedure Screening Induction RD PBSC mobilization Consolidation MEL200 Maintenance R PD Extension study CC Follow-up Cycles 1-4 Cycles days from Baseline Every 28 days 13 Within 2 months from last RD Day -2 During treatment Every 28 days Every 28 days Informed consent Eligibility criteria Clinical history Randomization Physical examination 1, vital signs, weight Symptoms-directed physical examination X X X X X X X 9 X X X X X X X X 9 X X X X X Karnofsky performance status X X X 9 X X X X X 12-lead ECG 2 and cardiac function tests 3 Chest x-ray 2 and pulmonary function X X tests 2 CT or MRI if required 2 Skeletal Survey 4 X X X Bone marrow assessment 5 X X Hematology X X X 9 X X X X X Version 1,

16 14 Serum chemistry X X X 9 X X X X X Urinalysis X X X Myeloma protein in serum and urine X 6 X X 9 X X X X Serum FLC X 14 β2-mg and CRP and LDH X X Thyroid function X X 12 X 12 Pregnancy test 7 X 8 X 10 Serum testosterone (men only) X X 12 X 12 QoL assessment X 6 X X X X X X CD34 number X 11 Record adverse events X X X X X X X Record concomitant therapies/procedures X X X X X X X X Study drug (dispensing) X X X X Perform drug accountability X X X X Anti-cancer treatments Survival information X X 1. Including thrombosis and neurologic assessment 2. At screening and during treatment if required 3. ECHO or MUGA (if not performed within 60 days) 4. At screening and then once a year 5. Bone marrow aspiration and/or biopsy for morphology, immunophenotype and cytogetic assessment, to be performed at screening, when clinically indicated or to confirm complete remission 6. Protein electrophoresis (SPEP and UPEP), quantitative serum immunoglobulin levels, immunofixation studies if no evidence of monoclonal protein by SPEP and UPEP. 7. For women of childbearing potential only 8. Must occur within days and within 24 hour before the start of study drug administration 9. At day 1 and during the whole mobilization phase if required 10. Pregnancy test has to be performed every week during the first 4 weeks of R treatment and then every 4 weeks if menstrual cycles are regular or every 2 weeks if the cycles are irregular Pregnancy test has also to be performed if patient misses her period or has unusual menstrual bleeding 11. CD34 monitoring will start at approximately day 11 from the mobilization regimen, PBSC harvest will start when the CD34 count will be > 10 ul/kg 12. Optional 13. At day 14 for the first 2 cycles and then every 28 days. 14. Optional, to be performed at screening and then for scr definition if baseline values > 10 mg/l X Version 1,

17 15 Figure 1: Protocol schema Induction RD (4 cycles) (randomization for antithrombotic prophylaxis ASA, LMWH) Lenalidomide 25 mg/day, D1-21 every 4 weeks; Dexamethasone 40 mg/day D1, 8, 15, 22every 28 days; CY 4g/m 2 + G-CSF primed stem cell harvest Consolidation Arm A: MPR (6 cycles) Lenalidomide 10mg/day, D1-21 every 4 weeks; Melphalan 0,18mg/kg/day D1-4 every 4 weeks; Prednisone 2mg/kg/day D1-4 every 4 weeks; Arm B: MEL200 (2 cycles) Melphalan 200mg/m 2 D-2 every 4 months Stem cell support D 0 every 4 months Arm A1 Arm A2 Arm B2 Arm B1 no maintenance maintenance no maintenance R *Lenalidomide 10mg/day, D1-21 every 4 weeks Continuously until disease progression Extension phase MEL200 (2 cycles) Conventional chemotherapy Version 1,

18 16 4. TABLE OF CONTENTS 1 STUDY CONTACT INFORMATION SYNOPSIS SCHEDULE OF STUDY ASSESSMENT TABLE OF CONTENTS LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS INTRODUCTION STUDY OBJECTIVES PRIMARY OBJECTIVE SECONDARY OBJECTIVES STUDY ENDPOINTS PRIMARY ENDPOINT SECONDARY ENDPOINTS INVESTIGATIONAL PLAN OVERALL STUDY DESIGN Analyses and Reporting DESIGN RATIONALE STUDY POPULATION INCLUSION AND EXCLUSION CRITERIA Inclusion criteria Exclusion criteria TREATMENTS Treatment Assignments Dosing regimens Recommended concomitant therapy Prohibited concomitant therapy STUDY DRUG MATERIAL AND MANAGEMENT SUPPLIER(S) DOSAGE FORM PACKAGING SPECIAL HANDLING INSTRUCTIONS LABELING RECEIPT OF STUDY DRUG STORAGE UNUSED STUDY DRUG SUPPLIES RECORD OF ADMINISTRATION DOSE MODIFICATION OR INTERRUPTION DOSE MODIFICATION DURING RD CYCLES Dexamethasone Dose Modifications Lenalidomide Dose Modifications Initiation of a new RD cycle DOSE MODIFICATION DURING MPR CYCLES Lenalidomide and melphalan dose reduction Prednisone dose reduction Initiation of a new MPR cycle DOSE MODIFICATION DURING R MAINTENANCE CYCLES Lenalidomide Dose Modifications...51 Version 1,

19 Initiation of a new Maintenance Cycle DOSE MODIFICATION DURING THE EXTENSION PHASE DISCONTINUATION OF STUDY TREATMENT ASSESSMENTS EFFICACY ASSESSMENT Myeloma Monoclonal Protein and serum free-light chain Bone marrow examination Skeletal survey and other radiographs β 2 -microglobulin, C-reactive protein and LDH Karnofsky performance status Assessment of disease response SAFETY ASSESSMENT Medical History Physical Examination Thrombosis assessment Neurotoxicity assessment Cardiac and pulmonary tests Karnofsky Assessment Clinical Laboratory Evaluations Quality of Life Evaluation Adverse events Follow-Up Assessments Survival PROTOCOL AMENDMENTS/DEVIATIONS PROTOCOL AMENDMENTS PROTOCOL DEVIATIONS DATA MANAGEMENT STUDY MONITORING AND AUDITING BIOSTATISTICAL ANALYSIS STUDY POPULATION DEFINITIONS Intent-to-Treat Population Efficacy Evaluable Population Safety Population Interim Analysis Subgroup Analyses EFFICACY EVALUATION Study Endpoints Efficacy Analysis BACKGROUND AND DEMOGRAPHIC CHARACTERISTICS STUDY DRUG CONCOMITANT THERAPY SAFETY EVALUATION OTHER TOPICS Data Monitoring Committee Quality of Life Questionnaire Karnofsky Performance Status Central Cytogenetic Review SAMPLE SIZE AND POWER CONSIDERATIONS REGULATORY CONSIDERATIONS ETHICS COMMITTEE APPROVAL INFORMED CONSENT SUBJECT CONFIDENTIALITY STUDY RECORDS REQUIREMENTS PREMATURE DISCONTINUATION OF STUDY...74 Version 1,

20 Single center Study as a whole REFERENCES APPENDICES APPENDIX I APPENDIX II: DECLARATION OF HELSINKI APPENDIX III MULTIPLE MYELOMA DIAGNOSTIC CRITERIA...88 C IF A SOLITARY (BIOPSY-PROVEN) PLASMACYTOMA OR OSTEOPOROSIS ALONE (WITHOUT FRACTURES) ARE THE SOLE DEFINING CRITERIA, THEN > 30% PLASMA CELLS ARE REQUIRED IN THE BONE MARROW.18.4 APPENDIX IV STAGING APPENDIX V - CRITERIA FOR RESPONSE APPENDIX VI - CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE APPENDIX VII - KARNOFSKY PERFORMANCE STATUS SCALE APPENDIX VIII - SKELETAL SURVEY FILMS APPENDIX IX - FACT/GOG-NEUROTOXICITY QUESTIONNAIRE, VERS APPENDIX X - PREGNANCY TESTING GUIDELINES AND ACCEPTABLE BIRTH CONTROL METHODS EORTC QLQ-C30 QUALITY OF LIFE QUESTIONNAIRE EORTC QLQ-MY24 QUALITY OF LIFE QUESTIONNAIRE...99 Version 1,

21 19 5. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS AE Adverse event ADLS Activities of daily living ALT (SGPT) Alanine transaminase (serum glutamate pyruvic transaminase) ANC Absolute neutrophil count ASA Aspirin ASCO American Society of Clinical Oncology AST (SGOT) Aspartate transaminase (serum glutamic oxaloacetic transaminase) ATC Anatomical Therapeutical Chemical β-hcg β- Human Corion Gonadotropin β2- MG β2- microglobulin b-fgf β-fibroplast Growth Factor Bid Twice a day CC Conventional chemotherapy CFR Code of Federal Regulations CR Complete response CRF Case report form CRP C-reactive protein CT Computed tomography CTC Common toxicity criteria CUS Compression Ultrasonography CRP C-Reactive Protein CVA Cerebrovascular Accident CY Cyclophosphamide D-D Plasma D-Dimer Dex Dexamethasone DFS Disease Free Survival DLCO Diffusing Capacity for Carbon Monoxide DLT Dose Limiting Toxicity DMC Data Monitoring Commitee DVd Liposomal Doxorubicina-Vincristina-Dexamethasone EC Ethics Committee ECG Electrocardiogram EMEA European Agency for Evaluation of Medicinal Products FACT Functional Assessment of Cancer Therapy FDA Food and Drug Administration FEV 1 Forced expiratory volume Version 1,

22 20 FISH FLC FVC G-CSF GCP GOG HDCT HLA HZV ICH IFE IFN γ IL-1β IL-2 IL-6 IL-10 IL-12 IND IRB ITT IUD LDH Len LMWH LTFU LVEF MCH MCHC MCV MedDRA MM MP MPR MPT MRI MTD MUGA NCI Fluorescent in situ hybridization Free Light-Chain Forced Vital Capacity Granulocyte colony stimulating factor Good clinical practice Gynecology Oncology Group High Dose Chemotherapy Human Leucocyte Antigens Herpes Zoster Virus International Conference on Harmonization Immunofixation Interferon γ Interleukin-1β Interleukin-2 Interleukin-6 Interleukin-10 Interleukin-12 Investigational New Drug Institutional Review Board Intent-to-treat Intrauterine device Lactate dehydrogenase Lenalidomide Low Molecular Weight Heparine Long Term Follow Up Left Ventricular Ejection Fraction Mean corpuscular haemoglobin Mean corpuscular haemoglobin concentration Mean corpuscular volume Medical Dictionary for Regulatory Activity Multiple Myeloma Melphalan-Prednisone Revlimid-Melphalan-Prednisone Melphalan-Prednisone-Thalidomide Magnetic Resonance Imaging Maximum tolerated dose Multiple Gated Acquisition scan National Cancer Institute Version 1,

23 21 ncr OS PD PBSC PO PLT PFS PR QD QLQ-C30 QLQ-MY24 myeloma module QoL RBC RD Near Complete Response Overall survival Progressive disease Peripheral blood stem cell Oral administration Platelet Progression-free survival Partial response Once a day EORTC QoL Questionnaire for Patients with Cancer EORTC QoL Questionnaire for Patients with Multiple Myeloma Quality of Life Red blood cell (count) Lenalidomide-Dexamethasone SAE SPEP SWOG TD TNFα TPP TSH ULN UPEP US UTI VEGF VGPR VTE WBC FCBP Serious adverse event Serum protein electrophoresis South West Oncology Group Thalidomide-Dexamethasone Tumor Necrosis Factor α Therapeutics Product Program Thyroid stimulating hormone Upper limit of Normal Urine protein electrophoresis United States Urinary Tract Infection Vascular Endothelial Growth Factor Very Good Partial Response Venous Thrombo-Embolism White blood cell (count) Female of child bearing potential Version 1,

24 22 6. INTRODUCTION Multiple myeloma (MM) is an incurable disease that is characterised by the accumulation of clonal plasma cells in the bone marrow (11). It accounts for 10% of all haematological malignancies and it is estimated that approximately 40,000 MM patients are receiving treatment in the US with about 14,000 new cases and nearly 11,000 deaths from the disease yearly (12). In Europe, there are about 19,000 new MM cases and over 14,000 deaths from MM every year. In addition, MM is a disease of the elderly in that the median age of patients at diagnosis is 65 years (13). Oral melphalan and prednisone (MP) has been a standard treatment for patients with newly diagnosed MM for at least 35 years (11;14). Treatment with MP is associated with a 50% response rate, a median duration of response of years, and a median overall survival time of 2-3 years. MP therapy rarely results in complete responses (CRs). Many other standard combination chemotherapy treatments, including the use of maintenance therapy, have been evaluated, however most trials and meta-analyses of trials have not shown other chemotherapy combinations or the addition of maintenance therapy to be superior to MP induction treatment alone (15-17). More recently, the treatment approach for patients with newly diagnosed MM has been modified to include high-dose intravenous melphalan therapy accompanied by hematopoietic stem cell transplantation (1;4). High-dose chemotherapy supported by autologous stem cell transplantation is associated with an increased CR rate and a modest increase in median overall survival compared to conventional-dose chemotherapy and it is now considered the treatment of choice for patients with newly diagnosed MM who are 65 years of age of younger. Barlogie et al. at the University of Arkansas pioneered the use of tandem transplant in early management of MM in their Total Therapy I program. This program produced a CR rate of 41% and overall median survival of 79 months (18). The IFM 94 was the first randomized study comparing single and tandem transplant. This trial has shown superiority of tandem transplants over a single transplant with a seven year OS rate of 42% with tandem transplants versus 21% with a single transplant. (p =.01) (19). Table 3 summarizes the data available on other randomized trials, in general the data indicate that tandem transplant improves PFS with a variable effect on overall survival (19-22). Table 3: Randomized study comparing single versus double transplant Study N ORR % PFS OS Comment single tandem single tandem single tandem Attal Greatest benefit in patients in < VGPR after 1 st Version 1,

25 23 Fermand Cavo Greatest benefit in patients in < ncr after 1 st Sonneveld Prognostic factors More recently the combination of MP with thalidomide (MPT) showed first improvement of response rate and PFS in elderly newly diagnosed multiple myeloma patients. In this phase III trial comparing MP vs MPT, the association therapy showed a significantly higher response rate compared with standard treatment (similar to results produced by high-dose therapy) and a significantly longer event-free survival (5). Lenalidomide The encouraging activity of thalidomide in multiple myeloma has prompted the search for more potent and less toxic thalidomide derivatives. Lenalidomide, belongs to a proprietary class of Celgene compounds called IMiDs. IMiDs, of which thalidomide is the parent compound, have both immunomodulatory and anti-angiogenic properties which could confer antitumor and antimetastatic effects. Version 1, Lenalidomide has been demonstrated to possess anti-angiogenic activity through inhibition of bfgf, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response to bfgf (23). In addition, lenalidomide has a variety of immunomodulatory effects. Lenalidomide stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 production (24). Upregulation of T cell derived IL-2 production is achieved at least in part through increased AP-1 activity (25). Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of mechanisms are postulated to be responsible for lenalidomide s activity against multiple myeloma. Lenalidomide has been shown to increase T cell proliferation, which leads to an increase in IL-2 and IFN-gamma secretion. The increased level of these circulating cytokines augment natural killer cell number and function, and enhance natural killer cell activity to yield an increase in multiple myeloma cell lysis (26). In addition, lenalidomide has direct activity against multiple myeloma and induces apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone (27). Clinical experience in multiple myeloma In 2 phase I studies in multiple myeloma, a total of 41 patients have been treated with lenalidomide. In one study at the University of Arkansas, 15 patients who relapsed or were refractory to high dose melphalan therapy with stem cell transplant were treated for 4 weeks in an open-label safety study and were permitted to continue therapy in an extension phase of the trial. Patient cohorts were

26 24 treated at the following daily doses: 5mg, 10mg, 25mg, and 50mg (28). In a similar study at the Dana Farber Cancer Institute, 27 patients with rapidly advancing refractory multiple myeloma were enrolled (29). Anti-myeloma activity was observed in each of these 2 phase I studies. Decreases in neutrophil and platelet counts were the dose-limiting toxicities associated with lenalidomide. The maximum tolerated dose (MTD) was not reached within 28 days. Due to dose modifications associated with myelosuppression observed beyond Day 28 at the 25mg and 50mg daily dose levels, the dose schedule most widely used in future studies has been lenalidomide on Days 1-21, repeated every 28 days. Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I studies. Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg). Plasma lenalidomide declined in a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses. No plasma accumulation was observed with multiple daily dosing. Peak and overall plasma concentrations were dose proportional over the dosing range of 5mg to 50mg (30). A multicenter, randomized, phase II trial compared 2 syncopated dose schedules of lenalidomide used alone or in combination with dexamethasone in the treatment of relapsed or refractory multiple myeloma. All patients were treated on Days 1-21 of a 28-day cycle. Patients treated with 15mg BID experienced more myelosuppression and dose reductions compared with patients treated with 30mg daily. Anti-myeloma activity was observed with each dose and schedule of single agent lenalidomide. The addition of dexamethasone to lenalidomide yielded responses in some patients who had not responded to lenalidomide alone (31). A phase I/II trial of Liposomal doxorubicin (Doxil ), vincristine, dexamethasone (DVd) and lenalidomide in heavily pretreated relapsed/refractory multiple myeloma patients is ongoing. The MTD of lenalidomide was 10mg on Days 1-21 in combination with Doxil 40mg/m2 IVPB on Day 1, vincristine 2mg IVP on Day 1 and dexamethasone 40mg PO on Days 1-4 cycled every 28 days. All patients received amoxicillin, acyclovir and aspirin 81mg prophylactically. The dose limiting toxicity with lenalidomide 15mg on Days 1-21 in combination with DVd was sepsis/septic shock (32). Additional phase I trials of lenalidomide with chemotherapy in advanced malignancies are in progress. Two multicenter, randomized, double-blinded, placebo-controlled phase III trials [1 U.S. (MM-009) and 1 international (MM-010)] in patients with relapsed or refractory multiple myeloma (33-34). More than 350 patients were enrolled into each of these studies. All patients had to be Version 1,

27 25 considered sensitive to dexamethasone and were treated with dexamethasone 40 mg qd, Days 1-4, 9-12 and In addition to receiving dexamethasone, patients were randomized to lenalidomide 25mg qd or placebo, Days Cycles were repeated every 28 days. After 4 cycles, there was a predetermined reduction of the dexamethasone dose to 40 mg qd, Days 1-4 repeated every 28 days. In both studies, a pre-specified interim analysis conducted by an Independent Data Monitoring Committee demonstrated that subjects receiving the combination of lenalidomide (R) plus dexamethasone (Dex) had significantly longer times to progression and higher response rates than those treated with single-agent dexamethasone. A recent phase II trial utilizing lenalidomide plus dexamethasone for newly diagnosed multiple myeloma patients was recently reported by the Mayo Clinic. Lenalidomide was given orally 25 mg daily on days 1-21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1-4, 9-12, of each cycle. Objective response was defined as a decrease in serum monoclonal protein by 50% or greater and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed by two consecutive determinations at least 4 weeks apart. Thirty-one of 34 patients achieved an objective response, including 2 (6%) achieving complete response (CR), and 11 (32%) meeting criteria for both very good partial response and near complete response, resulting in an overall objective response rate of 91%. Of the 3 remaining patients not achieving an objective response, two had minor response (MR) and one stable disease. Forty-seven percent of patients experienced grade 3 or higher non-hematologic toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%). Rev/Dex is a highly active regimen with manageable side-effects in the treatment of newly diagnosed myeloma (35). Preliminary results of a phase I/II study of MPR association in elderly patients showed that this combination is highly effective newly diagnosed multiple myeloma. This trial was designed to define the DLT and MTD of lenalidomide and MP association (7). Four different dose-level were tested: Cohort 1: melphalan 0.18 mg/kg + prednisone 2 mg/kg + lenalidomide 5 mg Cohort 2: melphalan 0.25 mg/kg + prednisone 2 mg/kg + lenalidomide 5 mg Cohort 3: melphalan 0.18 mg/kg + prednisone 2 mg/kg + lenalidomide 10 mg Cohort 4: melphalan 0.25 mg/kg + prednisone 2 mg/kg + lenalidomide 10 mg Due to higher toxicity rate at dose level 4 (3 out of 6 patients showing DLT), the MTD was defined as level 3. Overall response rate after a median of 7 cycles in cohort 3 and 4 is 85.4%, with 41.5% Version 1,

28 26 of patients achieving at least a VGPR and 17.1% of patients achieving a immunofixation negative CR [unpublished data]. Adverse Events Most frequently reported adverse events reported during clinical studies with lenalidomide in oncologic and non-oncologic indications, regardless of presumed relationship to study medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection, cellulites, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, disease progression, death not specified and fractures. Complete and updated adverse events are available in the Investigational Drug Brochure and the IND Safety Letters. Given the significant clinical benefits observed with lenalidomide in the relapsed/refractory MM but also in newly diagnosed patients, the present study is designed to investigate the combination of lenalidomide with low-dose melphalan versus high-dose melphalan in newly diagnosed, symptomatic MM who are 65 years of age or younger. This study will be conducted in compliance with the protocol, good clinical practices (GCP), and applicable regulatory requirements. 7. STUDY OBJECTIVES 7.1 Primary objective To compare the efficacy of the combination of lenalidomide with low-dose melphalan versus high-dose melphalan in newly diagnosed, symptomatic MM patients who are 65 years of age or younger. 7.2 Secondary objectives To evaluate whether induction treatment with lenalidomide compromises subsequent mobilization of peripheral blood stem cells (PBSC). To assess the safety of lenalidomide in combination with low-dose melphalan compared to highdose melphalan in newly diagnosed, symptomatic MM patients. Version 1,

29 27 To assess the efficacy and safety of lenalidomide as maintenance treatment after the consolidation phase. 8. STUDY ENDPOINTS 8.1 Primary Endpoint Progression free survival (defined as time from start of treatment to the first documentation of progressive disease based on the International Uniform Response Criteria, Appendix V or death due to any cause during the treatment phase). 8.2 Secondary Endpoints Overall survival ([OS] defined as time from start of treatment to death due to any cause) Time to progression ([TTP] defined as time from start of treatment to the first documentation of progressive disease or death due to progressive disease during the treatment phase) Objective overall Response rate (including complete response [CR] and partial response [PR] using the International Uniform Response Criteria, Appendix V). Time to response (defined as time from start of treatment to the first documented objective response including CR and PR) Duration of response (applies to patients achieving at least PR by the criteria in Appendix V) measured from time of first observation of PR to the time of confirmed disease progression) Number of PBSC collected. Time to the next anti-myeloma therapy Incidence of Grade 3 and 4 haematologic and non-haematologic adverse events (AEs) Quality of Life assessment (QoL) (European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients with Cancer [EORTC QLQ-C30] and QoL Questionnaire for Patients with Multiple Myeloma [QLQ-MY24] Exploratory assessment on prognosis and cytogenetic abnormalities Version 1,

30 28 9. INVESTIGATIONAL PLAN 9.1 Overall Study Design This is a multicenter, randomized, open label study designed to compare the efficacy and safety of lenalidomide in combination with low-dose melphalan versus high-dose melphalan followed by stem cell support in newly diagnosed symptomatic MM patients who are 65 years of age or younger. Potential study subjects will sign an informed consent prior to undergoing any study related procedure. This study consists of 4 phases for each study subject: Pre-treatment, Treatment, Extension and Follow-up. Pre-treatment period: patients will undergo screening for protocol eligibility within 28 days (4 weeks) of randomization as outlined in Section 3: Schedule of Study Assessments. Subjects who meet all the inclusion criteria will be randomized (1:1 ratio) twice based on a computer-generated randomization schedule prepared by the Coordinating Center. The first randomization will occur for the consolidation treatment: Arm A (MPR) and Arm B (MEL200 and stem cell support). Within each arm patients will be then randomized for the maintenance treatment: Arms A1 (no maintenance) and A2 (maintenance with R), Arms B1 (no maintenance) and B2 (maintenance with R). Randomization will be concealed until the end of the induction period for the consolidation treatment and until the end of the consolidation treatment for the maintenance treatment. Patients will be stratified at randomization according to the International Staging System (8) and to age (< 60 years vs > 60 years). The start of the Treatment Period (Day 1 of study treatment) will occur on the same day the subject is randomized. Each subject will continue the Treatment Period until: 1) progressive disease (PD) occurs; or 2) therapy is discontinued permanently for any reason; 3) patients has died/lost to follow-up. Study visits and serial measurements of safety and efficacy will be performed as outlined in Section 3: Schedule of Assessments. Tumour response, including PD, will be assessed according to the International Uniform Response Criteria reported in Appendix V. The severity of AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Treatment period includes induction, consolidation and maintenance. During the induction and consolidation phases, all patients will attend periodic study centre visits in order to asses the safety and efficacy of the treatment. Patients receiving MEL200 will require two periods of in-patient care Version 1,