A Prospective Phase II study

Transcriptie

1 Bortezomib in combination with continuous low-dose oral cyclophosphamide and dexamethason followed by maintenance in primary refractory or relapsed bortezomib naïve multiple myeloma patients (REMM) A Prospective Phase II study Principal Sponsor and Investigator: Dr. S. Hovenga Contact information for trial related medical decisions: Study Coordinators: Dr. S. Hovenga Nij Smellinghe Hospital Drachten Prof.dr. E. Vellenga University Medical Center Groningen Data management: Statistician: IKNL Data Center Drs. L de Munck, IKNL Groningen Approved: 10/12/2008, METc University Medical Center Groningen; METc nr Amendment 1 22 March 2012 Eudract nummer Support for this Investigator Initiated Study Janssen-Cilag B.V. provides funding for this study and provides investigational product (bortezomib) for the maintenance phase of this protocol Correspondence: Dr. S. Hovenga Department of Internal Medicine Division Oncology Nij Smellinghe Drachten Compagnonsplein 1 Hanzeplein 1 Postbus Postbus Prof.dr. E. Vellenga Department of Internal Medicine Division Oncology University Medical Center 9202 NN Drachten 9700 RB Groningen s.hovenga@nijsmellinghe.nl e.vellenga@umcg.nl 1

2 2 Protocol Signature Sheet Name Site Signature Date Dr. S. Hovenga Nij Smellinghe Drachten Prof. dr. E. Vellenga UMCG Local Investigator(s) Name Site Signature Date By my signature, I agree to conduct this trial in compliance with the protocol, the ethical principles of the Declaration of Helsinki, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory requirements. 2

3 3 Table of contents Page 1. Title Page Protocol Signature Sheet 2 3. Table of contents Synopsis Rationale for amendments Investigators and study administrative structure 6 7. Introduction Rationale of the study 8. Study objectives Study design General 9.2 Patients 9.3 Re-induction chemotherapy with bortezomib, cyclophosphamide and dexamethasone 9.4 Maintenance therapy with bortezomib and cyclophosphamide 10. Study population Eligibility for registration 10.2 Inclusion criteria 10.3 Exclusion criteria 11. Treatments Re-induction phase with bortezomib, cyclophosphamide and dexamethasone cycles of 21 days each cycles of 35 days each Special management orders in conjunction with bortezomib Special management orders in conjunction with cyclophosphamide 11.2 Maintenance therapy with bortezomib and cyclophosphamide Eligibility criteria for Bortezomib and cyclophosphamide Administration of Bortezomib and cyclophosphamide Dose adjustment of Bortezomib Dose adjustment of cyclophosphamide 11.3 Bisphosphonates 11.4 Concomitant medication Guidelines for platelet transfusions Guidelines for red cell transfusions Forbidden concomitant medication during the study 11.5 Study drug information Physical description of study drug Package Labeling Preparation and handling Drug accountability 12. End of protocol treatment Required clinical evaluation Time of clinical evaluations 13.2 Medical history 13.3 Physical examination 13.4 Laboratory investigation 3

4 13.5 Specific investigations 13.6 During treatment and follow-up 14. Evaluation of response Toxicities Safety evaluations and adverse events reporting Definitions 16.2 Reporting of (serious) adverse events 16.3 Actions of the IKNL Data Center upon receipt of (S)AE reports 16.4 SUSAR reporting 17. Registration Forms and procedures for collecting data Monitoring 18.2 Data quality assurance 18.3 On-site audits 19. Statistical considerations Patients numbers and power considerations and efficacy analysis 19.2 Endpoints and statistical analysis 20. Ethics Independent ethics committee or institutional review board 20.2 Ethical conduct of the study 20.3 Patient information and consent 21. Trial insurance Publication policy Glossary of abbreviations References Appendices 24 A. WHO Performance status scale A. Response criteria for Multiple Myeloma B. Management of patients with bortezomib-related neuropathic pain and/or peripheral sensory neuropathy. C. Known Anticipated Risks of VELCADE by MedDRA System Organ Class, Observed Incidence, and Preferred Term D. Investigations at start, during treatment and follow-up E. Common Toxicity Criteria (CTCAE version 3.0) F. Patiënt information G. Registration form 4

5 4 Synopsis Study phase Study objectives Patient population Study design Duration of treatment Number of patients Adverse effects Planned start of recruitment Planned end of recruitment Phase II Evaluation of the safety and efficacy of bortezomib combined with cyclophosphamide and dexamethasone for induction and maintenance therapy Patients with bortezomib naive refractory or relapsed multiple myeloma, stage II-III, age minimal 18 years inclusive Prospective multi-centre study Expected duration of re-induction with bortezomib, cyclophosphamide and dexamethasone is 24 weeks. Maintenance therapy with bortezomib and cyclophosphamide will be given for 1 year. 73 patients registered Adverse effects will be documented if observed, mentioned during open questioning, or when spontaneously reported September 2012 September 5 Rationale for amendments Protocol version was amended to version 1-feb-2012In 2008 this project started to evaluate the safety and efficacy of bortezomib combined withcyclophosphamide and dexamethasone for induction and maintenance therapy in patients with bortezomib naive refractory or relapsed multiple myeloma. In December 2010 prof. Moreau presented data at the international congress of the American Society of Hematology from a randomized phase III study in which bortezomib was given in relapsed and refractory multiple myeloma patients via a subcutaneous route or the classical intravenous route. It was shown that subcutaneously administred bortezomib in patients with relapsed multiple myeloma was non-inferior in respect to efficacy but with an improved safety profile and that it may therefore be an alternative for intravenously administred bortezomib, The study was published in On January 23 rd 2012 the American Food and Drug Administration FDA approved the subcutaneous administration route for bortezomib. The subcutaneous route has not been approved by the European Medicines Agency yet but is awaited in From approval of REMM amendment 1 (version 1-feb-2012) onwards bortezomib may be administred by subcutaneous route or by intravenous route, as by discretion of the investigator. 5

6 6 Investigators and study administrative structure Responsibility Name Affiliation/Address Study coordinators Dr. S. Hovenga Nij Smellinghe Hospital Drachten Prof.dr. E. Vellenga University Medical Center Groningen Registration IKNL Data Center IKNL Postbus AH Groningen Tel: Fax: Datamanagement & monitoring Mw. A.M. Eerens IKNL Data Center Statistician Drs. L. de Munck IKNL Serious Adverse Events IKNL Data Center Fax (SAEs) notification Support of study Janssen-Cilag B.V. Dr. Paul Janssenweg RH Tilburg Tel

7 7 Introduction Multiple myeloma (MM) is a malignant disorder of plasma cells. It represents the second most common hematological malignancy. Treatment consists of intensive chemotherapy followed by autologous stem cell transplantation (ASCT) especially for the age group 65 years. Despite the use of high-dose chemotherapy and ASCT the underlying disorder frequently relapse. The 5-year survival rate for patients with multiple myeloma treated with conventional chemotherapy is 25%, while with intensified therapy this may increase to 50%. Therefore the introduction of novel agents might further improve the treatment results. Treatment with single-agent bortezomib (VELCADE ) at a dose of 1 3 mg/m 2 resulted at least in partial responses (PR) in 27% of patients with relapsed and refractory multiple myeloma (MM), 38% of patients with a relapse after one to three previous therapies and 50% in patients relapsing during or after first-line therapy. 1,2,3 In addition, the latter study indicates a possible dose response relationship (response rates in the 1.3 and 1.0 mg/m 2 arm 50% and 33% resp.) of bortezomib. Median time to progression (TTP) with single agent bortezomib was superior to high-dose dexamethasone (DEX) (6 months vs. 4 months). 3 Overall survival (OS) in relapsed and refractory MM was 17 months. 4 OS with bortezomib was predicted by tumor burden at baseline but not by elevated β 2 -microglobulin (β2m) or chromosome 13 deletion. 2 Combination with DEX in patients with either stable (SD) or progressive disease (PD) on bortezomib alone resulted in 11% to 18% additional responses. 1,2 However, it has not been demonstrated whether the addition of DEX confers benefit in terms of TTP and OS compared to bortezomib alone. 5 Conventional cytotoxic drugs may add to the efficacy of bortezomib. 6-9 In MM, bortezomib has been shown to restore both melphalan- and doxorubicin-sensitivity in resistant cell lines and to synergize with melphalan in killing myeloma cells. 10,11 In phase 1-2 trials assessing bortezomib and melphalan or doxorubicin combinations for relapsed or refractory MM, overall response rates (ORR) of 68 73% were achieved. 12,13 In elderly untreated myeloma patients, bortezomib plus melphalan and prednisone appeared significantly superior to historical melphalan and prednisone alone. 14 Cyclophosphamide, an alkylating agent without cross-resistance to melphalan has a well-established activity in MM Hematological toxicity following cyclophosphamide is not cumulative and there is only rare cardiotoxicity and virtually no neurotoxicity if the drug is administered at conventional doses. Cyclophosphamide is reasonably well absorbed following oral administration. When combined with thalidomide with or without DEX, oral cyclophosphamide yielded similar efficacy and toxicity compared to regimens employing intravenous cyclophosphamide for relapsed MM In addition, a continuous oral regimen should provide the flexibility for dose modifications during treatment cycles. Low dose cyclophosphamide might provide an anti-angiogenic effect by a more sustained apoptosis of endothelial cells within the vascular bed of the tumor. 21,22 Orally administrated, low dose continuous cyclophosphamide is a feasible, effective and well tolerated regimen in the management of advanced multiple myeloma. 23 In view of these findings it might be promising to combine both modalities since it makes use of different pathways that might induce cytotoxic effects on myeloma cells. In an attempt to further improve the efficacy of bortezomib/dex, the present phase 2 trial was initiated to study bortezomib/dex in combination with continuous low-dose cyclophosphamide administered orally. Since was shown that subcutaneously administred bortezomib in patients with relapsed multiple myeloma was noninferior in respect to efficacy but with an improved safety profile, 29 the administration of bortezomib as from this amendment on may be either by intravenous route or by subcutaneous route, on discretion of the investigator. 7.1 Rationale of the study Bortezomib and cyclophosphamide in combination with dexamethasone has already demonstrated high response rates in refractory multiple myeloma. Low dose continuous cyclophosphamide, also called metronomic scheduling, minimize toxic side effects and eliminate the obligatory rest periods. Combining cyclophosphamide with bortezomib might target distinct aspects of a myeloma functionality. The objectives of the present study are whether patients with refractory or relapsed multiple myeloma after reinduction with bortezomib, cyclophosphamide and dexamethasone will benefit from maintenance therapy with bortezomib and cyclophosphamide with acceptable side-effects. Recently two studies have shown with thalidomide that maintenance therapy might improve EFS and one study also the OS. 24,25 7

8 8 Study Objectives To assess the efficacy of bortezomib, cyclophosphamide and dexamethasone during re-induction and in maintenance therapy. To assess the safety of bortezomib, cyclophosphamide and dexamethasone during re-induction and in maintenance therapy in patients with refractory or relapsed multiple myeloma. 9 Study design 9.1 General This is a multi-center, prospective phase 2 study. 9.2 Patients In this study 73 patients will be included based on the defined in- and exclusion criteria. The study population consists of bortezomib naive patients with refractory or relapsed multiple myeloma, stage II-III. 9.3 Re-induction chemotherapy with bortezomib, cyclophosphamide and dexamethasone. All patients with first relapse or primary refractory multiple myeloma and bortezomib naive will be given 6 cycles of reinduction therapy. Patients will be evaluated for response after cycle 3 and Maintenance therapy with bortezomib and cyclophosphamide Maintenance therapy with bortezomib and cyclophosphamide will start at 4 weeks after the last cycle of re-induction chemotherapy if ANC 2.0 x 10 9 /l and platelets > 75 x 10 9 /l. Bortezomib is administered once every other week and cyclophosphamide (50 mg) every day for 1 year or until progression or death of any cause. 10 Study population 10.1 Eligibility for registration All eligible patients have to be registered before start of treatment Inclusion criteria Age 18 years Stage II-III Multiple Myeloma Relapse or primary refractory disease after initial chemotherapy WHO performance status 0 2 Life expectancy of at least 6 weeks ANC (absolute neutrophil count) 1.0x10 9 /l (or 0.5x109/l, if due to bone marrow infiltration by malignancy) Platelet count 75x10 9 /l (or 50x10 9 /l, if due to bone marrow infiltration by malignancy) Written informed consent (present in patient s file) Patient is able and willing to use adequate contraception during therapy and for at least 1 month after study Patient has the ability to understand the requirements of the study 8

9 10.3 Exclusion criteria Previous treatment with bortezomib Urine production < 1.5 l/24h Pre-existent polyneuropathy (grade 2 or higher, according to CTCAE 3.0) Pregnancy or positive pregnancy tests during study and for 1 month after final dose of thalidomide History of active malignancy during the past 5 years (with the exception of basal carcinoma of the skin) Active uncontrolled infections Additional uncontrolled serious medical or psychiatric illness 11 Treatments 11.1 Re-induction phase with bortezomib, cyclophosphamide and dexamethasone cycles of 21 days each During the first period of re-induction chemotherapy the patients will be treated according to the following schedule: Agent Dose/day Route Days Bortezomib 1.3 mg/m 2 i.v. rapid infusion All cycles Days 1, 4, 8 and 11 OR s.c. Cyclophosphamide 50 mg p.o. Day 1-14 cycle Dexamethasone 20 mg p.o. All cycles Days 1, 2, 4, 5, 8, 9, 11 and 12 Cycle 2 will start at day 22, cycle 3 will start at day 44. Assessment of response after cycle 3 is described in appendix B cycles of 35 days each During the second period of re-induction chemotherapy the patients will be treated according to the following schedule: Agent Dose/day Route Days Bortezomib 1.6 mg/m 2 i.v. rapid infusion All cycles Days 1, 8, 15 and 22 OR s.c. Cyclophosphamide 50 mg p.o. Day 1-28 cycle Dexamethasone 20 mg p.o. All cycles Days 1-2, 8-9, and Cycle 2 will start at day 36, cycle 3 will start at day 72. Assessment of response after cycle 6 is described appendix B, including bone marrow examination Special management orders in conjunction with bortezomib and cyclophosphamide Patients are treated on an outpatient basis. The appropriate amount of Bortezomib will be drawn from the injection vial and administered either as an IV push over 3 to 5 seconds followed by a standard saline flush or through a running IV line or receive bortezomib by SC injection at 1 injection site per dosing. The SC injection site will be rotated within a cycle. 9

10 Vials are for single use administration. The patient should be considered clinically stable by their physician before discharge. Before each Bortezomib dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). The detailed management instructions for handling Bortezomib are described later in this section. The following bortezomib SC injection guidelines will be observed: one SC dose will be given as a single injection anatomical sites of SC administration are thighs (right or left) or abdomen (right or left) the SC injection site will be rotated for successive injections within the same cycle, injections at the same site should be avoided; it is recommended to alternate between right and left abdomen, upper and lower quadrant, or between right and left thigh, proximal and distal sites. the selected SC injection site should be free from any skin condition that might interfere with the assessment of injection site reactions The location of each SC injection will be entered into the CRF. Cyclophosphamide intake is recommended during the morning. During the day extra liquid intake for adequate diuresis and at night at least one time diuresis. It is strongly recommended to give prophylactic treatment for pneumococcus infections and anti-fungal prophylaxis according to local protocols. In addition the patient has to be treated with Zelitrex (valaciclovir) 2 dd/500mg. All previously established or new toxicities observed any time, with the exception of neuropathic pain and peripheral sensory neuropathy for which separate guidelines are defined in appendix C, are to be managed as follows: Treatment with bortezomib and cyclophosphamide should be withheld if the following events occur: - febrile neutropenia - grade 4 hematological toxicity - grade 3 non-hematological toxicity Once toxicity is resolved, treatment with bortezomib and cyclophosphamide can be resumed at a 25% reduced dose. For short lasting myelosuppression, if only one dose of bortezomib and/or <8 doses (days) cyclophosphamide had to be held, both drugs will be continued at the same dose level. When bortezomib and cyclophosphamide is interrupted for up to 2 weeks or repeated grade 4 hematological toxicity occurred study drugs should be stopped Special management orders in conjunction with dexamethasone Dexamethasone should be withheld for up to two weeks for > grade 3 toxicity if the investigator considered the toxicity to be dexamethasone related. Once the toxicity resolved dexamethasone should be continued at a 25% reduced dose 11.2 Maintenance therapy with bortezomib and cyclophosphamide Eligibility criteria for Bortezomib and cyclophosphamide All patients who have achieved hematological recovery (neutrophils 2.0 x 10 9 /l, platelets > 75 x 10 9 /l) after the reinduction phase, are eligible for maintenance therapy with bortezomib and cyclophosphamide Administration of Bortezomib and cyclophosphamide during maintenance therapy Bortezomib will be given at a dose of 1.3 mg/m 2 every 2 weeks. Cyclophosphamide will be given at a dose of 50 mg/day. Maintenance therapy will be initiated 4 weeks after completion of the re-induction therapy. If bortezomib or cyclophosphamide has not been started within 8 weeks after re-induction therapy, the patient will go off protocol treatment. Bortezomib and cyclophosphamide maintenance will be given for one year and will be prematurely stopped at progression and also in patients who have not achieved at least a minimal response 6 months following start of maintenance. Assessment of response during bortezomib and cyclophosphamide maintenance is described in appendix B. 10

11 Agent Dose/day Route Days Bortezomib 1.3 mg/m 2 i.v. rapid infusion OR s.c. 1x / 2-weeks Cyclophosphamide 50 mg p.o. One dose/day for 1 year Dose adjustment of Bortezomib and cyclophosphamide during maintenance therapy See section Bisphosphonates It is an option to start treatment with i.v. bisphosphonates every 4-6 weeks. A commonly used regimen consists of zoledronate 4 mg or pamidronate (APD) mg i.v. once every 6 weeks Concomitant medication Guidelines for platelet transfusions Thrombocytopenia can occur as a consequence of bone marrow infiltration by myeloma cells or may be related to study drug administration. The clinical significance of thrombocytopenia experienced by a patient should be assessed in light of its aetiology (bortezomib/cyclophosphamide or disease or both), the state of the underlying myeloma (stable versus worsening disease), and whether the patient is bleeding or being prepared for a surgical procedure. The use of any platelet product should be considered in the following circumstances: As preparation for an invasive surgical procedure to maintain a platelet count >50 x 10 9 /l. If the patient has an active infection, high fever, rapid decrease in platelet count to 20 x 10 9 /l or coagulopathy, transfuse to maintain a platelet count to > 20 x 10 9 /l. If the patient is actively bleeding or has a platelet count below 10 x 10 9 /l, transfusion is indicated Guidelines for red cell transfusions The use of any red cell product should be considered in the following circumstances: If the patient has a hemoglobin < 5.0 mmol/l, transfusion is indicated The use of erythropoeitin is allowed Forbidden concomitant medication during the study The use of anti-neoplastic therapy, other than protocol-specified study medication, is not allowed until progressive disease is established and the patient has been taken off study Study drug information Physical description of study drug Bortezomib for injection is an anti-neoplastic agent available for i.v. use only. Each single dose vial contains 3.5 mg bortezomib as a sterile lyophilized powder. Inactive ingredient: 35 mg mannitol. 11

12 Packaging Bortezomib will be supplied as single-use vials containing 3.5 mg bortezomib and 35 mg mannitol. All study medication will be dispensed in child-resistant packaging Labeling of study drug for maintenance therapy only Study drug labels will contain information to meet the applicable regulatory requirements Preparation and handling Vials containing lyophilized bortezomib for Injection should be stored below 30º C. Vials should be stored in their carton to protect from light. Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and handling bortezomib. Refer to published guidelines regarding the proper handling and disposal of anticancer agents. The pharmacist should prepare bortezomib for Injection using a vertical laminar flow biological cabinet (hood) and proper aseptic techniques. Cytotoxic drugs should only be handled by staff specially trained in the safe handling of such preparations. The use of gloves and other appropriate protective clothing is recommended. If Bortezomib for Injection reconstituted solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Bortezomib for Injection reconstituted solution contacts the mucous membranes, flush thoroughly with water. Bortezomib will be supplied in sterile, single-use vials containing 3.5 mg of bortezomib. For IV administration, each vial of bortezomib for Injection should be reconstituted under a laminar flow biological cabinet (hood), within 8 hours before dosing, with 3.5 ml of normal (0.9%) saline, sodium chloride injection, so that the reconstituted solution contains bortezomib at a concentration of 1 mg/ml. For SC administration, each vial of bortezomib for Injection should be reconstituted under a laminar flow biological cabinet (hood), within 8 hours before dosing, with 1.4 ml of normal (0.9%) saline, sodium chloride injection, so that the reconstituted solution contains bortezomib at a concentration of 2.5 mg/ml. The reconstituted solution is clear and colorless, with a final ph of approximately 5 to 6. Dissolution is completed in approximately 10 seconds. Reconstituted bortezomib should be administered promptly and in no case more than 8 hours after reconstitution. In case of skin contact, wash the affected area immediately and thoroughly with soap and water and diluted hydrogen peroxide for 15 minutes. If product contacts eye, immediately flush eye thoroughly with water for at least 15 minutes. Always contact a physician after any form of body contact. All materials that have been used for preparation should be disposed of according to standard practices. A log must be kept of all disposed materials. Bortezomib for Injection drug product was found to be stable for at least 18 months under storage conditions from 2 C to 25 C with excursions permitted up to 30 C. The reconstituted product is preservative free and is chemically and physically stable for up to 8 hours when it is stored at 25 C Drug accountability The local investigator is responsible for ensuring that all study drug received at the site in the period during which study medication is used (maintenance therapy only) is inventoried and accounted for throughout the study. The dispensing of study drug to the subject, and the return of study drug from the subject (if applicable), must be documented. Study drug must be handled strictly in accordance with the protocol and the container label and will be stored under appropriate environmental conditions. Contents of the study drug containers must not be combined. The return of used study drug will be documented. Unused study drug and returned used study drug will be destroyed at the investigational site. Vials should be discarded in a safe manner. Destruction must be documented. Study drug should be dispensed under the supervision of the investigator, a qualified member of the investigational staff, or by a hospital/clinic pharmacist. Study drug will be supplied only to subjects participating in the study. Returned study drug must not be dispensed again, even to the same subject. Study drug may not be relabelled or reassigned for use by other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site other than the study sites agreed upon with the sponsor. 12

13 12 End of protocol treatment Reasons for going off protocol treatment are: Not eligible for bortezomib or cyclophosphamide treatment Not at least minimal response after 3 cycles of bortezomib, cyclophosphamide and dexamethasone during reinduction phase Not at least minimal response 6 months after start of bortezomib and cyclophosphamide maintenance Interruption for more than 8 weeks during maintenance therapy. Excessive toxicity (including toxic death) Progression / relapse Intercurrent death No compliance of the patient (especially refusal to continue treatment) Pregnancy (of female patient) Completion of protocol treatment 13 Required clinical evaluation Aim of the clinical evaluation during treatment and follow up is to determine response, toxicities and eligibility for further treatment. Before start of each treatment cycle, routine investigations like blood cell count and renal function will be performed according to local policy Time of clinical evaluation See appendix E Medical history Previous chemotherapy or oncological diseases. Performance status. Concomitant diseases, active at baseline Bone pain. Infections. Constipation. Polyneuropathy. Bleeding tendency Physical examination Standard physical examination including body weight and height, with special attention for: Macroglossia Kyphoscoliosis Orthostatic hypotension Carpal tunnel syndrome Polyneuropathy or other neurologic symptoms. Infections Edema Bleeding tendency 13.4 Laboratory investigation Hematology: Hemoglobin, leukocytes, differential count, platelets, MCV. Blood chemistry: BUN, creatinin, liver enzymes, calcium, phosphate, total bilirubin, alkaline phosphatase, total proteins, albumin, LDH, CRP, sodium, potassium, uric acid. 13

14 Qualitative and quantitative serum M-protein, including immunofixation to confirm CR. Qualitative and quantitative urine M-protein (24 hours), including immunofixation to confirm CR. Bone marrow aspirate for cytology Additional investigations Serum b2-microglobulin Radiographic skeletal survey including skull, pelvis, vertebral column and long bones Creatinin clearance if increased serum creatinin X-thorax ECG 14 Evaluation of response Response will be evaluated according to EBMT, IBMTR and ABMT criteria (see appendix B). Time points are after the third and sixth cycle of induction. During maintenance, disease status will be evaluated every 2 months. According to the response criteria a response should be confirmed after 6 weeks. 15 Toxicities Toxicities will be scored according to the NCI Common Toxicity Criteria, version 3.0 (Appendix F). 16 Safety evaluations and adverse events reporting 16.1 Definitions Adverse event (AE) An adverse event (AE) is any untoward medical occurrence in a patient or clinical study subject during protocol treatment. An AE does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Adverse reaction (AR) Adverse reactions (AR) are those AE s of which a reasonable causal relationship to any dose administered of the investigational medicinal product and the event is suspected. Serious adverse event (SAE) A serious adverse event is defined as any untoward medical occurrence that at any dose results 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 significant / persistent disability a congenital anomaly / birth defect any other medically important condition (i.e. important adverse reactions that are not immediately life threatening or do not result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed above) 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 SAE Unexpected Serious Adverse Events are those SAE s of which the nature or severity is not consistent with information in the relevant reference documents. For a medicinal product not yet approved for marketing in a country, a company s Investigators Brochure will serve as a reference document in that country. 14

15 Suspected unexpected serious adverse reaction (SUSAR) All suspected AR s which occur in the trial and that are both unexpected and serious. Protocol treatment period The protocol treatment period is defined as the period from registration until 30 days after stopping of the protocol treatment Reporting of (serious) adverse events Adverse event All AE s have to be reported on the Adverse events and/or Infection form and sent to the IKNL Data Center as soon as possible. All adverse events, with the exception of progression of multiple myeloma, will be reported from the first study-related procedure until 30 days following the last dose of study drug or until the start of subsequent systemic antimyeloma therapy, if earlier. Resolution information after 30 days should also be provided. Adverse events occurring after 30 days should also be reported if considered related to study drug. All Grade 3 or 4 adverse events considered related to study drug must be followed until recovery to Grade 0 or 1. Neuropathic and cardiac adverse events of Grade 2 or higher will be followed until improvement to Grade 0 or 1. The unresolved aforementioned events will be followed for a maximum of 6 months. SAE and Unexpected serious adverse event During protocol treatment all SAE s must be reported to the IKNL Data Center by fax ( ) within 24 hours of the initial observation of the event, except: hospitalization for a standard procedure for protocol therapy administration. Hospitalization or prolonged hospitalization for a complication of therapy administration will be reported as a Serious Adverse Event. hospitalization for the administration of blood or platelet transfusion. Hospitalization or prolonged hospitalization for a complication of such transfusion remains a reportable serious adverse event. hospitalization for a procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, sampling for laboratory tests, bone marrow sampling). Hospitalization or prolonged hospitalization for a complication of such procedures remains a reportable serious adverse event nce of an adverse event. hospitalization for a procedure that is planned (i.e., planned prior to starting of treatment on study; must be documented in the source document). Prolonged hospitalization for a complication remains a reportable serious adverse event. All details should be documented on the Serious Adverse Event 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 2 working days and sent to the IKNL Data Center. All SAE Reports must be dated and signed by the responsible investigator or one of his/her authorized study physician. At any time after the protocol treatment period, unexpected Serious Adverse Events that are considered to be at least suspected to be related to protocol treatment must also be reported to the IKNL Data Center using the same procedure, within 24 hours after the SAE was known to the investigator. The investigator will decide whether the serious adverse event is related to the treatment and the decision will be recorded on the serious adverse event form. The assessment of causality is made by the investigator using the following: 15

16 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 study medication). There is another reasonable explanation for the event (e.g. the patient s clinical condition, other concomitant treatments) There is some evidence to suggest a causal relationship (e.g. the event occurs within a reasonable time after administration of the study medication). However, the influence of other factors may have contributed to the event.(e.g. the patient s clinical condition, other concomitant treatments) There is evidence to suggest there is 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 judgment of the causal relationship Actions of the IKNL Data Center upon receipt of (S)AE reports AE The IKNL Data Center will notify Johnson & Johnson Pharmaceutical Research and Development (Janssen-Cilag B.V., dep. Pharmacovigilance) of all adverse events, in report format, at the end of the study. SAE and unexpected SAE The IKNL Data Center will forward all reports within 24 hours of receipt to the study coordinator, the study central datamanager and Janssen-Cilag B.V., the Netherlands. 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 pages for the involved patient with details of treatment and outcome. Patients without a report of an SAE are implicitly considered alive without SAE. This information will be used in monitoring the incidence of SAE s, the estimation of overall survival and safety monitoring. In addition, the IKNL Data Center will send copies to the investigators and Janssen-Cilag B.V. of any relevant correspondence with regulatory authorities regarding serious adverse events, irrespective of association with the Study Drug(s) in the course of the Clinical Trial, within one working day of such report or correspondence. The IKNL Data Center will receive, via the Janssen-Cilag B.V. Operating Company Representative, a quarterly frequency listing of the serious adverse event reports received for site reconciliation SUSAR reporting J&JPRD will notify the principal investigator of any new information, which becomes available during the course of the study, which may affect the overall safety profile of Bortezomib. Any suspected unexpected serious adverse reactions (SUSAR s), from any source, which are considered by J&JPRD to be reportable to investigators, Health Authorities and Ethics Committees will be sent to the IKNL Data Center within 15 calendar days of Janssen-Cilag B.V. personnel first becoming aware of such events, or 7 calendar days for fatal or lifethreatening reports. The IKNL Data Center will have responsibility for reporting such events to all applicable Health Authorities and the Ethics Committee which approved the study, within the required timelines. Additionally, the IKNL Data Center will report all such events within the required timelines to co-investigators (for multi-centre studies). Coinvestigators will report all such events to their Ethics Committees, where required. 16

17 17 Registration The patient should be registered immediately after having given informed consent, and before the start of chemotherapy. Patients need to be registered using the registration form (appendix H) at the IKNL Data Center Groningen (fax ), Monday through Friday, from 09:00 to 17:00. The following information will be requested at registration: Protocol number Institution name Name of caller/responsible investigator Patient s initials or code Patient s hospital record number (not obligatory) Sex Date of birth Eligibility criteria All eligibility criteria will be checked. Each patient will be given a unique patient study number. Patient study number will be confirmed by and regular post to the local investigator and to Janssen-Cilag B.V. 18 Forms and Procedures for collecting data 18.1 Monitoring IKNL datamanagers will perform on-site monitoring visits. At these visits, the monitor will compare the data entered into the CRFs with the hospital or clinic records (source documents). The nature and location of all source documents will be identified to ensure that all sources of original data required to complete the CRF are known to the sponsor and investigational staff and are accessible for verification by the sponsor site contact. At a minimum, source documentation must be available to substantiate: subject identification, eligibility and participation; proper informed consent procedures; dates of visits; adherence to protocol procedures; records of safety and efficacy parameters; adequate reporting and follow-up of adverse events; administration of concomitant medication; drug receipt/dispensing/return records; study drug administration information; date of subject completion, discontinuation from treatment, or withdrawal from the study, and the reason if appropriate. Specific items required as source documents will be reviewed with the investigator before the study. Direct access to source documentation (medical records) must be allowed for the purpose of verifying that the data recorded in the CRF are consistent with the original source data. The sponsor expects that, during monitoring visits, the relevant investigational staff will be available, the source documentation will be available, and a suitable environment will be provided for review of study-related documents Data quality assurance Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified investigators and appropriate study centers, review of protocol procedures with the investigator and associated personnel before the study, and monitoring visits by the sponsor. CRF completion guidelines will be provided. The data will be entered into the clinical study database and verified for accuracy. Local datamanagement will be performed preferably by datamanagers from Comprehensive Cancer Centers 17

18 18.3 On-site audits The local investigator/institution will permit site-visits to carry out an audit of the study in compliance with regulatory guidelines. These audits will require access to all study records, including source documents, for inspection and comparison with the CRF s. Subject privacy must, however, be respected. Similar auditing procedures may also be conducted by agents of any regulatory body reviewing the results of this study in support of a regulatory submission. The investigator should immediately notify the sponsor and J&J if they have been contacted by a regulatory agency concerning an (upcoming) inspection. 19 Statistical considerations 19.1 Patient numbers, power considerations and efficacy analysis For the calculation of the required number of patients to be entered in the study, the response will be considered as primary endpoint. This study has been designed to explore the feasibility of bortezomib combined with cyclophosphamide and dexamethasone. In a historical control group treated with thalidomide and cyclophosphamide, 65 % of the treated patients had a complete or partial response (defined as > 50% decrease in measurable M-protein or bone marrow infiltration). Based on an expected response rate of 80%, a sample size of 66 patients is needed in order to show that, at an alpha of 5% and with a power of 90%, the response rate of treatment including bortezomib is higher than 65%, the historical response rate based on treatment with thalidomide and cyclophosphamide. Assuming that 10% of the included patients is ultimately not assessable for response rate (due to drop-out or other reasons), the sample size will be 73 patients Endpoints and statistical analysis The primary endpoint of this study is: - Toxicity during induction and maintenance therapy Secondary endpoints are: - Response (Non, minor, partial remission (PR), very good partial remission (VGPR) and complete remission (CR) - Progression free survival (PFS) - Overall survival (OS) Definition of study endpoints Response criteria are described in appendix B PFS is defined as the time from registration to disease progression, date of death from any cause or the date of last contact for patients still alive at study closure, whichever occurs first. OS is defined as the time from registration to the date of death form any cause or the date of last contact for patients still alive at study closure, whichever occurs first. Statistical analysis For the response evaluation the best response from the start of treatment to disease progression will be assessed in patients who actually started bortezomib, cyclophosphamide and dexamethasone treatment. Response duration, defined as the time between best response and disease progression will be estimated by strata of best achieved response. PFS and OS will only be evaluated for patients who were eligible and had no major protocol violations, irrespective of actual start of bortezomib, cyclophosphamide and dexamethasone treatment. PFS and OS will be estimated using the Kaplan-Meier method. For the estimation of PFS patients who did not die due to MM or associated paraneoplastic events and patients still alive or lost to follow-up at study closure are censored at the date of death or the date on which these patients were last known to be alive, respectively. For the estimation of OS patients still alive or lost to follow-up at study closure are censored at the date of death or the date on which patients were last known to be alive, respectively. Actuarial competing risks estimates of probability of death will be split by cause of death where a difference will be made between death due to or after relapse or refractory disease and death due to side effects of treatment. 18

19 Toxicity will be evaluated only in patients who actually started bortezomib, cyclophosphamide and dexamethasone treatment. The analysis of treatment toxicity will be done primarily by tabulation of the incidence of side effects and infections with CTC grade 2 (appendix E) or more, both cumulative over all cycles and by cycle number. Side effects will be seperated into haematological and non-haematological events. Where appropriate (e.g. serious adverse events, treatment discontinuation because of toxicity or toxic deaths) more detailed information will be provided. Toxicity analysis All toxicity and response analysis will be descriptive. Were appropriate 95% confidence bounds will be provided for point estimates (i.e. for response rates). No formal tests will be performed. 20 Ethics 20.1 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 Ethical conduct of the study The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki (Edinburgh, Scotland, 2000), the ICH-GCP Guidelines of 17 January 1997 and conducted according Medical Research involving Human Subjects Act. 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 options for therapy in multiple myeloma will be explained to the patient. 21 Trial insurance Each participating center has a liability insurance which is in accordance with article 7, subsection 6 after WMO. Each participating center will insure the participating subject in that center in accordance with the Measure regarding Compulsory Insurance for Clinical Research in Humans. 22 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 by the IKNL Data Center. A draft manuscript will be submitted to the Data Center and all coauthors and Johnson & Johnson PRD/Millennium for review. After revision by the Data Center, the other co-authors and Johnson & Johnson PRD/Millennium, the manuscript will be sent to a peer reviewed scientific journal. Authors of the manuscript will include the study coordinator(s), all local investigators, the statistician(s) and the IKNL datamanager in charge of the trial. Interim publications or presentations of the study may include overall results and may be made publicly available before recruitment is discontinued. Any publication, abstract or presentation based on patients included in this study must be approved by the study coordinator(s). This is applicable to any individual patient in the trial. Such a publication cannot include an analysis of any of the study end-points unless the final results of the trial have already been published. 19

20 23 Glossary of abbreviations (in alphabetical order) AE ANC BJ BM BMT BRDU BUN Ca CAD CKTO CR CRF CRP CTC ECG ECOG EBMT EFS EORTC FISH GCP G-CSF GI GMMG HB HDM HIV HLA HOVON ICH IFM ISS ITT IU KCl LDH METC MM NaCl NCI NMSG NYHA OS PAD PB PBSC PD PO PR SAE SC SCT SD SNP TBI ULN VAD Adverse Event Absolute Neutrophil Count Bence Jones Bone Marrow Bone Marrow Transplant Bromo Deoxy Uridine Blood Urea Nitrogen Calcium Cyclophosphamide, Doxorubicin (Adriamycin), Dexamethasone Commissie voor Klinisch Toegepast Onderzoek Complete Remission Case Report Form C-Reactive Protein Common Toxicity Criteria Electrocardiogram Eastern Cooperative Oncology Group European Group for Blood and Marrow Transplantation Event Free Survival European Organization for Research and Treatment of Cancer Fluorescence In Situ Hybridization Good Clinical Practice Granulocyte-Colony Stimulating Factor Gastro-intestinal German-speaking myeloma multi-center group Hemoglobin High Dose Melphalan Human Immunodeficiency Virus Human Leukocyte histocompatibility Antigen Dutch-Belgian Hematology-Oncology Cooperative Group International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use Intergroup Français de Myelom International Staging System Intention To Treat International Units Potassium chloride Lactate Dehydrogenase Medical Ethical review committee Multiple Myeloma Sodium Chloride National Cancer Institute Nordic Myeloma Study group New York Heart Association Overall Survival Bortezomib, Doxorubicin (Adriamycin), Dexamethasone Peripheral Blood Peripheral Blood Stem Cell(s) Progressive Disease Per Os Partial Response Serious Adverse Event Subcutaneous Stem Cell Transplantation Stable Disease Single Nucleotide Polymorphism Total Body Irradiation Upper Limit of Normal Vincristine, Doxorubicin (Adriamycin), Dexamethasone 20

21 WHO WMO World Health Organization Wet Medisch Wetenschappelijk Onderzoek met mensen 21

22 24 References (1) Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348: (2) Richardson PG, Barlogie B, Berenson J et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood. 2005;106: (3) Jagannath S, Barlogie B, Berenson J et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127: (4) Richardson PG, Barlogie B, Berenson J et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma:: final time-to-event results from the SUMMIT trial. Cancer. 2006;106: (5) Kropff MH, Bisping G, Wenning D et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk Res. 2005;29: (6) Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res. 2001;100: (7) Cusack JC, Jr., Liu R, Houston M et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappab inhibition. Cancer Res. 2001;61: (8) Shah MA, Schwartz GK. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin Cancer Res. 2001;7: (9) Kropff M, Bisping G, Wenning D, Berdel WE, Kienast J. Proteasome inhibition in multiple myeloma. Eur J Cancer. 2006;42: (10) Ma MH, Yang HH, Parker K et al. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res. 2003;9: (11) Mitsiades CS, Mitsiades NS, McMullan CJ et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A. 2004;101: (12) Orlowski RZ, Voorhees PM, Garcia RA et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood. 2005;105: (13) Berenson JR, Yang HH, Sadler K et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2006;24: (14) Mateos MV, Hernandez JM, Hernandez MT et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006;108: (15) Bergsagel DE, Cowan DH, Hasselback R. Plasma cell myeloma: response of melphalan-resistant patients to high-dose intermittent cyclophosphamide. Can Med Assoc J. 1972;107: (16) Brandes LJ, Israels LG. Weekly low-dose cyclophosphamide and alternate-day prednisone: an effective low toxicity regimen for advanced myeloma. Eur J Haematol. 1987;39: (17) Celesti L, Clavio M, Poggi A et al. The association of cyclophosphamide and dexamethasone in advanced refractory multiple myeloma patients. Haematologica. 1997;82: (18) Kropff MH, Lang N, Bisping G et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. Br J Haematol. 2003;122: