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IND No: 11346 EudraCT No: 2004-000353-38 Study agent: Chimeric monoclonal antibody cG250 (Rencarex£)
Study Title: A randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with clear cell RCC and high risk of recurrence
Clinical Protocol No.: WX-2003-07-HR
Original Protocol: 10 Feb 2004 Amendment 1: 06 Jul 2005 Amendment 2: 21 April 2006 Amendment 3: 26 March 2007 Amendment 4: 02 Feb 2012
Sponsor: Wilex AG Grillparzerstrasse 10 D-81675 Munich Germany Phone: +49-89-41 31 38-0 Fax: +49-89-41 31 38-99
No part of this protocol may be passed on, reproduced or published without written permission of Wilex AG, Clinical Research and Development.
Confidential WX-2003-07-HR Original Protocol Date: 10 Feb 2004 Amendment 1: 06 Jul 2005 Amendment 2: 21 Apr 2006 Amendment 3: 26 March 2007 Amendment 4: 02 Feb 2012
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1.4 Declaration by the Investigator
I have read this protocol and agree that it contains all the necessary details for carrying out this study. I will conduct the study as described and will complete the study within the time designated. I verify that I am suitably qualified by education, scientific medical training and experience to conduct the study. Documentation of my qualifications and professional affiliations are contained in my up-to-date curriculum vitae. I will provide copies of the protocol supplied and all information relating to pre-clinical and prior clinical experience (e.g. Investigator’s Brochure) to all staff in my unit who participates in this study. I will discuss this material with them to ensure that they are fully conversant with the medical treatment in and the conduct of the study, and that they will handle the data and information generated in the study confidentially. I will conduct the study in accordance with Good Clinical Practice, the Declaration of Helsinki, and the moral, ethical and scientific principles that justify medical research. The study will be conducted in accordance with the relevant laws and regulations relating to clinical studies and the protection of patients of the country in which the study will be performed. All patients will be informed comprehensively about the nature of the study and will give their written consent to participate before entry into the study. They will be informed that they may withdraw from the study at any time. I will use only an information sheet and consent form approved by Wilex and the Ethics Committee (EC) which has reviewed this study. I will supply Wilex with any material written by myself (e.g. summary of study) which is given to the EC in support of the application. Where applicable and required the information contained in the case report forms will be transcribed from my records, reports and manuscripts. The case report form may be the original source document for certain items. Either I or an appointed person will attest to the authenticity of the data and accuracy and completeness of the transcription by signing the case report form. I agree to the audit and monitoring procedures which involves verification of study records against the original records. Should it be requested by government regulatory agencies, I will make available additional background data from my records and where allowed from the hospital or institution where the study was conducted. I certify that any laboratory, excluding the central laboratory(s) appointed for the study in which laboratory parameters will be determined is subject to regular external quality control. I understand that the case report forms and other data pertinent to this study are the property of Wilex and are confidential. I will supply Wilex with the study data in such a way that the patient normally cannot be personally identified.
Investigator: ______Signature Date Name and Address: ______
______
Telephone number: ______
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Table of Contents
1 SIGNATURES / PROTOCOL APPROVAL AND RELEASE ...... 2 1.1 Wilex AG (Wilex) ...... 2 1.2 Director of Clinical Investigation (for German sites only) ...... 2 1.3 Statistician (Aptiv Solutions) ...... 3 1.4 Declaration by the Investigator ...... 4 2 SCIENTIFIC BACKGROUND ...... 9 2.1 Renal Cell Carcinoma ...... 9 2.2 Patients with high risk of recurrence to be included in the study ...... 10 2.3 Chimeric monoclonal antibody cG250 ...... 12 2.4 Human Anti-Chimeric Antibody (HACA) ...... 13 2.5 Risk-benefit analysis for using cG250 in the adjuvant treatment of RCC ...... 14 3 TRIAL OBJECTIVES AND PURPOSE ...... 14
4 TRIAL DESIGN ...... 15 4.1 Endpoint criteria ...... 15 4.2 Design ...... 15 4.3 Randomization ...... 15 4.4 Duration of the study ...... 16 4.5 Stopping rules / Discontinuation criteria ...... 16 5 SELECTION AND WITHDRAWAL OF SUBJECTS ...... 16 5.1 Inclusion criteria ...... 16 5.2 Exclusion criteria ...... 17 5.3 Subject withdrawal criteria ...... 17 5.4 Screening log ...... 18 6 STUDY PROCEDURES ...... 19 6.1 Procedures ...... 19 6.1.1 Study flow charts ...... 19 6.1.2 Regular assessments ...... 20 6.1.3 Quality of life ...... 21 6.1.4 Assessments after detection of relapse ...... 21 6.2 Documentation of medical history ...... 22 6.2.1 Concomitant therapy ...... 22 6.2.2 Prohibited medication ...... 22 6.3 Procedures for assuring subject compliance ...... 22 6.4 Central pathological review ...... 22 6.4.1 Collection and assessment of paraffin blocks of tumor tissue ...... 22 6.4.2 Assessment of G250 (MN) antigen expression ...... 23
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6.4.3 Assessment of other biomarkers in tissue samples ...... 23 6.4.4 Evaluation of cG250 drug levels in serum samples ...... 24 7 STUDY MEDICATION ...... 24 7.1 Preparation and administration ...... 24 7.2 Procedure in case of missed doses ...... 24 7.3 Drug accountability ...... 24 7.4 Delivery ...... 25 7.5 Package labeling and formulation ...... 25 7.6 Storage ...... 25 7.7 Identification of investigational products in emergency situations ...... 26 8 ASSESSMENT OF EFFICACY ...... 27 8.1 Efficacy parameters ...... 27 8.2 Patient evaluability for primary endpoints ...... 27 8.3 Methods of assessments ...... 27 8.3.1 Assessment of disease-free survival ...... 27 8.3.2 Assessment of overall survival ...... 28 9 ASSESSMENT OF SAFETY ...... 29 9.1 Safety parameters ...... 29 9.2 Laboratory values ...... 29 9.3 HACA ...... 29 9.4 Patient evaluability for safety analysis ...... 29 9.5 Adverse Event reporting ...... 29 9.6 Serious Adverse Event reporting ...... 30 9.7 Relationship of Adverse Events and Serious Adverse Events to study agent(s) ...31 10 ASSESSMENT OF QUALITY OF LIFE ...... 32
11 STATISTICS...... 33 11.1 Primary endpoints ...... 33 11.2 Secondary endpoints ...... 33 11.3 Statistical model ...... 33 11.4 Hypotheses and testing procedures ...... 34 11.4.1Primary hypothesis testing ...... 34 11.4.2Secondary hypothesis: Quality of Life ...... 35 11.5 Data sets to be evaluated ...... 35 11.6 Final analysis and reporting ...... 36 11.6.1Analysis of demographics ...... 36 11.6.2Analysis of efficacy ...... 36 11.6.3Exploratory analyses ...... 37 11.6.4Analysis of safety ...... 37 11.6.5Planned interim analyses ...... 37 11.6.6Quality of life evaluation ...... 38 11.7 Sample size determination ...... 38
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11.8 Handling of missing data ...... 39 11.9 Data management ...... 39 11.10 Independent Data Monitoring Committee (IDMC) ...... 39 11.11 Data handling after early stopping ...... 39 12 DOCUMENTATION AND HANDLING OF STUDY DATA ...... 39 12.1 Case Report Forms ...... 39 12.2 Source documents...... 40 12.3 Monitoring ...... 40 12.4 Data storage ...... 40 13 QUALITY ASSURANCE / AUDIT ...... 41
14 ETHICS AND REGULATIONS ...... 41 14.1 Declaration of Helsinki ...... 41 14.2 Informed Consent ...... 41 14.3 Ethics Committee / Institutional Review Board ...... 41 14.4 Regulatory Affairs ...... 42 14.5 Pre-study documentation requirements ...... 42 14.6 Confidentiality of patient data ...... 42 14.7 Protocol amendments ...... 42 14.8 Premature study termination ...... 43 15 FINANCING AND INSURANCE ...... 43
16 PUBLICATION POLICY ...... 43
17 REFERENCES ...... 44
APPENDIX I: THE MINIMIZATION METHOD FOR RANDOMIZATION...... 46
APPENDIX II: ECOG / KARNOFSKY PERFORMANCE SCALE ...... 47
APPENDIX III: NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) ...... 48
APPENDIX IV: ADMINISTRATION OF THE STUDY MEDICATION ...... 49
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ABBREVIATIONS ADCC Antibody Dependent Cellular Cytotoxicity AE Adverse event ALAT Alanin aminotransferase AP Alkaline phosphatase ANC Absolute neutrophil count ASAT Aspartate aminotransferase BP Blood pressure Ca Calcium CBC Complete Blood Count CIOMS Council for International Organization of Medical Sciences CNS Central nervous system CRF Case Report Form CRO Contract Research Organization CT Computer tomography CTCAE Common Terminology Criteria for Adverse Events EC Ethics Committee ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group ELISA Enzyme linked immunosorbent assay FDA Food and Drug Administration HACA Human Anti Chimeric antibody Hgb Hemoglobin ICH International Conference on Harmonization IDMC Independent data monitoring committee IFN-Į Interferon alpha IL-2 Interleukin-2 i.m. intramuscular INN International nonproprietary name IRR Independent radiological reviewer ITT Intent-to-treat IV/iv Intravenous K Potassium LDH Lactate dehydrogenase MIU Million internal units MRI Magnetic Resonance Imaging MVI Microscopic vascular invasion Na Sodium NCI National Cancer Institute (USA) NYHA New York Heart Association PLT Platelets PP Per protocol PS Performance Scale QoL Quality of Life RBC Red blood cells RCC Renal Cell Carcinoma SAE Serious adverse event s.c. subcutaneous TTP time to progression WBC White blood cells WHO World Health Organization
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2 SCIENTIFIC BACKGROUND
2.1 Renal Cell Carcinoma
It is estimated that 41,325 new cases of renal cell carcinoma (RCC) were diagnosed in the European Union in 1995, with 21,728 deaths resulting from the disease (EUCAN database, 1995). According to the United States Department of Health and Human Services about 30,000 new cases are diagnosed annually, with about 12,000 RCC related death (USPHS, NIH, SEER Cancer Statistics Review, 1999). About 50-60% of patients initially present with stage I or II disease (localized RCC). After surgical removal of the primary tumor, these patients have a good prognosis with 5-year survival rates of 60-80% (stage I) and 40-60% (stage II) respectively. The remaining patients have less favorable prognosis. Although most patients with stage III disease, i.e. non-metastatic disease at the time of diagnosis (20-25% of total patients) will also undergo surgery, their 5-year survival rate is only 20% to 40%. Such patients, despite the absence of clinically detectable tumor, are clearly at high risk of tumor recurrence. Patients with stage IV (metastatic) disease (10-20% of total patients) have a 5- year survival rate of 0-20% 1. A prospective cohort study with outcome assessment in 814 patients was able to define five different categories with significant differences in both disease-specific and overall survival 2. These categories were converted to risk groups, defined by the 1997 TNM classification, Fuhrman’s grade and ECOG performance status. Of 468 non-metastatic patients (abbreviated NM), 128 (27%) were low-risk (NM-LR), 190 (41%) were intermediate-risk (NM-IR), and 150 (32%) were high-risk (NM-HR) patients. The 5-year overall survival between these groups differed significantly with 84%, 72% and 44%, respectively. In the high risk group, 42.5% patients had a relapse within the first two years after nephrectomy. Adjuvant therapy in high risk RCC: The concept of adjuvant therapy is generally accepted and well established in several tumors such as breast and colon carcinoma. Due to increased early diagnosis of RCC patients and the high incidence of relapses after surgery, the need for adjuvant treatment is becoming more apparent. For nephrectomized patients who subsequently relapse, the median time to relapse is 15 to 18 months with 85% of relapses occurring within 3 years 3. No drug has been approved so far for the adjuvant treatment of RCC nor have clinical trials reported promising results. A large adjuvant study in RCC with 247 patients was reported by Pizzocaro et al. 4. Half of the patients received IFN-α at 6 MIU three times a week i.m. over a period of 6 months, starting within one month of surgery. The other half of the patients was observed only. The 5-year overall and event free survival probabilities showed no statistically significant difference. In 97 lymph node negative patients, a statistically significant harmful effect was seen in the treated group. In a small sub-group of 13 treated patients with pN2/pN3 (see 2.2. for classification) a protective effect could be observed when the 3 year cumulative probability of survival was reviewed. Due to the small size of this patient group, these data are not statistically significant. 55 % of patients showed signs of toxicity caused by IFN-α and 28% required a dose reduction and/or suspension of the therapy. In another study, 237 high risk RCC patients received lymphoblastoid Interferon (L-IFN). The results showed a higher death rate and a higher recurrence rate in the IFN treatment arm with 13% of the patient experiencing grade 4 toxicities. The role of IL-2 in the adjuvant setting has not been finally defined yet. One study being conducted by the Cytokine Working Group in the US is currently evaluating high dose IL-2 compared with observation only 5. Due to the lack of positive study outcomes, combined with significant toxicities, the current standard of care after nephrectomy is close observation.
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Although new therapies have been approved in recent years for the treatment of metastatic RCC, the survival rates for renal cell carcinoma have not significantly changed for decades. The currently available compounds have shown relatively poor efficacy results and significant systemic toxicity. Consequently, there is a substantial unmet medical need for new treatment options, in particular non-toxic treatments for RCC patients with high risk for recurrence after nephrectomy with no evidence of macroscopically detectable disease. In view of its excellent safety profile and the available initial efficacy data, cG250 will be evaluated for its potential to prevent or delay tumor recurrence.
2.2 Patients with high risk of recurrence to be included in the study
It is generally accepted that the main parameter to rate the prognosis of a RCC patient after surgery is the pathologic stage depicted by the TNM classification 6. The classification has been revised in 2002 as follows:
T1 Tumor ≤ 7 cm in greatest dimension, limited to the kidney T1a Tumor ≤ 4 cm in greatest dimension, limited to the kidney T1b Tumor > 4 cm but ≤ 7 cm in greatest dimension, limited to the kidney T2 Tumor > 7 cm in greatest dimension, limited to the kidney T3 Tumor invades into larger veins or adrenal gland or perinephric tissue but not beyond Gerota’s fascia T3a Tumor directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota’s fascia T3b Tumor grossly extends into renal vein or its segmental (muscle-containing) branches, or vena cava below the diaphragm T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond Gerota’s fascia N0 No regional lymph node metastasis N1 Metastases in a single regional lymph node N2 Metastasis in more than one regional lymph node NX Regional lymph nodes cannot be assessed M0 No distant metastasis M1 Distant metastasis
In a patient collective of 675 patients with radical nephrectomy evaluated retrospectively in one hospital, 48% of the patients had pT1, 20% pT2, 10% pT3a, 20% pT3b and 2% pT4 7.
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In the trial described in this protocol, the sponsor intends to investigate the potential of cG250 in the treatment of patients at high risk of recurrence. Patients to be included should have one of the following (referring to TNM classification, 6th edition UICC, 2002): • Risk group I: T3aN0/XM0 or T3bN0/XM0 or T3cN0/XM0 or T4N0/XM0 • Risk group II: any T stage and N+ disease and M0 • Risk group III: T1bN0/XM0 or T2N0/XM0, each with grading G ≥ 3 (Fuhrman or any other nuclear grading system with at least 3 grades)
In risk groups I and III, patients with N0 (no metastases in regional lymph nodes) or NX (regional lymph nodes not assessed for metastases) are eligible for the study. Therefore, the decision whether to perform a lymphadenectomy of non-enlarged lymph nodes is left to the surgeon who will take into account the surgical conventions and standard of care in his/her specific country. As a consequence, not every patient will be assessed for the presence or absence of metastases in the regional lymph nodes. As stated above, the lymph node status of non-assessed patients will be classified as NX (“not known”). The patients with NX classification will be stratified into risk group 1 or 3 in the same manner as patients with N0 classification. Rationale for risk groups: Risk group I: In a prospective cohort study of 814 patients, RCC was subclassified into risk groups to predict clinical outcome. One group, named “non-metastatic high risk” (NM-HR) contained patients with non-metastatic, N0 tumors of T3 or greater and different combinations with other factors (performance scale, nuclear grading). This group with a relapse rate of approximately 42% at 24 months had a significantly worse prognosis than the intermediate and low risk group 2. Recently published data show that cancer-specific survival of pT3a patients does not differ greatly from pT3b patients and is virtually the same within the first 2 years of follow-up 8. This is in line with clinical experience. It has been noted that the relapse risk of patients with pT3a tumors is high and their relapse risk estimate is similar to that of patients with pT3b, pT3c and pT4 tumors. Therefore, pT3a tumors are now included in risk group I. Risk group II: It has been shown in the past that the probability of relapse is significantly higher in node positive than in other patient categories. In the node positive group, 80% of patients relapsed within 30 months. Patients with node-negative disease had a much better prognosis, with only 40% relapsing at 3 years 9 10. Risk group III: For risk group III, the combination of staging and high grading G is used to select an appropriate patient population with a similar prognosis. This group includes patients with aggressive (i.e. high grade) tumors which are organ contained (T1b, T2). The aggressive potential of these latter tumors is related to both microscopic vascular invasion (MVI) and high grading. It was shown that patients with high grade tumors (e.g. Fuhrman grade 3 and 4) have a poorer cancer specific survival and metastasis free survival than patients with low grade tumors (grade 1 and 2) 11.Several studies have addressed the presence of microscopic vascular invasion (MVI) for its prognostic value 12,13,14. Using multivariate statistical analysis it was found that the two variables, i.e. grade of anaplasia and MVI are prognostically interconnected as MVI was particularly frequent among tumors with a high grade of anaplasia and less frequent in low grade tumors, with 56% vascular invasion for nuclear grading G2-G3 and 24% vascular invasion in G1 tumors 15. Based on this information, it would appear to be redundant to
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screen patients for the presence of both parameters especially as screening for MVI is not part of clinical practice in the United States and many other countries. Therefore, verification of high grading alone, defined as grading G 3 (Fuhrman or any other nuclear grading system with at least 3 grades) for small organ-contained tumors appears to be adequate. Moreover, this approach is in line with the recommendations provided by the central pathologists for this trial.
2.3 Chimeric monoclonal antibody cG250
Chimeric monoclonal antibody cG250 is a IgG1 kappa light chain chimeric version of an original murine monoclonal antibody mG250, first described by Oosterwijk et al. 16. Chimeric G250 (cG250) has been shown to be equivalent to murine mG250 in competitive binding assays and shows similar binding reactivities on human cancer cell lines as mG250. G250 detects a cell-surface antigen (MN antigen) on renal cancer cells. In immunohistochemical assays on sections of fresh frozen tissues, G250 reacts with 95% of renal cancers of the clear cell type and with a much lower proportion of colon cancers and other cancers. Reactivity with renal cancers is homogeneous (greater than 75% reactive cells) in 75% of renal cancers. The reactivity of cG250 with normal human tissues is restricted to the gastric epithelium and the biliary ducts in the liver 17 18. The chimeric antibody can be radiolabeled with Iodine-131 with minimal loss of immunoreactivity. In a study with 16 patients with metastatic RCC, 131I-labeled antibody was infused one week before nephrectomy 18. After infusion the radiolabeled antibody gradually localized into the tumor with the remainder being excreted from the body. The percentage of labeled antibody that localized into the tumor was among the highest ever reported in clinical trials with anti-tumor antibodies. In a phase I multiple dose study with the unlabeled formulation of the cG250 antibody, 12 metastatic RCC patients received weekly doses for 6 weeks in a dose escalating setting. The results showed that the antibody is safe at all dose levels of 5, 10, 25 and 50 mg/m2. One objective response was seen and 8 out of 12 patients presented with disease stabilization after the first 6- week-cycle of treatment 19. In addition, in a phase II study (WX-2000-01-nak) where the unlabeled cG250 antibody was administered as monotherapy, 32 evaluable patients with metastatic RCC were treated up to 20 weeks with 50 mg cG250 once weekly. The study confirmed the excellent safety profile of long term treatment with the antibody. No serious drug related adverse events were reported and no allergic reactions occurred. In two patients very low human anti-chimeric antibody (HACA) levels were seen (see 2.4, data on file at Wilex; 20). Of the 32 patients, 9 patients achieved stabilization of disease for at least 6 months. Thereof one patient experienced a minor response. In addition, one complete response was seen 4 months after the end of treatment in the follow up period. The median overall survival was determined to be 15 months and 41% of the ITT population was still alive after two years. Data are available from a study in which 20 mg cG250 was given weekly in combination with low dose IL-2 (WX-2000-04-gil). In the ITT population of 35 patients, 2 patients achieved a partial remission. A total of seven patients had stabilization of their previously progressive disease for almost six months. The median survival time was determined to be 22 months. Another recently completed study in metastatic RCC explores the efficacy and safety of 20 mg cG250 when combined with 3 x 3 MIU of IFN-Į per week. Of the 26 evaluable patients, about 45% started study treatment within 10 months post nephrectomy. All patients were progressive at study entry as rated by the local radiologist and investigator. Two patients responded to this combined treatment and 11 patients achieved tumor stabilization for almost six months. All studies have confirmed the excellent tolerability of cG250. The mechanism of action of cG250 is ADCC, although other mechanism of actions may be possible. In vitro studies indicate that 0.5 μg/ml of cG250 is adequate for the induction of ADCC 21.
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This suggests that a clinical dosing regimen delivering levels of cG250 of at least 0.5 μg/ml should be efficacious, provided the drug is able to reach the target. In addition, the results from a dose escalation study using tracer doses of radiolabeled cG250 indicate that single doses above 10 mg per patient should be optimal for saturating all antigen positive tumor cells for a period of one week 18. A dosing regimen of either 20 mg or 50 mg cG250 per patient on a weekly cycle will deliver concentrations above 0.5 μg/ml and therefore should be adequate for efficacy. In terms of ADCC, increasing the dose from 20 mg to 50 mg would appear to offer little additional benefit. Dosing schemes with weekly infusions of either 20 or 50 mg of cG250 for up to 20 weeks appear to be well tolerated and do not lead to significant HACA development. From the analysis of pharmacokinetic data collected in studies WX-2000-01-nak and WX-2000-04- gil, it appears that trough plasma levels of cG250 reach a plateau level in both studies in six to ten weeks of treatment. The trough level in the WX-2000-04-gil study, where the dose was 20 mg per week levels-out at 5.5 μg/ml after 10 weeks of treatment. Interestingly, this is almost the same trough level (4.2 μg/ml) as that achieved one week following a single dose of 50 mg (WX-2000-01- nak study). This suggests that achieving steady-state plasma levels with a weekly dose of 20 mg will be accelerated by giving a prior loading dose of 50 mg. In terms of activity profile, patients who were eligible for treatment extension and received cG250 for up to 20 weeks, achieved durable clinical benefit for about 6 months or more, which is considered clinically relevant in this patient population. A prolonged treatment schedule, e.g. for 24 weeks may therefore be warranted. In conclusion, a dosing scheme selected for the present study consisting of a single loading dose of 50 mg (week 1) followed by weekly infusions of 20 mg of cG250 (week 2-24) would seem to be adequate in terms of safety and the potential for clinical benefit.
2.4 Human Anti-Chimeric Antibody (HACA)
The cG250 antibody is a murine-human chimeric antibody. The murine parts of this antibody can be immunogenic, giving rise to the development of HACA. The presence of HACA may lead to rapid clearance and may thus interfere with the biolocalization to renal cancer cells. In addition HACA may lead to allergic reactions. In most studies using other antibodies, any allergic events that occurred could be controlled without lasting sequelae by administration of anti-histamines. In a study in which patients received single doses of 131Iodine labeled cG250, ranging from 2 to 50 mg, two out of 16 patients (both dosed with 10 mg) had low titers of HACA in sera obtained at 12 weeks 19. No HACA was found at earlier time points. In a second study, in which 10 patients received two injections of 5 mg radiolabeled cG250 spaced by one week, no HACA was observed 22. In a third study patients received courses of repeated 5 mg injection of 131Iodine labeled cG250 spaced by 2-3 days. In this study in 15 metastatic RCC patients, the total number of cG250 injections given varied from 5 to 20. One patient developed HACA after 4 injections, without showing clinical symptoms. Results of a study with multiple injections of the unlabeled cG250 administered in different dose levels from 5 to 50 mg/m2 showed development of HACA in one out of 12 patients. This patient did not have any clinical symptoms. In this study nine out of 12 patients received between six and about 65 weekly cG250 infusions without HACA development. In the previously mentioned phase II trial with unlabeled cG250 (section 2.2, 2.3 data on file at Wilex) 32 evaluable patients received weekly infusions of 50 mg cG250 for up to 20 weeks. In only 3 sera of 2 patients HACAs at very low titers were observed. From these data it is clear that with the dosing regimen selected for this study HACA may develop but that in the vast majority of
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patients HACA does not occur even after numerous repeated injections. In the rare cases where HACA could be detected in patients who had received cG250, this observation was not associated with any clinical symptoms or allergic reactions.
2.5 Risk-benefit analysis for using cG250 in the adjuvant treatment of RCC
This proposed clinical study will evaluate cG250 as an adjuvant treatment in patients with surgically completely resected clear cell renal cell carcinoma at high risk of recurrence. It is expected that the therapeutic benefits of cG250 therapy previously seen in metastasized RCC patients may be maximized in earlier stages of the disease, i.e. in patients after nephrectomy and no evidence of macroscopically detectable tumor manifestation but with a high risk of recurrence. Effective treatment at earlier stages could significantly reduce the relapse rate and prolong disease-free and overall survival. Expected benefit, however, has to be balanced against possible treatment related side effects. Consequently, treatment modalities with low or even lacking toxicity will be needed for this patient population. The previous studies in which cG250 was either applied at 50 mg doses for up to 20 weeks or in combination with low dose cytokines (IL-2 or IFN-Į) at doses of 20 mg for up to 18 weeks have proven that the antibody is very well tolerated with barely any toxicity. In addition, cG250 treatment showed clinical benefit in this group of advanced and metastatic RCC patients. Thus, based on the data mentioned above the risk/benefit analysis is considered positive for an adjuvant treatment with the chimeric monoclonal antibody cG250 in a patient population at high risk for renal cell cancer recurrence. It is generally acknowledged that for this patient population a substantial unmet medical need for new treatment options exists.
3 TRIAL OBJECTIVES AND PURPOSE This is a prospective, multi-center, phase III study to evaluate the efficacy and safety of adjuvant cG250 treatment versus placebo in clear cell RCC patients after surgery with no evidence of residual disease and with a high risk of recurrence. The main objective is to evaluate the efficacy of the treatment by assessing the disease-free survival and overall survival in the treatment arm compared to the placebo arm. In addition, the safety of the antibody therapy and the impact on the quality of life will be assessed and a population pharmacokinetic analysis will be performed.
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4 TRIAL DESIGN 4.1 Endpoint criteria
The primary objectives are:
- To evaluate disease-free survival on cG250 therapy as compared to placebo
- To evaluate overall survival on cG250 therapy as compared to placebo The secondary objectives are:
- To assess quality of life in the treatment and placebo arms using a validated questionnaire
- To evaluate safety
- To perform a population pharmacokinetic analysis that provides an understanding of cG250 pharmacokinetics in patients receiving cG250 as adjuvant therapy
4.2 Design
This is a prospective, two arm, randomized double-blind phase III multicenter trial in patients with clear cell renal cell carcinoma after nephrectomy. Patient fulfilling the criteria for high risk of recurrence (see inclusion criteria under 5.1) will be randomized to either weekly treatment with cG250 or placebo over a period of 24 weeks. 856 patients will be equally assigned to both study arms. The cG250 treatment and the placebo will be administered as an intravenous infusion over 15 minutes. Approximately 150 sites in Europe, North and South America are planned. Other regions may be considered, if required. For details on the statistical requirements please refer to section 11 of this protocol.
4.3 Randomization
Before entering patients into the trial, written Institutional Review Board / Ethics Committee approval of the protocol must be obtained. All patients will receive written patient information and have to give written informed consent prior to study entry. Some of the examinations needed to determine the eligibility of the patient may be routine exams the results of which are already available (e.g. CT scan post nephrectomy, bone scan, recent lab assessment etc.). However, blood collection for HACA evaluation and the ECG are solely required for the study and should not be performed before the patient has given written informed consent. Once eligible to enter the trial, patients will be randomly assigned to one of the two treatment groups in a 1:1 ratio. The randomization will be centralized and stratified for risk criteria (risk group I, II and III as defined in protocol section 2.2), region (US vs. Non-US) and center. Study medication will be packaged according to a computer-generated random code list provided by assigned CRO’s (Aptiv Solutions) biostatistics department. To ensure appropriate treatment allocation balance within stratification factors and overall, the ‘minimization’ method will be used for treatment allocation 23. For randomization method details, see Appendix I.
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The central randomization will be performed by Aptiv Solutions biostatistics department (randomization group). Once a patient is eligible to enter the trial, the investigator is requested to notify the central randomization group at Aptiv Solutions by using the “Randomization Sheet” which is part of the Case Report Form. The central randomization group at Aptiv Solutions will notify the investigator of the attributed randomization number by fax. This number identifies the medication box number to be used exclusively for this randomized patient. Patients should begin treatment no later than 14 days after the date of randomization. The patient code will consist of the attributed randomization number plus two patient initials (first name, surname) and is to be used consistently by the study site to assure unequivocal identification of each enrolled patient.
4.4 Duration of the study
Recruitment of patients is expected to start in March 2004. The duration of treatment for an individual patient in both arms is 24 consecutive weeks. Monitoring of survival will continue until 419 deaths have occurred or 60 months after the last patient has enrolled, whichever is the later.
4.5 Stopping rules / Discontinuation criteria
Upon recommendation by the Independent Data Monitoring Committee (IDMC, see Section 11.10), the trial may be stopped early for the following reasons: Probability of a positive study outcome at the final analysis is very unlikely based on the results of a interim futility analysis which will be performed after 100 DFS events have occurred (see Section 11.6.5). The cG250 antibody treatment is associated with unacceptable adverse events. No early stopping for efficacy reasons is planned.
5 SELECTION AND WITHDRAWAL OF SUBJECTS
5.1 Inclusion criteria • Prior (partial or total) nephrectomy of primary renal cell carcinoma with documented clear cell histology • No evidence of macroscopic and microscopic residual disease (enlarged lymph nodes should be removed) • Patients diagnosed of having one of the following (referring to TNM classification, 6th edition UICC, 2002 ):
- Risk group I: T3aN0/XM0 or T3bN0/XM0 or T3cN0/XM0 or T4N0/XM0 - Risk group II: any T stage and N+ disease and M0
- Risk group III: T1bN0/XM0 or T2N0/XM0, each with grading G ≥ 3 (Fuhrman or any other nuclear grading system with at least 3 grades) • ECOG of 0-1(see Appendix II)
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• Not more than 12 weeks between date of nephrectomy and randomization • Negative HIV I and II test • Negative Hepatitis B surface antigen (HbsAg) or Hepatitis C antibody result • Negative pregnancy test for women of child-bearing potential (urine or serum) • Women of child-bearing potential must be taking adequate contraceptive precautions • Willingness to return to the study site for long term control visits until recurrence • Age 18 years • Ability to provide written informed consent
5.2 Exclusion criteria
• Pre-exposure to murine/chimeric antibody therapy • Patients who require or are likely to require systemic corticosteroids above Cushing doses for another disease (patients on physiologic corticosteroid replacement therapy may be included in the study at the discretion of the investigator) • Prior organ transplantation • Laboratory values obtained ≤ 3 weeks before randomization: • White blood cells (WBC) ≤ 3.0 x 108/dl • Platelet count ≤ 100 x 108/dl • Hemoglobin ≤ 6.2 mmol/l (equals 10 g/dl) • Total bilirubin ≥ 1.5 x upper limit of normal (ULN) • ASAT, ALAT ≥ 3 x ULN • Serum creatinine ≥ 2 x ULN • History of prior malignancies within the last 5 years, except for surgically-cured non- melanoma skin cancer, or cervical carcinoma in situ. • Prior radiation or immunotherapy or chemotherapy within the last 5 years • Patients who are pregnant, nursing or of reproductive potential and are not practicing an effective method of contraception • Any unrelated illness, e.g. active infection, inflammation, medical condition or laboratory abnormalities, which in the judgment of the investigator will significantly jeopardize patients’ clinical status (for details on New York Heart Association Classification (NYHA) see Appendix III). Patients with NYHA III and IV are excluded from the study.
5.3 Subject withdrawal criteria
In accordance with the Declaration of Helsinki and ICH Good Clinical Practice Guidelines (GCP), a patient has the right to withdraw from the study at any time for any reason without prejudice to his/her future medical care by the physician or the institution. The investigator and Wilex also have the right to withdraw patients from the study (see below). Should a patient decide to withdraw or be withdrawn, all efforts will be made to complete and report the observations as thoroughly as
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possible. Patients may be withdrawn from treatment if one or more of the following events occur: • Significant protocol violation or noncompliance on the part of the patient or investigator • Refusal of the patient to continue treatment or follow-up • Decisions by the investigator or Wilex that termination is in the patient’s best interest • Unrelated medical illness or complication • Loss to follow-up • Pregnancy
Patients will be withdrawn from treatment if one of the following unacceptable toxicities occur (the NCI Common Terminology Criteria for Adverse Events (CTCAE) will be used): • Acute allergic reaction CTC grade ≥ 3 • Any acute reaction such as reduced blood pressure or change in pulse rate during and immediately following the administration of cG250 that is felt to be clinically unacceptable and requires immediate action (stop of infusion and/or therapeutic intervention) if confirmed after re-exposure to the study medication • More than 3 missed administrations of cG250 due to persistent therapy related toxicity • Laboratory adverse event CTC grade 4 (hematology or clinical chemistry) except transient events that return to grade ≤ 2 within 24h • Any other toxicity that is judged unacceptable at the discretion of the Investigator In the case of acute allergic reaction(s) ≥ CTC grade 3 the infusion must be discontinued immediately. Rechallenge is not permitted. The patient will be withdrawn from the study. A complete final evaluation including CT scan, laboratory tests, assessment of adverse events and vital signs should be made at the time of patient withdrawal. The final evaluation must be documented in the case report form indicating the reason for withdrawal. Patients withdrawn due to unacceptable toxicity must be followed until resolution of toxicity. If therapy with the study medication is stopped - irrespective of the time or the reason – alternative treatment may commence at the discretion of the investigator. In this case the reason for withdrawal must be documented (see Chapter 5.4) and a CT evaluation, laboratory tests, assessment of adverse events and vital sign control (see Study Flow Chart, item 6.1.1) must be done after the stop of the study medication and before the start of a potential off-study treatment. In case of early termination, the investigator will notify Wilex or its representative immediately.
5.4 Screening log
Each of the participating centers will keep a log of all patients with renal cell carcinoma screened for this study. Patients who were not entered into the study should be documented in this log, with the reason why they were not entered, e.g. due to not meeting inclusion/exclusion criteria or consent not given to study participation.
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6 STUDY PROCEDURES
6.1 Procedures
The study procedures are described in detail in this section. A general overview of the tests and procedures planned for this protocol is given in the study flow charts, as follows. All baseline assessments must be done no later than 3 weeks prior to patient randomization.
6.1.1 Study flow charts STUDY FLOW CHART COVERING PROCEDURES IN THE FIRST YEAR: Tests and procedures Baseline Treatment: Follow up: Follow up: Week 1 to 24 Month 9 Month 12 Obtain informed consent x History, height, pregnancy test1 x Review inclusion/exclusion criteria x Central pathologic review for patients x of high risk group 3 Physical examination x wk 12, 24 Weight x wk 12, 24 x x Vital signs (pulse, BP, temp) 2 x x Performance Scale x x x x Weekly administration of 20 mg x3 cG250 or placebo Assess Adverse Events x x4 x Concomitant medication x x x ECG (12-Lead) x wk 24 HIV and hepatitis serology x Hematology panel5 x wk 4, 8, 12, x 16, 20, 24 Chemistry panel6 x wk 4, 8, 12, x 16, 20, 24 Electrolytes 7 x x Blood samples8 for HACA & x wk 4, 8, 12, x biomarkers and for the measurement 16, 20, 24 of cG250 drug levels Quality of life questionnaire x wk 12, 24 x CT chest9 x10 wk 12, 24 x x CT abdomen9 x10 wk 12, 24 x x CT pelvis9 x10 wk 12, 24 x x Bone scan11 x immediately at any time clinical or laboratory parameters give suspicion of bone metastasis9 MRI immediately when bone metastasis is suspected from clinical symptoms or laboratory values and the bone scan was negative
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1 For women of childbearing potential only 2 At each visit in the first month: prior to cG250 infusion and at 30 min post infusion. If the infusion is well tolerated and no adverse reactions are observed in the first four weeks, then from week 5 the vital signs after the infusion no longer need to be checked unless an acute clinical indication is present. 3 A single loading dose of 50 mg cG250 will be administered in week 1 followed by weekly infusions of 20 mg of cG250 in week 2-24 4 Weekly documentation of adverse events starting after first infusion 5 Hematology panel: Hemoglobin; hematocrit; whiteblood cell count ; red blood cell count; platelets 6 Chemistry panel: total bilirubin at baseline only; creatinine; aspartase aminotransferase (ASAT); alanine aminotransferase (ALAT); alkaline phosphatase; lactate dehydrogenase 7 Electrolytes: sodium; potassium; calcium 8 These blood samples must be taken prior to study treatment. 9 CTs to be performed from lung apices to pubic symphysis. When neurologic symptoms are present, a CT or MRI of the brain should be performed. 10 CT scans at baseline must be post nephrectomy. 11 In cases of suspected bone metastases e.g. in the limbs, X-rays may be performed in addition to the bone scan.
STUDY FLOW CHART FOR FOLLOW UP OF TIME TO PROGRESSION:
Tests and procedures Follow-up year 2: Follow-up years Follow up year 5: every 3 months 3 and 4: yearly every 6 months CT chest, Month 15, 18, 21, 24 Month 30, 36, 42, 48 Month 60 abdomen, pelvis Bone scan immediately at any time clinical or laboratory parameters give suspicion of bone metastasis MRI immediately when bone metastasis is suspected from clinical symptoms or laboratory values and the bone scan was negative
CTs to be performed from lung apices to pubic symphysis. When neurologic symptoms are present, a CT brain or MRI brain should also be performed. In cases of suspected bone metastases e.g. in the limbs, X-rays may be performed in addition to the bone scan.
6.1.2 Regular assessments Laboratory: Patients will be monitored closely for safety reasons by weekly checks of vital signs, assessment of adverse events, Performance Status and with regular laboratory tests, e.g. CBC, blood chemistry. All blood draws will be performed before the administration of the study medication. The total volume of the blood obtained per patient will not exceed 110 ml over the course of the entire study. Additional laboratory tests (CBC, blood chemistry) are required at time of drop-out (if applicable). In addition, blood will be taken for later testing of human anti-chimeric antibodies (HACA) as well as for the measurement of cG250 drug levels to perform a population PK analysis. At baseline, approximately 5 ml will be taken and at the following time points (week 4, 8, 12, 16, 20 and 24 and month 9) 2 ml each will be obtained. These samples may also be used to evaluate the presence of soluble MN-antigen as well as soluble urokinase-type plasminogen activator receptor (suPAR) in the serum. The latter is considered to be a prognostic marker in several solid tumors.
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Tumor diagnostics: For early detection of local tumor recurrence/metastasis, all patients will undergo regular examinations with the following diagnostic procedures: CT scan of chest, abdomen and pelvis (performed from lung apices to pubic symphysis): At baseline and at regular intervals during the study (every 3 months in year 1-2, every 6 months in year 3 and 4, yearly thereafter) until signs of recurrence are observed.
When neurologic symptoms are present, a CT or MRI scan of the brain should be performed. If clinical or laboratory signs indicate bone metastasis a bone scan and/or radiographs should be done in additionall In the event of a negative bone scan an MRI scan should be done.
The radiological examinations should be performed in the first and second year (all following years) within ± 1 week (within ± 2 weeks) of the next calculated visit date.
All patients should be followed up by CT until there is clear evidence of recurrence demonstrated at a protocol-defined subsequent follow up time-point. Adverse events: Patients should be questioned about their adverse events/symptoms starting with the signature of the Informed Consent Form. The last inquiry should be made at the follow-up visit in month 9 and should cover a time period of 30 days after the final dose. 6.1.3 Quality of life In this study all patients will be requested to complete the EORTC questionnaire QLQ C30, a validated instrument to measure quality of life in oncology. It is a self-administered form consisting of 30 questions. The forms should be handed out by the study staff to the patients upon arrival at the hospital for their visits at the baseline visit, in month 3 (=week 12), month 6 (=week 24) and month 12. The questionnaire should be administered before the patient sees the physician, so that the interaction between the patient and the physician will not influence the patient’s answers to the questionnaire. Patients will be asked to thoroughly fill in the questionnaire (this will take about 10 minutes). If patients ask what a specific question means, staff should not try to explain but only re- read the question verbatim. All patients should answer the questions based on what they think it means, or the study results may be biased. The doctors and/or study nurses are requested to collect the forms at the end of the visit and to check each form for completeness. The results should not be discussed with the patients. 6.1.4 Assessments after detection of relapse For patients who relapse while on study treatment (week 1 - week 24) and do not continue with study drug, all week 24 assessments (see Section 6.1.1) must be performed at the next possible occasion. Such patients will then enter the follow-up period for overall survival. Patients who relapse during the treatment phase may continue the study medication until week 24 at the discretion of the investigator. In this case all assessments (e.g. physical examinations, vital signs, adverse events, concomitant medication, and laboratory parameter) except the CT scans must be performed for the respective visit until final assessment at month 9. For patients who relapse after the treatment phase has been completed, i.e. after week 24, the assessments for the next scheduled visit should be performed at the next possible occasion. Again, such patients will then enter the follow-up period for overall survival.
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6.2 Documentation of medical history
Only the medical history relevant to the inclusion and exclusion criteria and objectives of the study should be documented in the CRF. Regarding the tumor, the date of nephrectomy and details on pathology (TNM according classification of 2002, lymphadenectomy if performed, microscopic vascular invasion, grading) will be documented. 6.2.1 Concomitant therapy Patients should receive full supportive care during the trial, including transfusion of blood and blood products, and treatment with antibiotics, anti-pyretics, anti-emetics and analgesics when appropriate. All blood products and concomitant medications received by patients from the first dose of study drug/until the next visit after the end of study medication (covering 30 days after the final dose) will be recorded in the case report form, listing generic name, indication, quantity administered, and dates of administration. 6.2.2 Prohibited medication - systemic corticosteroids, except for the acute management of allergic events (corticosteroids are allowed below Cushing doses at the discretion of the investigator if physiologic replacement therapy after adrenalectomy is required) - immunosuppressive agents,e.g. Cyclosporin, FK506 - simultaneous or prior chemo-, immuno-, and radiation therapy in the last 5 years
6.3 Procedures for assuring subject compliance
The study staff is requested to stress to patients the importance of attending the study visits during the treatment and follow up periods. In the event of inadequate compliance, such as missing a visit, premature termination of study participation is possible. Such patients should be followed-up as completely as possible and be requested to contact the investigator immediately in case of any unusual events.
6.4 Central pathological review
A central pathology review has been implemented for this study with the objective to allow uniform verification of tumor typing and grading G as specified in the inclusion criteria. This central review will be performed by two pathologists: There will be one central pathologist for sites in North and South America and another central pathologist for sites in Europe. A description of the process is available in the “Charter of the Central Pathology”.
6.4.1 Collection and assessment of paraffin blocks of tumor tissue The assessment of tumor tissue (in paraffin blocks) by the central pathologists will be performed according to the scheme outlined below: (1) For all patients (risk groups I-III), the local pathologist will provide paraffin blocks of tumor tissue to the corresponding central pathologist for assessment of tumor typing, i.e. confirmation of the clear cell histology. This result is not a pre-requisite for randomization.
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(2) For patients belonging to risk group III, paraffin blocks of tumor tissue must be sent to the central pathologist prior to randomization for confirmation of the grading according to the following scheme: T1bN0/X M0 and grading G 3: confirmation of grading G.G T2 N0/X M0 and grading G 3: confirmation of grading G. These patients may only be randomized to the study when the diagnosis has been confirmed by the central pathology result. G Upon request, paraffin blocks will be returned to the local pathologists after slides have been made. Details on the preparation of tissue blocks and shipping procedures, shipping envelopes and address labels will be supplied to all sites.
6.4.2 Assessment of G250 (MN) antigen expression The primary purpose of the independent histopathology review is the confirmation of diagnosis (see 6.4.2). In addition, the tissue blocks will be used to determine retrospectively the level of the target antigen. For the measurement of target antigen expression, the central pathologist will perform immunohistochemistry staining on slides obtained from the tissue blocks. A qualified assay will be developed to allow quantification as to the percentage of tumor staining (for example 1+ staining will be less than 25% of the tumor, 2+ will be 25-50%, 3+ will be 50-75%, and 4+ greater than 75%) and also allow for the assessment of the intensity of staining (1+ being weak, 3+ strong, and 2+ intermediate). The results of these investigations will be used to explore the relationship between “outcomes” and the levels of G250 antigen. Methods and the statistical model described by Bui et al., (Clinical Cancer Research, Vol 9, 2003, pp 802-822) will be employed. There are currently no data in the adjuvant setting to construct statistical hypotheses and this investigation will therefore be exploratory in nature. A prospective and detailed plan for the measurement and analysis of target antigen expression in patients’ tumor will be provided in a separate protocol.
6.4.3 Assessment of other biomarkers in tissue samples The primary purpose of the independent histopathology review is the confirmation of diagnosis (regarding typing and grading) (see 6.4.2). However, the tissue blocks may also to be used for retrospective assessment of the levels of the following markers (in addition to the target antigen, see 6.4.3): • CD87 (uPAR) • p27 (cell cycle protein to assess down-stream events) • pRb (cell cycle protein to assess down-stream events) There are currently no data in the adjuvant setting to construct statistical hypotheses and these investigations will therefore be exploratory in nature.
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6.4.4 Evaluation of cG250 drug levels in serum samples Trough serum samples for HACA determination (see Section 6.1.2.) will also be analysed for cG250 drug levels with the objective to perform a population pharmacokinetic analysis. The data and methodology used to support this approach are described in the Population PK Data Analysis Plan.
7 STUDY MEDICATION
7.1 Preparation and administration
The monoclonal antibody cG250 will be supplied as a sterile, pyrogen free 5 mg/ml solution in a volume of 4 ml (20 mg in 4 ml per vial). The corresponding placebo will also be supplied. During the randomization procedure, each notified patient will be attributed a number. Only medication vials with this number may be administered to the respective patients. For the treatment of a single patient, a large box containing 26 vials which all carry the same number will be provided. The box also contains 24 low-protein-binding 0.2 μm filters. The study medication must be pre-filtered through the filter before infusion to exclude possible proteinaceous particles. The study medication will be administered once a week (plus or minus two days) by intravenous infusion on 24 consecutive weeks. A single loading dose of 50 mg of cG250 will be administrated in week 1 followed by weekly infusions of 20 mg of cG250 in week 2-24. Missed doses will not be made up for. Care must be taken to avoid shaking the study medication. The infusion will be given over 15 minutes. The solution will be withdrawn with a syringe and must be pre-filtered with the 0.2 μm filter before being added to 100 ml normal saline. An additional 2 ml of normal saline will be used to flush the filter to avoid loss of study medication in the filter. The details of the procedure are summarized in Appendix IV. For the first four administrations, the patients must be monitored for at least 30 minutes after completion of the infusion for presence of allergic symptoms. Pulse, blood pressure and temperature should be obtained prior to infusion, and at 30 minutes post infusion. If the administration is well tolerated and no adverse reactions have been observed in the first four weeks, monitoring of the post infusion vital signs is no longer required beginning in week 5 unless an acute clinical indication is present. Patients must be seated or supine during infusion.
7.2 Procedure in case of missed doses
In the event that a dose can not be administered within the permitted range of ± 2 days, counted from the day of administration of first dose, (e.g. due to adverse events, toxicities etc.), the respective dose will be skipped without substitution. Every effort should be made to avoid unnecessary deviations from the dosing schedule.
7.3 Drug accountability
The investigator is obligated to keep appropriate documentation of the delivery, use and destruction, or return of unused, used, or partially used packages of the study medication. The documentation must include dates, quantities, patient numbers, batch/serial numbers or other identification number, expiry dates and the means to identify the patient to whom it was given. The investigator should maintain records that document adequately that the patients were provided the doses specified in the protocol and reconcile the medication received for the study. Before
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destruction of the drug, the investigator must allow the monitor to perform a drug reconciliation. The entries in the case report form will be compared with the returned and residual amounts of study medication, with clarification of any discrepancies or inconsistencies. The label of each vial has a detachable section with the patient number which has to be fixed in the CRF at the designed place. The investigator may assign some or all of the investigator‘s duties for drug accountability to an appropriate pharmacist or another appropriate individual who is under supervision of the investigator.
7.4 Delivery
Wilex is responsible for supplying the investigator with the investigational product cG250 and the corresponding placebo. Study drug will not be delivered until all required documentation (EC approval, signed contract and protocol, curriculum vitae, laboratory normal ranges and certification) is present at Wilex or its representative, the CRO Aptiv Solutions that is responsible for randomization and authorization of drug shipment to study sites. If any discrepancy in the packages should arise, this is to be communicated immediately to Wilex or Aptiv Solutions.
7.5 Package labeling and formulation
Each vial will contain the following information on the label:
WX-2003-07-HR Batch: 01A0304 1 vial (4 ml) contains: 20 mg chimeric IgG monoclonal antibody cG250 or Placebo
Excipients: NaCl, sodium phosphate monobasic/dibasic, polysorbate 20, water f. injections
Concentrate for solution for infusion For intravenous infusion after dilution For clinical trial use only Store at: 2°C - 8°C
Wilex AG, Grillparzerstr. 16, 81675 Munich, Germany
The information on the flag-label is given in the official language of the participating country, except for countries which accept the English text (e.g. Russia). In addition the label contains a detachable section with the patient number which has to be fixed onto the CRF. Where applicable the label text must be adapted to comply with local regulations. The labeling of the investigational product will be performed by Wilex or its representatives and will be in compliance with local regulations where applicable. The monoclonal antibody cG250 formulated bulk has been produced by Avid Bioservices Inc., Tustin, USA and was vialed by Rentschler Biotechnologie GmbH & Co. KG, Laupheim, Germany. It is available as a sterile, pyrogen free 5 mg/ml solution in a volume of 4 ml (20 mg/4 ml per vial). All production, formulation and packaging is done in accordance with applicable current Good Manufacturing Practices (GMP).
7.6 Storage
The study medication will be stored at 2-8oC. Freezing below 0°C is to be avoided. Care must be taken to avoid shaking the vial prior to removing the solution as the protein might denature.
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7.7 Identification of investigational products in emergency situations
In previous clinical studies treatment with cG250 has led to no serious drug related adverse reactions. However, in the event of an acute reaction leading to the discontinuation of the infusion, the physician should treat the patient’s acute symptoms. The knowledge of whether the infusion contained the antibody or the placebo does not have any impact on the immediate symptomatic treatment. Nevertheless, the investigator may call the Aptiv Solutions Drug Safety Department to unblind a case at the numbers given below:
International Code +41-61 487 1681
The investigator must document the date, time and reason for unblinding any patient and report the event by fax to the Wilex Drug Safety Department within one working day, using the Serious Adverse Event Form (for more details see section 9.6). Unblinded patients may continue treatment if there is agreement of the investigator and the sponsor.
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8 ASSESSMENT OF EFFICACY
8.1 Efficacy parameters
A significantly better disease-free survival in the treatment arm compared to the placebo arm is considered proof of efficacy of the treatment. This will be subsequently confirmed by determining the overall survival (median survival and 5-years-survival). The radiologic assessment will serve to document the presence of tumor recurrence. The CT scans at baseline and during the course of the study will be assessed centrally by two independent radiologic reviewers for signs of metastatic disease or local recurrence. Disease-free survival Disease-free survival will be calculated from the date of randomization up to and including the date of documented relapse. The median is reached when 50% of all patients have relapsed. Relapse will be defined as signs of metastatic disease or local recurrence as confirmed by computer tomography, death (excluding deaths unrelated to the disease) or start of new anti-tumor therapy. Overall survival Overall survival is calculated from the date of randomization to the date of death or last follow-up. Patients with no documented death will be censored at the date of their last evaluation on study.
8.2 Patient evaluability for primary endpoints
All patients meeting the eligibility criteria who have signed a consent form and have been randomized are evaluable for the primary endpoints. All patients who have been randomized will be included in the intention to treat analysis. The primary efficacy analysis will be based on the “intention-to-treat” (ITT) population and the secondary efficacy analysis on the “per protocol” (PP) population. Only patients who have received at least eight consecutive administrations of study medication (week 1 to 8) will be evaluated for the “per protocol” set.
8.3 Methods of assessments
Patients and investigators should be aware that the study includes a long term follow up to determine disease-free survival and overall survival. It is essential to the evaluation of the primary endpoints that patients attend all follow up visits. 8.3.1 Assessment of disease-free survival Assessment of tumor recurrence will be based on contrast-enhanced computer-tomography (CT) scan of the chest, abdomen and pelvis (venous phase) with a contiguous slice thickness of 7.5 mm performed in the radiology department of the study site following the site imaging guidelines (“CT, Nuclear Medicine and X-ray Imaging and Submission Guidelines”). For quality reasons the scans will be stored digitally on CD-ROM. In exceptional cases provision of data on film will be acceptable, e.g. if digital data can not be obtained at a certain assessment time point. The CT scans will be forwarded by courier to the Independent Radiologic Reviewers (IRRs). Specific guidelines on the requirements and parameters for the radiologic procedures will be provided separately (“Charter for the Independent Review of Images”).
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8.3.1.1 Timing of procedures for inclusion
For inclusion of the patient, the baseline CT scans should be obtained no later than three weeks before randomization. This baseline CT scan must be done after nephrectomy in the radiology department of the site or associated with the study site. When sending the randomization request to the registration center, the study investigator must confirm in writing that the baseline examinations show no sign of tumor.
8.3.1.2 Assessment of tumor recurrence in year 1 and 2
Patients will be evaluated according to the following schedule in the first two years.
Test procedure Time point (in months) CT chest, abdomen, pelvis Baseline, week 12, week 24, months 9, 12, 15, 18, 21, 24 Bone scan Baseline and when bone metastasis is suspected from clinical symptoms or laboratory values
For the assessment of the relapse, patients with neurologic symptoms must also have a CT or MRI scan of the brain. If bone metastasis is suspected from clinical symptoms or laboratory values and the bone scan was negative, a MRI scan will be performed. In cases of suspected bone metastases e.g. in the limbs, X-rays may be performed in addition to the bone scan.
8.3.1.3 Long term follow up of patients for tumor recurrence (year 3-year 5)
The patients will be followed for disease-free survival by CT scan of the chest, abdomen and pelvis:
- every 6 months in year 3 and 4 (time range for examination ± 2 weeks)
- every 12 months thereafter (time range for examination ± 2 weeks)
8.3.1.4 Independent review of images
Central review of images (CT scan, MRI scan, bone scans, X-rays) will be performed by two external Independent Radiologic Reviewers (IRRs) not involved in the conduct of the study. The IRRs will be blinded with regard to the respective study arm. Specific guidelines on the requirements and parameters for the radiologic review procedures will be provided separately (“Charter for the Independent Review of Medical Images”). Should it not be possible to locally blind the digitally supplied CT exam regarding the patients’ name, the external radiologic reviewers are required to keep all data confidential and to refrain from passing the data on to third parties. The patients will be informed about this possibility in the informed consent. 8.3.2 Assessment of overall survival The participating centers will be required to provide ongoing patient status reports (alive, date and reason of death). Follow-up of overall survival will continue until 419 events have occurred or 60 months after the last patient has enrolled, whichever is the latter.
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9 ASSESSMENT OF SAFETY
9.1 Safety parameters
In order to assess the safety of the applied study medication, lab values, occurrence of adverse events and appearance of human anti-chimeric antibodies (HACA) will be documented. Severity of toxicities must be graded using the most up to date NCI Common Terminology Criteria for Adverse Events (CTCAE). A booklet containing all NCI CTC items will be supplied by the sponsor.
9.2 Laboratory values
A table of the reference ranges for each of the laboratory parameters measured with a description of the methods used is to be supplied to the sponsor or his representative by the test laboratory before the start of the study. Changes in the reference ranges or in the methodology during the study must be communicated to the monitor by the investigator and will be assessed in accordance with the NCI CTC criteria.
9.3 HACA
In order to examine the potential production of human anti-chimeric antibodies, the blood samples will be collected prior to treatment (within 21 days of start), and in months 1, 2, 3, 4, 5, 6 and 9. The baseline sample will be 5 ml; 2 ml will be obtained for subsequent time points. For patients who drop out before month 9, the sample will be taken at time of drop out. Samples must be collected in an unheparinized (clotted) tube. For blood cell sedimentation the manufacturer instructions should be followed. The tube should be allowed to set for up to 30 minutes at ambient temperature or stored overnight at 2-8°C to allow cell sedimentation. After centrifugation at 1000-2000 rpm for 10 minutes, the serum will be pipetted into a labeled cryovial and stored at –20°C or below. Samples from each patient should be stored separately in the boxes supplied. Upon notification by the sponsor, the samples will be shipped on dry ice to Wilex AG; Grillparzerstrasse 10, D-81675 München, Germany. The presence of human anti-chimeric antibodies (HACA) in sera of patients will tested using a sandwich-type enzyme-linked immunosorbent assay (ELISA), according to Steffens et al. 22. The storage boxes will be closed at the clinical site with a special seal that can not be removed without leaving sign of destruction. The boxes will be stored in a controlled freezer and will remain sealed until use. The number and severity of toxicity incidents will indicate the level of tolerance for cG250 in the treatment of advanced RCC. An effort will be made to investigate any relation between HACA and clinical, biological or laboratory adverse events.
9.4 Patient evaluability for safety analysis
Patients receiving at least one dose of study medication will be considered evaluable for safety and for HACA analysis.
9.5 Adverse Event reporting
All adverse events from the date of signing the Informed Consent Form until 30 days after the last dose will be recorded. Thus, for patients who have received the complete number of infusions, the
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last assessment will be made at the follow-up visit in month 9 and must cover an interval of 30 days after the final dose. For patients discontinuing the study prematurely, every effort should be made to follow them for adverse events for 30 days after last administration of study medication. An adverse event (AE) is any new undesirable medical experience or change of an existing condition which occurs during or after administration of the study medication, whether or not it is considered drug-related. Abnormal laboratory findings considered by the investigator to be clinically significant, e.g., those that are unusual or unusually severe for the population being studied, will also be considered adverse events. Recurrence of cancer will be considered a study endpoint and not an adverse event. All AEs must be followed up according to conventional practice until they have completely resolved or cannot resolve any further and every effort should be made to clarify the underlying cause. If in any patient the same AE occurs at several investigation times, then the AE in question must be documented and assessed anew each time.
9.6 Serious Adverse Event reporting
A serious adverse event is any experience that suggests a significant hazard to the patient and includes any event that • is fatal • is life-threatening (places the patient at immediate risk of death) • requires or prolongs hospitalization • is permanently disabling • is a congenital anomaly/birth defect • is an important medical event that, based upon appropriate medical judgment may jeopardize the patient and may require medical or surgical intervention to prevent one of the above listed outcomes. All serious adverse events occurring during the study must be recorded on the patient’s Adverse Event Form, and must include the following information: description; date of onset and date of resolution; severity; relationship to the study medication; action taken and outcome; investigator’s name, address and phone number. Severity of toxicities (for adverse events as well as for serious adverse events, see 9.5) must be graded using the most up to date NCI Common Terminology Criteria for Adverse Events (CTCAE). The investigators will receive a compilation of all NCI CTC in a separate booklet. All serious adverse events (irrespective of suspected cause), including deaths which occur while the patient is on study or within 30 days of the last day on which an investigational agent was administered, must be reported by fax by the investigator to the addressee given below within one working day of discovery, using the Serious Adverse Event Form. An initial information by phone is acceptable as long as the SAE form is provided on the same day. Additionally, SAEs must be recorded in the AE section of the Case Report Forms. The addressee to be immediately informed in case of an SAE depends on the location of the investigator: Investigators from Europe, the United States, Canada, South America and the Ukraine should fax the initial/follow up SAE reports and clarification forms (CFFs) to the Drug Safety Department of Wilex:
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Wilex AG Tel.: +49 (0)89-41 31 38- 48 Fax: +49 (0)89-41 31 38- 92 Drug Safety Officer Email: [email protected] Grillparzerstrasse 10 81675 Munich Germany
Investigators from Russia should fax the initial/follow up SAE reports and clarification forms (CFFs) to Aptiv Solutions’ local office:
Averion Ltd RUSSIA Orbita Technopark Tel: + 7 495 7819700 Business Center Fax number (within Russia) +8 495 781 9701 20, bld 1A, Kulakova str., General fax number : +7 495 7819701(24h) Moscow, Russia,123592
Serious adverse events will be reported by the investigator to the Institutional Review Board / Ethics Committee when this is required by local law. If the trial is discontinued for any reason, the investigator will notify the Institutional Review Board / EC and will indicate the reasons for discontinuation. Wilex and/or Aptiv Solutions will report to the Institutional Review Board / EC and any local regulatory authorities, as soon as possible, any trial that has been stopped for any reason. Follow-up information related to serious adverse events and reportable deaths must be documented on the SAE Report form as follow up and must be submitted to the addressee given above by fax as soon as relevant data are available. If necessary, follow up information will be requested by Wilex Drug Safety to help ensure reporting to authorities within the relevant time frame according to the national drug laws.
9.7 Relationship of Adverse Events and Serious Adverse Events to study agent(s)
The relationship of adverse events to the investigational agent will be determined by the investigator on the basis of their clinical judgment, using the following definitions: Definitely related: An adverse event that occurs during or shortly after administration of the investigational agent, that follows a known response pattern to the investigational agent, that improves after stopping the investigational agent and that reappears after repeated exposure to the investigational agent (rechallenge). Depending on the nature of the adverse event, rechallenge may not be possible, in which case only a probable relationship can be established. Probably related: An adverse event that occurs during or shortly after administration of the investigational agent that follows a known response pattern to the investigational agent that improves after stopping the investigational agent, and that cannot be reasonably explained by the known characteristics of the patient’s clinical state or by other therapies.
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Possibly related: An adverse event that occurs during or shortly after administration of the investigational agent that follows a known response pattern to the investigational agent but that could have been produced by the patient’s clinical state or by other therapies. Unlikely related: An adverse event for which the temporal sequence is unlikely to have had any reasonable association with the event and/or the event could have been produced by the patient’s clinical state or by other therapies. Unrelated: An adverse event for which sufficient information exists to indicate that the etiology is unrelated to the investigational agent. Another etiology must be specified. Insufficient data: Sufficient information for judgment not available at this time (e.g. insufficient evidence, conflicting data or poor documentation). Follow up necessary.
10 ASSESSMENT OF QUALITY OF LIFE The QLQ-C30 developed by the EORTC is composed of both multi-item scales and single-item measures 24 25. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items – no item occurs in more than one scale. The statistical package for the coding of the scoring procedure has been provided by the EORTC and will be performed in SAS. QLQ-C30 will be performed as per the schedule under item 6.1.1.
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11 STATISTICS
11.1 Primary endpoints
The primary study endpoints are disease-free survival and overall survival. Disease-free survival is calculated from the date of randomization up to the date of documented relapse. Patients with no documented relapse will be censored at the date of their last evaluation on study. Relapse will be defined as signs of metastatic disease or local recurrence as confirmed by computer tomography, death (excluding deaths unrelated to the disease) or start of new anti-tumor therapy. Overall survival is calculated from the date of randomization to the date of documented death. Patients with no documented death will be censored at the date of their last evaluation on study.
11.2 Secondary endpoints
Secondary endpoints are: • Quality of life (EORTC QLQ-C30 questionnaire) • Incidence of clinical adverse events • Laboratory values graded in accordance with the NCI CTC criteria • Population pharmacokinetic analysis to provide an understanding of cG250 pharmacokinetics in patients receiving cG250 as adjuvant therapy and determine the influence of patient factors that may influence pharmacokinetic variability (see Population PK Data Analysis Plan)
11.3 Statistical model
Hierarchical testing will be applied for disease-free survival and overall survival to keep the global significance level to 5% for DFS and overall survival. Both primary study endpoints, disease-free survival and overall survival, will be compared between the cG250 arm and the placebo arm using the log-rank test and the Kaplan-Meier method. The significance levels within the analysis of overall survival will be adjusted using the O'Brien- Fleming approach for group sequential methods with an overall significance level of 5%. This implies using a significance level of p=0.0052 at the interim OS analysis, and a significance level of p=0.048 at the final OS analysis. The primary analysis of DFS and overall survival will be based upon the intent-to-treat population (defined as all patients randomized). The 95% confidence interval for proportions will be calculated using the exact method (Pearson- Clopper). Kaplan-Meier curves for disease-free survival and overall survival will be displayed by treatment group. Data from the QoL questionnaire will be reported in summary tables over time. Descriptive statistics will be used. Missing values will not be replaced.
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The potential effect of prognostic factors on both disease-free survival and overall survival will be investigated using the Cox proportional hazard model for time to event parameters. The objective will be to explore the sensitivity of the statistical significance after adjusting for the “main prognostic factors”. The “main prognostic factors” deemed to have potential prognostic value are reflected in the TNM classification and the stage of disease at study entry. These are the three high risk criteria as defined in the protocol at study entry as they adequately reflect risk factors with prognostic value identified in renal cell carcinoma at the time of this protocol amendment. Separate stratification of US and Non-US sites will be performed. All efficacy analyses will be performed using the intention-to-treat population as primary analysis set and will be repeated using the per protocol population. Secondary statistical analysis tests will be performed at an alpha level of 5% and will be regarded as exploratory. Therefore no adjustment for multiplicity will be made. Handling of patients unblinded during treatment: unblinded patients may continue treatment if there is agreement between the investigator and the sponsor. Data from unblinded patients will be used for the safety analysis only. Any efficacy of treatment in patients who have received less than eight cG250 infusions will be evaluated in a descriptive manner. These patients will not be included in the statistical analysis of the per protocol set.
11.4 Hypotheses and testing procedures
11.4.1 Primary hypothesis testing A hierarchical testing procedure will be applied for the test of both primary parameters to maintain the global significance level of 5%. Hypothesis (1) for disease-free survival The comparison of disease-free survival between the cG250 arm and the placebo arm will be evaluated by testing the following statistical hypothesis: A proportional hazard for relapse of disease between the cG250 arm and the placebo arm is assumed.
Let hP(t) and hT(t) denote the hazard rate for relapse of disease for the placebo arm and the treatment arm respectively. Let λ denote the constant hazard rate hP(t)/ hT(t). H01: λ = 1 (there is no difference in disease-free survival between cG250 arm and placebo arm) H02: λ ≠ 1 (disease-free survival differs between cG250 arm and placebo arm) To test the hypothesis above, a log-rank test with a 5% alpha level will be used. The statistical test will be based upon the intent-to-treat population (defined as all patients randomized).
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Hypothesis (2) for overall survival The comparison of overall survival between the cG250 arm and the placebo arm will be evaluated by testing the following statistical hypothesis: A proportional hazard for death between the cG250 arm and the placebo arm is assumed.
Let hSP(t) and hST(t) denote the hazard rate for death for the placebo arm and the cG250 treatment arm respectively. Let λS denote the constant hazard rate hSP(t)/ hST(t).
H11: λ S = 1 (there is no difference in overall survival between cG250 arm and placebo arm) H12: λ S ≠ 1 (overall survival differs between cG250 arm and placebo arm) To test the hypothesis above, Kaplan-Meier curves will be compared using a log-rank test with a type I error of 5%. The significance levels within the analyses of overall survival will be adjusted using the O'Brien-Fleming approach for group sequential methods to keep the overall significance level to 5%. The statistical test will be based upon the intent-to-treat population (defined as all patients randomized). Hierarchical testing Hierarchical testing will be applied for hypothesis (1) and (2) to keep the global significance level of 5%. The procedure is as follows:
Step 1 Second hypothesis can not be not significant Test Hypothesis (1) interpreted as confirmative
significant
Step 2 Test Hypothesis (2)
The interpretation of the test of hypothesis (2) is confirmative only, if hypothesis (1) was significant. Otherwise, the global significance level of 5% has failed and hypothesis (2) has an explorative nature only. Due to this stepwise procedure, the significance level of hypothesis (1) and hypothesis (2) are 5% each and the global significance level is still 5%. 11.4.2 Secondary hypothesis: Quality of Life The hypothesis of no difference between the cG250 arm and the placebo arm will be tested using the methods described in section 11.3.
11.5 Data sets to be evaluated
Safety Population The safety population will include all randomized patients who received any study medication. Intent-to-treat Population (ITT) The Intention-to-treat population will include all randomized patients. Patients will be analyzed in their randomized treatment group.
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Per Protocol Population (PP) The per protocol population will include all patients from the ITT population who fulfill the following criteria: At least 8 consecutive weeks of treatment (week 1-8) and a final diagnostic assessment. No significant deviation from inclusion/exclusion criteria. Confirmed clear cell histology of the tumor. No administration of prohibited concomitant medication. Absence of major protocol violations likely to affect the efficacy evaluation e.g. a poor compliance with study medication, visit schedule or study procedures. No unblinding has occurred. The final list of major protocol violations will be documented when not more than 30% of the total expected study data is available and prior to unblinding. All efforts will be made to ensure that the per protocol population contains the originally planned number of patients.
11.6 Final analysis and reporting
The data from all centers that participate in this study will be combined. Data base lock (for DFS) and unblinding will take place when the number of DFS events is reached on which the final analysis of DFS will be based. 11.6.1 Analysis of demographics Demographic and other baseline characteristics will be tabulated by assigned group and for the total for each of the analysis populations defined above. 11.6.2 Analysis of efficacy The first step in the primary analysis will be a comparison of disease–free survival between the cG250 arm and the placebo arm, using the intent-to-treat analysis set. This comparison is based on a log-rank test with a significance level of 5%. The primary efficacy analysis will be based upon the results from an independent review of images (also see section 8.3). • The final analysis of the primary endpoint disease-free survival will be performed after 360 DFS events have been reported by the investigational sites. The second step in the hierarchical testing procedure of the primary analysis will be the comparison of overall survival between the cG250 arm and the placebo arm, using the intent-to- treat analysis set. This comparison is based on a log-rank test using the adjustment of the significance level according to the group sequential methods of O’Brien-Fleming. This adjustment will keep the significance level for the testing of overall survival within 5%. One interim analysis of overall survival will be performed at the same time point as the final analysis for DFS. A final (conclusive) analysis of overall survival will be performed after 419 events have occurred with the possibility of a robust result at the 1% significance level. The scheduled analyses of DFS and OS with time point and local significance level are summarized in the following table:
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Time point / Events Significance level / further details Final (conclusive) analysis of DFS: After 360 DFS events α=0.05 have been reported by Interim analysis of overall survival: the investigational α sites =0.0052 (group sequential method acc. to O'Brien-Fleming, overall significance level 0.05, hierarchical testing, DFS must be significant to get confirmative testing for OS at this stage) Final (conclusive) analysis of overall survival: After 419 OS events or α= 0.048 (group sequential method acc. to O'Brien-Fleming, overall 60 months after the significance level 0.05) last patient has been α enrolled, whichever is Possibility of a robust result at =0.01 level because of additional the later patient enrollment and extended follow-up (p 0.0098*). * final (not nominal) p-value that adjusts for the results of the interim analysis to determine whether test results are robust at 0.01 significance level The method accounts for multiplicity testing and the overall type I error for DFS and OS is kept ≤ 5%. If the real event rate is lower than expected, this will be compensated by a prolonged follow up period. The final analysis of DFS will be performed after 360 DFS events have been reported by the investigational sites. Provided that the results of the DFS final analysis are positive, the data will be used for regulatory purposes in regions where this is possible. Follow-up of overall survival will continue until 419 OS events have occurred or 60 months after the last patient has enrolled, whichever is the later. As a supportive analysis, all DFS events which have occurred between the final DFS analysis and the final OS analysis will be analyzed as well.
11.6.3 Exploratory analyses Exploratory sub-group efficacy analyses will be performed for the following subgroups: • By high risk groups (see section 2.2) • By gender • By center/country • By age (≤ 60, > 60) • By ethnicity • Target antigen expression (patient subsets expressing specific levels of target antigen)
11.6.4 Analysis of safety Safety data will be evaluated using the safety population. The overall incidence rates of adverse events in each treatment group will be summarized by system organ class and preferred term (MEDDRA). Adverse events will also be tabulated by severity and presumed relationship to treatment. Laboratory data will be graded according to NCI CTC criteria and summarized by treatment group. 11.6.5 Planned interim analyses The statistical design foresees the conduct of two interim analyses, as follows:
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Interim Analysis for futility after 100 DFS events have occurred Interim Analysis of overall survival which coincides with the Final Analysis of DFS after 360 DFS have been reported by the investigational sites The execution of the interim analysis for futility is a completely confidential process assigned to the Independent Data Monitoring Committee (IDMC, also see section 11.10). After unblinding of the study, the statistical analyses will be performed by the study evaluation team of the CRO (Aptiv Solutions). Details on the interim analysis for futility including the pre-specified stopping rule have been agreed with the IDMC and are laid down in a separate document attached to the IDMC Charter 28. Details on the interim analysis of overall survival including information about data collection are found in section 11.6.2. No early stopping for efficacy reasons is planned. 11.6.6 Quality of life evaluation Quality of life will be evaluated using the EORTC QLQ-C30 questionnaire. Data will be scored according to the algorithm described in the EORTC QLQ-C30 scoring manual. Scoring will be done using SAS software. All scales and single items are scored on categorical scales and linearly transformed to 0-100 scales where:
- A high score for a functional scale represents a high or healthy level of functioning
- A high score for the global health status/QoL represents a high QoL
- A high score for a symptom scale or item represents a high level of symptomatology /problems. Data will be summarized using descriptive statistics N, Mean, SD, Median, Minimum and Maximum for linearly transformed scores and frequencies and percentages for (original categorical) single item scores, by treatment at each of the assessment time points. The global health status / QoL scale will be regarded as an overall measure of QoL. Treatment arms will be compared using Wilcoxon-Mann-Whitney test (or t-test, depending on the distribution of the data). To investigate compliance of completing QoL questionnaires at each time point, the total number of patients still on study and number of patients still on study with missing questionnaires will be reported for each time point.
11.7 Sample size determination
The primary objective of the study is to detect a statistically significant difference in disease-free survival and overall survival for the cG250 arm relative to the placebo arm. The disease-free survival rate at 24 months in the placebo arm is expected to be about 40% (corresponding to a median disease-free survival time of about 18 months assuming an exponential model). A total number of 343 events is required to detect a 35% increase in hazard rate in the placebo group as compared to the treatment group, with 80% power at final analysis, using a two-sided log- rank test at 5% alpha level and a 1:1 randomization ratio between the placebo arm and the cG250 arm. With 360 events as reported by the investigational sites, the final analysis will allow for a slightly more robust result. The sample size calculation was performed using the program Pass2002.
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Power considerations for Overall Survival: It is assumed that the 5 year overall survival will be 40% in the placebo group and 52% in the cG250 group, i.e., a 30% increase in overall survival at 5 years with cG250 therapy compared to placebo 29.. The log-rank test for comparison of overall survival between the treatment groups will result in a power of 80% at the final analysis after 419 events.
11.8 Handling of missing data
Assessments of safety, efficacy or QoL that were not performed or not recorded will be treated as missing data.
11.9 Data management
All data concerning the study will be documented exclusively on CRFs designed specifically for this study. Each CRF will consist of an original plus two copies. One copy will remain in the study center, the original and one copy will be collected by the Wilex representative. The CRF data will be processed by double-data entry. A data validation plan will be prepared that describes the check of the data for plausibility and completeness. Spurious and missing data will be checked by query at the investigational site.
11.10 Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will be constituted before the start of the study to assess at intervals the progress of the clinical trial, and review the safety and efficacy data and will be empowered to recommend continuation, modification, or termination of the trial. This Committee will be composed of independent experts in the field of Clinical Oncology, RCC and Biostatistics. These members will be independent of the trial and familiar with the methodology of oncology trials. The mission and procedures for the IDMC will be detailed in the IDMC Charter which will be issued by the study coordination team.
11.11 Data handling after early stopping
Should the IDMC recommend early stopping of the study due to futility or for safety reasons the recruitment of further patients will be stopped. Patients on either study medication or placebo will be discontinued immediately.
12 DOCUMENTATION AND HANDLING OF STUDY DATA
12.1 Case Report Forms
The case report form will be used to record all of the information required by the protocol for each study patient. Wilex will supply the case report forms to the investigator. Case report forms must be completed in English. International nonproprietary names (INN) for concomitant medications should be used. All forms will be completed using a black ball-point pen, and entries must be legible. Errors should be crossed by a single line but not obliterated, the correction inserted, and the change initialed and dated by the investigator or an authorized member of the study staff. Erasing typing over of errors, and use of correction fluid or tape are not permitted. The investigator or a sub-
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investigator will sign and date at the indicated places of the case report form. This signature will indicate a thorough inspection of the data on the case report form has been made, and it will certify the contents of the form. The case report form contains non-carbon copy pages to simplify the documentation. After completion and monitoring, the monitor will detach the top and first copy pages and send them to the Aptiv Solutions. The second copy page remains at the investigator’s site. When queries require subsequent corrections or additions to the entries in the case report form, they will be listed on a correction sheet. This will be sent to the investigator requesting him to confirm or make the correction, or enter additional or missing data as required. This will be done directly on the correction sheet which will then be returned to Aptiv Solutions. The investigator will receive a photocopy. The investigator must keep records of the changes and corrections. All clinical documentation and data arising from the study are to be kept by the investigator. Signatures of the investigator or delegated person must be made by hand, stamps are not allowed.
12.2 Source documents
Clinical documentation relevant to the study includes all records in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, X-rays, and electrocardiograms) that describe or record the methods, conduct and/or results of the study, the factors affecting the study and the actions taken. Source data is all information in original records and certified copies of original records of clinical findings, observation, or other activities in a clinical study necessary for the reconstruction and evaluation of the study. Source data are contained in source documents which comprise clinical documentation, data and records (e.g. hospital records, clinical and office charts, laboratory notes, memoranda, patients‘ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments and data and records arising from other departments such as the pharmacy, laboratory and medico-technical departments). Copies of the laboratory values will be printed, signed by the investigator and enclosed to the CRF. No extra entry into the CRF will be performed.
12.3 Monitoring
It is understood that an outside monitor and other authorized personnel may contact and visit the investigator, and that they will be allowed to inspect the various records of the trial on request (case report forms and source documents), provided that patient confidentiality is maintained, and that the monitoring is conducted in accordance with local regulations. It is the monitor’s responsibility to inspect the case report forms at regular intervals throughout the trial to verify adherence to the protocol, the completeness, accuracy and consistency of the data, and adherence to ICH-Good Clinical Practice guidelines. The monitor should have access to patient charts, laboratory reports and other patient records needed to verify the entries on the case report forms. The investigator agrees to cooperate with the monitor and to ensure that any problems detected during the course of these monitoring visits are resolved.
12.4 Data storage
The investigator must retain a comprehensive and centralized filing system of all trial-related documentation that is suitable for inspection by Wilex and representatives of regulatory authorities. On completion of the trial, the sponsor generates a summary report. This report must also be
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submitted to the Institutional Review Board. The investigator must arrange for the retention of the patient identification codes for at least 15 years after the completion or discontinuation of the trial. Patient files and other source data (including copies of protocols, case report forms, original reports of test results, agent-dispensing logs, correspondence, records of informed consent, and other documents pertaining to the conduct of the trial) must be kept for the maximum period of time permitted by the institution. No documentation will be destroyed without prior written agreement between Wilex and the investigator. Should the investigator wish to assign the study documentation to another party or move them to another location, written agreement must be obtained from Wilex.
13 QUALITY ASSURANCE / AUDIT Inspections by local, regional, national or international authorities (eg EMEA) may take place at any study site. The investigator is obliged to co-operate with these inspections and has to make sure that study documents are available for inspection, and that source data will be at the disposal of the inspector. In addition the sponsor may initiate a full source data audit as part of quality assurance.
14 ETHICS AND REGULATIONS
14.1 Declaration of Helsinki
The investigator will ensure that this study is conducted in full conformity with the current version of the Declaration of Helsinki, with the ICH Good Clinical Practice Guidelines, and local law, whichever affords the greater protection to the patient.
14.2 Informed Consent
It is the investigator’s responsibility to obtain written informed consent from the patient after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before entry to the study. The patient should be given a copy of the signed and dated informed consent documentation. The original signed and dated copy of the informed consent must be retained in the institution’s records, and is subject to inspection by representatives of the sponsor, or representatives from regulatory agencies.
14.3 Ethics Committee / Institutional Review Board
A copy of the protocol and proposed informed consent form must be submitted to the EC / Institutional Review Board. Written approval of the protocol and informed consent must be obtained prior to recruitment of patients into the study and shipment of study medication. The investigator must inform, and obtain approval from, the EC / Institutional Review Board for all subsequent protocol amendments and amendments to the informed consent form. Serious or unexpected adverse events occurring during the trial likely to affect the safety of the subjects or the conduct of the trial will also be reported to the EC / Institutional Review Board. The investigator will be responsible for assuring that continuing review (at least once per year) of the study is performed by the EC / Institutional Review Board throughout the duration of the study. Copies of the investigator’s reports and of the notice of approval must be sent to the sponsor.
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14.4 Regulatory Affairs
This study will be carried out in compliance with legal regulations. Before initiating the study the investigator and Wilex, if required by the applicable regulatory body will submit any required documentation to the appropriate authority(ies) for review, acceptance, and/or permission to begin the study. A copy of the submission will be held in the central files at Wilex.
14.5 Pre-study documentation requirements
The following documents may be required before the study medication can be shipped from the sponsor: • signed protocol; • copy of approved informed consent form; • copy of the Institutional Review Board/ EC approval of the protocol and informed consent form; • curricula vitae of the investigator; • name and address of the Institutional Review Board/ EC and membership of the Institutional Review Board/ EC • laboratory normal ranges; • local regulatory approval and approval to import the study medication (if required) • agreement to destroy unused study medication supplies at the site according to local written procedures, if applicable; and • signed letter of (financial) agreement, if applicable.
14.6 Confidentiality of patient data
Permission for direct access to patients’ data will be sought in writing by the investigator and from the patient as part of the informed consent procedure. This gives permission to examine, analyze, verify and reproduce any records and reports that are important to the evaluation of the study. Any party (e.g. domestic and foreign regulatory authorities, monitors and auditors) with direct access must take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of the patients’ identity and sponsor’s proprietary information. It is the monitor’s responsibility to verify that each patient has consented, in writing, to direct access. The investigator must ensure that documents given to Wilex or its representatives do not contain the name or address of the patient, or other information that would affect the anonymity of the patient (apart from his initials). An exception may be the CT or MRI examination which will be provided as a digital file on CD-ROM and may contain the full patient name. The consent of the patient to this procedure will be asked in the patient informed consent. The data will only be legible to the Independent Radiologic Reviewers (IRRs) by using special software. The IRRs are physicians who are obliged to keep strict confidentiality of all study related data and will assure that no other person has access to these files.
14.7 Protocol amendments
Proposed amendments of this protocol must be submitted to Wilex for review and approval, and then to the Institutional Review Board/ EC. Amendments may be implemented only after a copy of the Institutional Review Board’s or EC’s approval letter has been transmitted to Wilex. Amendments that are intended to eliminate an apparent immediate hazard to patients may be implemented prior to receiving Institutional Review Board/ EC approval. However, in this case,
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approval must be obtained as soon as possible after implementation.
14.8 Premature study termination
The study may be prematurely terminated (by the Ethics Committee, by regulatory authorities, by Wilex upon recommendation by the IDMC or the Director of Clinical Investigation („LKP“) according to German Drug law § 40 for the German sites) if the perception of the benefit/risk becomes unfavorable for the patient’s continuation in the study. In addition, based on a recommendation from the IDMC, the sponsor may stop the study for futility. A decision by Wilex to cease the study in all centers is binding on all investigators. If the study is prematurely terminated or suspended the investigator should promptly inform the patients, should assure appropriate therapy and follow-up for the patients, and the institution where the study was being performed.
15 FINANCING AND INSURANCE Financial terms will be agreed upon in a separate contract document. For each participating patient the sponsor has taken out insurance covering the amount determined by respective national laws. All participating patients will be informed about the existence of the insurance in detail in the patient informed consent. They have the right to review the terms and conditions described therein.
16 PUBLICATION POLICY It is agreed that the sponsor and the investigators will jointly prepare the results of this study for scientific publication and decide upon the authorship, timing and topics of manuscripts. The aim is to have investigators with a higher patient recruitment rate and complete evaluability ranked higher in the order of authorship. Wilex supports the interest of the investigators to publish results. However, to protect Wilex’ business interest the investigator agrees to publish any results generated under this Agreement only after the prior written approval of the sponsor. In order to give Wilex the opportunity to make comments and acquire or protect any intellectual property rights, the investigator will submit for review by Wilex any intended written or oral publication one (1) month prior to its submission for publication. Wilex will send its comments thereon without undue delay, at the latest within (1) month after receipt of the manuscript. In case Wilex identifies patentable inventions the investigator agrees to withhold the publication until the patent application has been filed. In case Wilex has reasonable objections against a publication, the publication will be discussed in good faith in order to reach a mutual agreement thereon.
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17 REFERENCES
1. DeVita V.T. & Hellman,S.R.S.A. Cancer: principles and practice of oncology. Lippincott Williams & Wilkins, (2001). 2. Zisman, A. et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J. Clin. Oncol. 20, 4559-4566 (2002). 3. Lipton, A. Effects of Renal Cell Carcinoma on the Skeleton. Perry, M. American Society of Clinical Oncology Educational Book (38th annual meeting), 633-634. 2002. American Society of Clinical Oncology. 4. Pizzocaro,G. et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J. Clin. Oncol. 19, 425-431 (2001). 5. Dutcher, J.P. Introduction to the session on integration of immunotherapy and surgery in metastatic renal cell carcinoma. Piantadosi, S. American Socity of Clinical Oncology Educational Book(38th annual meeting), 630-632. 2002. American Society of Clinical Oncology. 6. Sobin, L. & Wittekind,C. TNM Classification of Malignant Tumors, 6th edition. John Wiley & Sons, (2002). 7. Ficarra, V. et al. Prognostic factors in patients with renal cell carcinoma: retrospective analysis of 675 cases. Eur. Urol. 41, 190-198 (2002). 8. Frank I. et al. pT2 classification for renal cell carcinoma, can its accuracy be improved? J. Urol. 173, 380-384 (2005). 9. Mulders, P.F. & De Mulder,P.H. The role of adjuvant immunotherapy in renal cell carcinoma. Curr. Urol. Rep. 3, 44-49 (2002). 10. Porzsolt, F. Adjuvant therapy of renal cell cancer with interferon-alpha. Delta-p gruppe. Proc.Am.Soc.Clin.Oncol. 11, 202 (1992). 11. Fuhrman, S.A., Lasky,L.C. & Limas,C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am. J. Surg. Patholog. 6, 655-663 (1982) 12. Lang, H. et al. Microscopic venous invasion: a prognostic factor in renal cell carcinoma. Eur. Urol. 38, 600-605 (2000). 13. Van Poppel, H. et al. Microscopic vascular invasion is the most relevant prognosticator after radical nephrectomy for clinically nonmetastatic renal cell carcinoma. J. Urol. 158, 45-49 (1997). 14. Griffiths, D.F. et al. Contribution of grade, vascular invasion and age to outcome in clinically localized renal cell carcinoma. BJU. Int. 90, 26-31 (2002). 15. Sanchez, d.l.M. et al. Renal cell carcinoma: vena caval invasion and prognostic factors. Eur. Urol. 19, 284-290 (1991) 16. Oosterwijk,E. et al. Monoclonal antibody G 250 recognizes a determinant present in renal- cell carcinoma and absent from normal kidney. Int. J. Cancer 38, 489-494 (1986). 17. Oosterwijk,E. et al. Antibody localization in human renal cell carcinoma: a phase I study of monoclonal antibody G250. J. Clin. Oncol. 11, 738-750 (1993). 18. Steffens, M.G. et al. Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250. J. Clin. Oncol. 15, 1529-1537 (1997). 19. Wiseman, G.A. Chimeric G250 monoclonal antibody (cG250) Phase I dose escalation trial in patients with advanced renal cell carcinoma (RCC). ASCO Meeting San Francisco May 2001 (2001). 20. Beck, J. et al. A phase II trial with monoclonal antibody WX-G250 in advanced RCC. 2nd International Kidney Cancer Symposium Chicago 2001. 30-10-2001.
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21. Surfus, J. et al. Anti-renal-cell carcinoma chimeric antibody G250 facilitates antibody-dependent cellular cytotoxicity with in vitro and in vivo interleukin-2-activated effectors. J. Immunother. 19, 184- 191 (1996). 22. Steffens, M.G. et al. Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I- labeled chimeric monoclonal antibody G250. Clin. Cancer Res. 5, 3268s-3274s (1999). 23. Pocock, S.J. and Simon, R. “Sequential treatment assignment with balancing for prognostic factors in the controlled trials”, Biometrics, 31, 103-115 (1975) 24. Aaronson, N.K. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl. Cancer Inst. 85, 365- 376 (1993). 25. Fayers, P.M. et al. The EORTC QLQ-C30 Scoring Manual (3rd Edition). European Organisation for Research and Treatment of Cancer, Brussels, (2001). 26. Wang S.K. & Tsiatis A.A. Approximately optimal one-parameter boundaries for group sequential trials. Biometrics 43, 193-200 (1987). 27. Jennison C. & Turnbull B.W. Group Sequential Methods with Applications to Clinical Trials. Chapman & Hall/CRC (2000). 28. Wilex internal document: Interim Analysis for Futility and Stopping Rule for study WX-2003-07-HR dated 21 April 2006 29. Warnaar S., Overall survival data of surgically resected Renal Cell Carcinoma (RCC) patients, Internal report, Wilex AG, January 2004
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Appendix I: The minimization method for randomization
The minimization method [Pocock, S.J. and Simon, R. “Sequential treatment assignment with balancing for prognostic factors in the controlled trials”, Biometrics, 31, 103-115 (1975)] is used to balance treatments allocations within stratification factors margins. For the measurement of imbalance within stratification factors margins the study procedure will use the range (difference in marginal sums of patient numbers in each treatment group). The global imbalance resulting from a given new treatment allocation will be calculated as a weighted sum of the marginal stratification factors imbalances (Global treatment imbalance = 3 * treatment imbalance within Risk Group + 2 * treatment imbalance within Region + 1* treatment imbalance within Center).
For every new patient, the procedure will assign a treatment using a random process with a probability of 95% of choosing the treatment that would lead to the smallest global imbalance. When the global imbalance is the same for the two treatment groups, the procedure will randomly assign one of the two treatments with a probability of 50% of choosing each of the two treatments.
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Appendix II: ECOG / Karnofsky Performance Scale
ECOG Performance Status Karnofsky Performance Scale
)XOO\DFWLYHDEOHWRFDUU\RQDOOSUH 1RUPDOZLWKQRFRPSODLQWVRU GLVHDVHSHUIRUPDQFHZLWKRXW HYLGHQFHRIGLVHDVH UHVWULFWLRQ $EOHWRFDUU\RQQRUPDODFWLYLW\EXW ZLWKPLQRUVLJQVRILOOQHVV SUHVHQW
5HVWULFWHGLQSK\VLFDOO\VWUHQXRXV 1RUPDODFWLYLW\EXWUHTXLULQJHIIRUW DFWLYLW\EXWDPEXODWRU\DQG 6LJQVDQGV\PSWRPVRI DEOHWRFDUU\RXWZRUNRID GLVHDVHPRUHSURPLQHQW OLJKWRUVHGHQWDU\QDWXUHHJ OLJKWKRXVHZRUNRIILFHZRUN $EOHWRFDUHIRUVHOIEXWXQDEOHWR ZRUNRUFDUU\RQRWKHUQRUPDO DFWLYLWLHV
$PEXODWRU\DQGFDSDEOHRIDOOVHOI $EOHWRFDUHIRUPRVWQHHGVEXW FDUHEXWXQDEOHWRFDUU\RXW UHTXLUHVRFFDVLRQDODVVLVWDQFH DQ\ZRUNDFWLYLWLHV8SDQG DERXWPRUHWKDQRI ZDNLQJKRXUV &RQVLGHUDEOHDVVLVWDQFHDQGIUHTXHQW PHGLFDOFDUHUHTXLUHG VRPH VHOIFDUHSRVVLEOH
&DSDEOHRIRQO\OLPLWHGVHOIFDUH 'LVDEOHG UHTXLULQJVSHFLDOFDUHDQG FRQILQHGWREHGRUFKDLUPRUH DVVLVWDQFH WKDQRIZDNLQJKRXUV 6HYHUHO\GLVDEOHG KRVSLWDOL]DWLRQ UHTXLUHGEXWGHDWKQRW LPPLQHQW
&RPSOHWHO\GLVDEOHGFDQQRWFDUU\RQ ([WUHPHO\LOO VXSSRUWLYHWUHDWPHQW DQ\VHOIFDUH7RWDOO\FRQILQHG DQGRUKRVSLWDOL]DWLRQ WREHGRUFKDLU UHTXLUHG ,PPLQHQW'HDWK
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Appendix III: New York Heart Association Classification (NYHA)
Class I Patients with cardiac disease but without resulting limitations of physical activity Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain.
Class II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain.
Class III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain.
Class IV Patients with cardiac disease resulting in inability to carry out physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased
(The Criteria Committee of the New York Heart Association, In: Diseases of the Heart and Blood Vessels; Nomenclature and Criteria for Diagnosis, 6th ed. Boston, Little, Brown 1964)
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Appendix IV: Administration of the study medication
- Antibody or placebo will be supplied as 20 mg substance in 4 ml solution. - Solution will be drawn from the vial into the syringe Ö for the fist administration in week 1 a total of 10 ml (=50mg) will be drawn from 3 vials into the syringe Ö for all further consecutive administrations in weeks 2-24 a total of 4 ml (=20 mg) will be drawn from the vial into the syringe - The drawn solution will be injected into 100 ml normal saline (sterile 0.9 % sodium cloride in water) using the 0.2 μm low protein binding filter provided with the medication. - The syringe will be removed from filter, 2 ml of normal saline drawn into the syringe and the same syringe will be attached to the filter again. - The 2 ml normal saline will be injected into the infusion solution, flushing the filter to avoid loss of antibody in the filter. - Needle will be removed, syringe and filter discarded and the empty vial retained in the patients’ medication box. - Infusion with 112 ml for week 1 and accordingly 106 ml for weeks 2-24 will be administered over 15 minutes with the patient seated or supine.
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