Use of Early Tumor Shrinkage To Predict Long-term Outcome in Metastatic Colorectal Cancer Treated With Cetuximab

Transcription

1 Use of Early Tumor Shrinkage To Predict Long-term Outcome in Metastatic Colorectal Cancer Treated With Cetuximab Piessevaux, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors ( only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 EMD EMR Cetuximab Clinical Study Protocol Study protocol No. EMR Title : CETUXIMAB COMBINED WITH IRINOTECAN IN FIRST-LINE THERAPY FOR METASTATIC COLORECTAL CANCER Open, randomized, controlled, multicenter phase III study comparing 5-FU/FA plus irinotecan plus cetuximab versus 5-FU/FA plus irinotecan as firstline treatment for epidermal growth factor receptor-expressing metastatic colorectal cancer Study phase Coord./Principal Investigator Sponsor Coordinating Study Manager Date/Version III Prof. Eric Van Cutsem, MD, PhD University Hospital Gasthuisberg Herestraat Leuven, Belgium Merck KGaA, Darmstadt, Germany Jean-Claude Vedovato, MD ClinicalDevelopment Merck Lipha Santé 116, rue Carnot Suresnes France March 29 th, 2004/Final Version Confidential This document is the property of Merck KGaA, Darmstadt, Germany and may not - in full or part be passed on, reproduced, published or used without express permission of Merck KGaA, Darmstadt, Germany Copyright 2004 by Merck KGaA, Darmstadt, Germany. All rights reserved. Document No d18005aba0v1.0 C O N F I D E N T I A L 1 /205

3 Signature Sheet I agree to conduct the study in accordance with the protocol described in this document and in compliance with Good Clinical Practice and applicable regulatory requirements. Main Author Oliver Kisker, MD Clinical R&D, Medical Sciences Oncology Merck KGaA Frankfurter Strasse Darmstadt Germany Tel.: Fax: oliver.kisker@merck.de Date:.. Signature: Study Coordination Jean-Claude Vedovato, MD Clinical Development Merck Lipha Santé 116, rue Carnot Suresnes France Tel.: Fax: jean-claude.vedovato@merck.fr Date:..Signature: This document has been approved electronically. Additionally, a printout of the document has been signed by the responsible persons and archived for regulatory purposes. A paper copy of the signature sheet is available on request. Document No d18005aba0v1.0 C O N F I D E N T I A L 2 /205

4 I agree to conduct the study in accordance with the protocol described in this document and in compliance with Good Clinical Practice and applicable regulatory requirements. Statistical Processing Michael Schlichting, Dipl.-Stat. Biostatistics and Data Sciences Merck KGaA Frankfurter Strasse Darmstadt Germany Tel.: Fax: michael.schlichting@merck.de Date:..Signature: Indication Manager Danny Bets, MSc Department of Clinical Development Merck BV Basisweg AP Amsterdam The Netherlands Tel.: Fax: danny.bets@merck.nl Date:..Signature: This document has been approved electronically. Additionally, a printout of the document has been signed by the responsible persons and archived for regulatory purposes. A paper copy of the signature sheet is available on request. Document No d18005aba0v1.0 C O N F I D E N T I A L 3 /205

5 I agree to conduct the study in accordance with the protocol described in this document and in compliance with Good Clinical Practice and applicable regulatory requirements. Coordinating Investigator Prof. Eric Van Cutsem, MD, PhD University Hospital Gasthuisberg Herestraat Leuven Belgium Tel.: Fax: eric.vancutsem@uz.kuleuven.ac.be Date:..Signature: This document has been approved electronically. Additionally, a printout of the document has been signed by the responsible persons and archived for regulatory purposes. A paper copy of the signature sheet is available on request. Document No d18005aba0v1.0 C O N F I D E N T I A L 4 /205

6 List of abbreviations used in the text 5-FdUMP 5-FU ADR AE ARF Β-HCG BSA CR CRC CRF CT CTC DSMB ECG ECOG EGF EGFR EORTC 5-fluorodeoxyuridine monophosphate 5-fluorouracil adverse drug reaction adverse event Alert Report on Serious Adverse Event form beta human chorionic gonadotropin body surface area complete response colorectal cancer case report form computed tomography Common Toxicity Criteria Drug Safety Monitoring Board electrocardiogram Eastern Cooperative Oncology Group epidermal growth factor epidermal growth factor receptor European Organization for Research and Treatment of Cancer EORTC QLQ-C30 EORTC quality of life core questionnaire FA FDA FOLFIRI GMP folinic acid (leucovorin) US Food and Drug Administration folinic acid+fluorouracil+irinotecan good medical practice Document No d18005aba0v1.0 C O N F I D E N T I A L 5 /205

7 ICH IRC ITT mcrc MedDRA MOP MOPI MRI NC NCI NE PD PFS PR QoL SAS SAE SD SOPD TGFα TMN VCL WBC WHO International Conference on Harmonization Independent Review Committee intention-to-treat metastatic colorectal cancer Medical Dictionary for Regulatory Affairs Manual of Operations Manual of Operations for Investigators magnetic resonance imaging no change National Cancer Institute not evaluable progressive disease progression-free survival partial response quality of life Statistical Analysis System serious adverse event stable disease sum of the products of diameters transforming growth factor α Tumor-Lymph Nodes-Metastasis classification of malignant disease virtual central laboratory white blood cells World Health Organization WHO-DRL World Health Organization Drug Reference List Document No d18005aba0v1.0 C O N F I D E N T I A L 6 /205

8 1 Synopsis 12 2 Investigators and study administrative structure 19 3 Background information Epidermal growth factor receptor in cancer Epidermal growth factor receptor inhibition and the cell cycle Cetuximab In vitro cetuximab tissue binding studies Toxicology and nonclinical pharmacokinetics of cetuximab Dose selection criteria and clinical pharmacokinetics of cetuximab Anti-cetuximab antibody response Clinical efficacy Clinically relevant adverse events related to cetuximab Study rationale Risk/Benefit assessment 26 4 Study objectives Primary objective Secondary objectives 28 5 Investigational plan Overall study design and plan Discussion of study design Selection of the study population Inclusion criteria Exclusion criteria Removal of patients from the study or study treatment Before randomization After randomization Study discontinuation 34 6 Treatments Treatments administered Cetuximab Irinotecan Fluorouracil plus folinic acid Description of the investigational product Method of assigning patients to treatment groups Blinding Procedure for emergency code-breaks 38 Document No d18005aba0v1.0 C O N F I D E N T I A L 7 /205

9 6.4 Selection, timing and modification of dose for each patient Cetuximab Dose modifications and treatment alterations for cetuximab Management of cetuximab-specific adverse events Allergic/hypersensitivity reactions Skin toxicity Interruption and discontinuation of cetuximab Chemotherapy Dose modifications after the first cycle of chemotherapy and criteria for restarting treatment Dose modifications after the first cycle of chemotherapy Criteria for restarting treatment on scheduled day Management of irinotecan-specific adverse events Management of 5-fluorouracil-specific adverse events Preparation of the investigational product Packaging and labeling of the investigational product Storage, issue, and return of investigational product Prior and concomitant therapy Other study conditions Surgery for metastases Treatment compliance Methodology Demographic and other baseline characteristics Demographic data EGFR determination Diagnosis of primary tumor Medical history Vital signs and physical examination Performance status Quality of life assessment ECG Chest X-ray CT or MRI scans for tumor assessment Clinical laboratory evaluation Pregnancy testing and contraception Assessment of efficacy during the study 55 Document No d18005aba0v1.0 C O N F I D E N T I A L 8 /205

10 7.2.1 Documentation of tumor assessments Criteria for index and non-index lesions Response criteria per time point Confirmation criteria and best overall response according to modified WHO criteria Independent Review Committee Quality of life assessments Assessment of safety Adverse events Definition of adverse event, adverse drug reaction and serious adverse event Methods of recording and assessing adverse events Procedure for reporting serious adverse events Monitoring of patients with adverse events Overdose and intoxication with the study drug Special precautions Cetuximab administration Chemotherapy administration Laboratory assessments Laboratory investigations every 8 weeks Other laboratory investigations Vital signs, body surface area and physical examination Pharmacokinetic assessment Pharmacodynamic assessment Other assessments Schedule of assessments Prescreening visit Screening and baseline visit First 2 cycles; first visit of each cycle (Groups A and B) First 2 treatment cycles; all subsequent treatment visits (every 7 days) Further cycles; first visit of each cycle (Groups A and B) Further cycles; all other subsequent treatment visits (groups A only) Assessment visits every 8 weeks after baseline (Groups A and B) Final Tumor Assessment Visit (Groups A and B) End-of-Study Visit (Groups A and B) 72 Document No d18005aba0v1.0 C O N F I D E N T I A L 9 /205

11 monthly follow-up 72 8 Statistics Statistical objectives Target variables Primary variable Secondary variables Safety variables Further variables of interest Analysis sets Description of statistical analyses General considerations Primary analysis Secondary analyses Safety analyses Analysis of further variables Interim analysis Sample size 81 9 Ethical and regulatory aspects Responsibilities of the investigator Patient information Patient consent Compensation to patients Ethics committee or institutional review board Notification to authorities Study management Case report form handling Source data and patient files Investigator Site File and archiving Monitoring, quality assurance and inspection by authorities Changes to the study protocol Study report and publication policy References Investigator signature page 93 Appendix I Study flow chart 94 Appendix II Patient information and consent form - Master document - 97 Appendix III Declaration of Helsinki 115 Document No d18005aba0v1.0 C O N F I D E N T I A L 10 /205

12 Appendix IV Extract of EC Note for Guidance on Good Clinical Practice 121 Appendix V NCI-CTC version Appendix VI Handling instructions for irinotecan 186 Appendix VII EORTC QLQ-C30 Questionnaire 189 Appendix VII Insurance certificate 192 Document No d18005aba0v1.0 C O N F I D E N T I A L 11 /205

13 1 Synopsis Study Title Open, randomized, controlled, multicenter phase III study comparing 5-FU/FA plus irinotecan plus cetuximab versus 5-FU/FA plus irinotecan as first-line treatment for epidermal growth factor receptor-expressing metastatic colorectal cancer Study number EMR Sponsor Study phase Merck KGaA, Darmstadt, Germany Clinical phase III Study under IND yes no FDA covered study yes no Study centers/countries Planned study period Study objectives: Approximately 140 centers in Europe, Australia, South Africa, Latin America and Asia. The study will start in May 2004 and run for 4 5 years. The recruitment period will be from May 2004 to November Primary: To assess whether the progression-free survival time under 5-FU/FA plus irinotecan plus cetuximab is longer than that under 5-FU/FA plus irinotecan as firstline treatment for epidermal growth factor receptorexpressing metastatic colorectal cancer. Secondary: To compare between the 2 treatment groups for: Overall survival time Response rate (modified WHO criteria) Disease control rate To determine: Duration of response Quality of life (EORTC QLQ-C30 Questionnaire) Safety Document No d18005aba0v1.0 C O N F I D E N T I A L 12 /205

14 Study design and plan: This is an open, randomized, controlled, multicenter phase III study comparing 5-FU/FA plus irinotecan plus cetuximab (Group A) and 5-FU/FA plus irinotecan (Group B) as first-line therapy in EGFR-expressing metastatic colorectal cancer. Randomization will be 1:1, stratified according to center and performance status (Eastern Cooperative Oncology Group). Only patients with epidermal growth factorexpressing tumors are eligible. Efficacy will be assessed every 8 weeks. Tumor scans will be assessed by an Independent Review Committee. Treatment will be continued until progressive disease or unacceptable adverse events occur. After the end of study treatment, information on further anticancer treatment and survival will be collected every 3 months. Regular safety assessments and all adverse events will be documented throughout and until the End-of-Study Visit. Safety follow-up: The outcome of adverse events ongoing at the Final Tumor Assessment Visit will be followed up at the End-of-Study Visit (6 weeks after the last administration of study medication but before second-line anticancer treatment, and not earlier than 30 days after the end of study treatment). Skin toxicity present at the Endof-Study Visit will be followed up until outcome is known. An Independent Drug Safety Board will be established to monitor all adverse events. Planned number of patients Schedule of visits and assessments About 1300 patients will be screened for epidermal growth factor expressing tumors to identify 1080 patients eligible for randomization: 540 in each group. Prescreening visit: Epidermal growth factor receptor assessment Demographics, and primary tumor diagnosis Screening and baseline visit: Pregnancy test Safety laboratory(hematology and biochemistry) Medical history, vital signs, physical examination ECOG performance status Electrocardiogram Concomitant therapy; previous treatment for colorectal cancer Imaging for baseline tumor assessment Quality of life questionnaire Document No d18005aba0v1.0 C O N F I D E N T I A L 13 /205

15 Treatment phase assessments, including Final Tumor Assessment Visit: First 2 cycles Weekly: Vital signs and body surface area Platelet and white blood cell count (differential) and bilirubin in the 48 hours before study treatment Further cycles First week of each cycle (Groups A and B, before chemotherapy infusion): Body surface area Platelet and white blood cell count (differential) and bilirubin in the 48 hours before study treatment Every 8 weeks Physical examination and vital signs ECOG performance status Safety laboratory (hematology and biochemistry) Imaging for tumor assessment Quality of life questionnaire (every 4 cycles) Continuous Adverse events (including follow-up of outcome after end of treatment); concomitant medication Final Tumor Assessment Visit: Vital signs, physical examination ECOG performance status Electrocardiogram Imaging for tumor assessment Safety laboratory (hematology and biochemistry) Quality of life questionnaire Adverse events and concomitant therapy End-of-Study visit (6 weeks after the last administration of study medication but before second-line anticancer treatment and not earlier than 30 days after the end of study treatment): Survival status Follow-up of adverse events present at Final Tumor Assessment Visit Document No d18005aba0v1.0 C O N F I D E N T I A L 14 /205

16 3-monthly follow-up: Survival status Follow-up of skin toxicity present at End-of-Study Visit until outcome is known Further anticancer treatment Diagnosis and criteria for inclusion and exclusion Inclusion criteria: Signed written informed consent (first and second) Inpatient or outpatient 18 years of age Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum Inoperable metastatic disease Immunohistochemical evidence of epidermal growth factor receptor expression in tumor tissue Life expectancy of at least 12 weeks Presence of at least 1 bi-dimensionally measurable index lesion (not lie in an irradiated area) ECOG performance status of 2 atstudyentry Effective contraception for both male and female patients if the risk of conception exists White blood cell count /L with neutrophils /L, platelet count /L, hemoglobin 5.6 mmol/l (9 g/dl) Total bilirubin 1.5 upper reference range AST 2.5 upper reference range, or 5 upper reference range in case of liver metastasis Serum creatinine 1.5 upper reference range Recovery from relevant toxicity to previous treatment before study entry Exclusion criteria: Previous exposure to epidermal growth factor targeting therapy Previous irinotecan-based chemotherapy Previous chemotherapy for colorectal cancer except adjuvant treatment if terminated >6 months before the start of treatment in this study Radiotherapy, surgery (excluding prior diagnostic biopsy) or any investigational drug in the 30 days before the start of treatment in this study Concurrent chronic systemic immune therapy or hormone therapy not indicated in this study protocol Document No d18005aba0v1.0 C O N F I D E N T I A L 15 /205

17 Known hypersensitivity reaction to any of the components of study treatments Pregnancy (absence to be confirmed by ß-hCG test) or lactation period Brain metastasis (known or suspected) Clinically relevant coronary artery disease, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease Previous malignancy other than colorectal cancer in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix Known alcohol or drug abuse Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent Participation in another clinical study within the past 30 days Significant disease which, in the investigator s opinion, would exclude the patient from the study Legal incapacity or limited legal capacity Investigational product Cetuximab in ready-to-use 50 ml vials of 2 mg/ml solution (100 mg/vial). In Group A, cetuximab will be administered before the chemotherapy described below and will be continued if chemotherapy is delayed or discontinued for related toxicity. The dose can be modified in the presence of toxic effects. Every 7 days First infusion Subsequent infusions Cetuximab 400 mg/m² intravenous infusion over 120 min 250 mg/m² intravenous infusion over 60 min Reference therapy Chemotherapy will be based on the simplified de Gramont regimen plus irinotecan (modified FOLFIRI regimen) repeated every 14 days. All patients in Groups A and B will receive the same chemotherapy. The chemotherapy will be given after cetuximab in Group A and will be continued if cetuximab is delayed or discontinued for related toxicity. Document No d18005aba0v1.0 C O N F I D E N T I A L 16 /205

18 Reference therapy Order Drug Dose First Second Third Irinotecan min infusion on day 1 Folinic acid 120-min infusion on day 1 5-Fluorouracil day mg/m² 400 mg/m² (racemic) or 200 mg/m² (L-form) 400 mg/m² bolus on day 1 followed by a 46-hour continuous infusion of 2400 mg/m² Planned treatment duration per patient Primary target variable Secondary target variables Tolerability/safety variables Pharmacokinetics Other assessments Patients will be treated until progressive disease is documented or unacceptable toxicity occurs. The median progression-free survival time is estimated to be 8 months in Group B and 10 months in Group A (with cetuximab). Progression-free survival time. Tumor assessments will be based on an independent read. Overall survival time Best overall response Duration of response Disease control rate Time to response Quality of life Incidence and type of adverse events Extent of exposure Skin toxicity Laboratory investigations No pharmacokinetics will be performed in this study. None Document No d18005aba0v1.0 C O N F I D E N T I A L 17 /205

19 Statistical methods: The primary confirmatory analysis will test the superiority of 5-FU/FA plus irinotecan plus cetuximab (Group A) over 5-FU/FA plus irinotecan (Group B) in terms of progression-free survival time using a stratified, 2-sided log rank test at a significance level of α=0.05 in the intention-to-treat population (patients as randomized). Kaplan-Meier estimates will be provided. The study will require 633 events (documented progressive disease) to have 80% power for the statistical test chosen to detect a difference between treatment groups of at least 2 months, anticipating a median progression-free survival time of 8 months in Group B and 10 months in Group A. Thus, with 80% power, a hazard ratio (Group A:Group B) of 0.8 can be detected, representing a progression-free survival time 25% longer in Group A than in Group B. An accrual rate of 60 patients per month is expected. Thus, it is estimated that accrual will last for 18 months. This study is expected to detect an increase in overall survival time from 17 months in Group B to 21 months in the Group A (an improvement of 23.5%) with 80% power when at least 705 deaths have been observed The final analyses on progression-free survival time and further tumor assessment-related secondary endpoints will be conducted after the following 2 conditions are met: 4 months have elapsed since the last patient was randomized and 633 patients have developed radiologically confirmed progressive disease. Final analyses of survival will be conducted after at least 705 deaths have been observed, which is anticipated approximately 3.5 years after study start. Document No d18005aba0v1.0 C O N F I D E N T I A L 18 /205

20 2 Investigators and study administrative structure Merck KGaA, Darmstadt, Germany is the sponsor of this clinical study with cetuximab. Approximately 140 centers in Europe, Australia, South Africa, Latin America and Asia will participate in the study. The coordinating investigator is Prof Eric Van Cutsem, University Hospital Gasthuisberg, 3000 Leuven, Belgium. The study will be coordinated by the Clinical Department of Merck Lipha Santé, Suresnes, France. Site monitoring will be performed by the clinical operations staff of the local affiliates of Merck KGaA or a designated contract research organization. The department of Biostatistics and Data Sciences at Merck KGaA will supervise data management, statistical analysis and randomization to be performed by a designated contract research organization. The department of Drug Safety at Merck KGaA or their designated representatives will supervise drug safety and the timely reporting of adverse events (AEs) and serious AEs (SAEs). An Independent Drug Safety Monitoring Board (DSMB) will be established to monitor all AEs. Expression of the epidermal growth factor receptor (EGFR) in tumor tissue will be evaluated by local or regional laboratories. Merck KGaA will supply the cetuximab. Cetuximab will be produced under Good Manufacturing Practice conditions by a third party provider, and will be finally released by the department of Clinical Trial Supplies at Merck KGaA. This multinational study requires a significant logistic and administrative structure for its efficient execution. Details of such structures and associated procedures will be defined in a separate Manual of Operations (MOP). This will be prepared under the supervision of the Study Coordination Team in close collaboration with the responsible units at Merck KGaA. The primary study endpoint will be derived from an independent and objective blinded assessment conducted by an Independent Review Committee (IRC). Safety laboratory assessments will be performed locally and forwarded to a virtual central laboratory (VCL). All other laboratory assessments, e.g. for study drug administration, will be performed locally at the study centers. Details of procedures for laboratory assessments will be described in the Manual of Operations (MOP). Document No d18005aba0v1.0 C O N F I D E N T I A L 19 /205

21 3 Background information As from April 28, 1999, cetuximab was the name adopted for C225 by the United States Adopted Names Council. On May 8, 2000, cetuximab attained the status of a proposed international nonproprietary name. Cetuximab is a joint development of Bristol-Myers Squibb, ImClone Systems Incorporated and Merck KGaA. A marketing authorization application for cetuximab dossier in the indication of metastatic colorectal cancer (mcrc) after failure of irinotecan was submitted to several authorities including the European Agency for the Evaluation of Medicinal Products, the US Food and Drug Administration, and Swissmedic in mid Swissmedic granted marketing approval in December 2003 for cetuximab (Erbitux ) in combination with irinotecan for the treatment of patients with EGFR-expressing mcrc after failure of an irinotecan-including cytotoxic therapy. The Food and Drug Administration granted marketing approval in February 2004 in the United States for the use of Erbitux in combination with irinotecan for the treatment of EGFR-expressing mcrc in patients who are refractory to irinotecan-based chemotherapy and as monotherapy for patients who are unable to tolerate irinotecan. Comprehensive background information on nonclinical pharmacology, pharmacokinetics and toxicology can be found in the Investigator Brochure (1). 3.1 Epidermal growth factor receptor in cancer The EGFR is a commonly expressed transmembrane glycoprotein of the tyrosine kinase growth factor receptor family. EGFR is expressed in many normal human tissues, and activation of these proto-oncogenes results in overexpression in many types of human tumor. As a transmembrane glycoprotein, the extracellular domain of the EGFR is a ligand-binding site for transforming growth factor alpha (TGFα), epidermal growth factor (EGF) and other factors. Upon ligand binding, the intracellular domain of the EGFR is activated, thereby triggering cellular mechanisms that regulate cell growth, inhibition of tumor cell invasion and angiogenesis (1, 2). In vitro analysis using cells that express high numbers of EGFRs and produce ligands for these receptors has shown that the EGFR may be activated through an autocrine pathway, thereby leading to the proliferation of cells in culture (3). In order to inhibit proliferation of EGFR-rich cells, antagonists to EGFR have been produced that block the ligand-binding site. In this capacity, monoclonal antibodies to EGFR have been shown to inhibit the proliferation of cells that produce both TGFα and EGF (4). An antagonist directed against the ligand-binding site of EGFR offers an interesting approach to the therapy of cancers involving upregulated EGFR-dependent pathways. Among cancers that overexpress EGFR are some of the most prevalent including: Colorectal (72%), head and neck (92%), pancreatic (95%), ovarian (35 70%), renal cell (50 90%), non-small cell lung cancer (40 80%), and gliomas (40 50%) (1, 5, 6). The prognosis for many of these malignancies is poor if not diagnosed at an early stage, and therapy for advanced disease is limited. Document No d18005aba0v1.0 C O N F I D E N T I A L 20 /205

22 3.1.1 Epidermal growth factor receptor inhibition and the cell cycle The effects of EGFR blockade on cell cycle progression have been investigated in several human cell types, including DiFi colon adenocarcinoma cells, non-transformed breast epithelial MCF10A cells, A431 squamous epithelial cancer cells, and DU145 prostatic cancer cells. These studies suggest that blocking EGFR with monoclonal antibodies such as cetuximab leads to cell cycle arrest in G1, which is accompanied by a decrease in cyclin-dependent kinase 2 activity, and an increase in the expression of cyclin-dependent kinase inhibitor p27 KIP1 (7, 8). In addition to inducing G1-phase arrest, EGFR blockade has also been shown to lead to cell death via apoptosis in DiFi colon adenocarcinoma cells (9). 3.2 Cetuximab Cetuximab, a chimerized antibody of the IgG 1 subclass, was originally derived from a mouse myeloma cell line. The chimerization process resulted in an antibody with binding affinity to EGFR greater than the natural ligand EGF (10). Cetuximab blocks binding of EGF and TGFα to the EGFR and inhibits ligand-induced activation of this tyrosine kinase receptor. Cetuximab also stimulates EGFR internalization, effectively removing the receptor from the cell surface for interaction with ligand (11). Cetuximab was created by chimerization of the murine monoclonal antibody M225 developed at the University of California, San Diego, USA (12). It was genetically engineered by cloning the heavy and light chains of M225 and adapting them for expression together with the constant regions of the human kappa light chain and human gamma 1 heavy chain. In an in vitro study performed to establish the biological activity of cetuximab and its specificity for human EGFR as compared to a murine antibody directed at EGFR (M225), both cetuximab and M225 inhibited cell growth to a similar extent, i.e. 30% of the control (10) In vitro cetuximab tissue binding studies A series of immunohistochemical studies performed to characterize the binding of cetuximab to human and animal tissues demonstrated that cetuximab reacted positively and specifically with epithelium of human placenta (1). Specific staining was observed also in normal epithelia of skin, digestive tract, urogenital system and tonsillar crypts, and in squamous cell cancer and large cell cancer of the lung. Specific staining was absent in cancers originating from other organs, in melanomas, and in lymphoid tumors. In an interspecies study, human placental control tissues showed positive staining for cetuximab; however, no staining was observed in hepatic tissues of adult Cynomolgus and Rhesus monkeys, baboons, rodents, or dogs. Specific details of these studies are available in the Investigator Brochure (1). Document No d18005aba0v1.0 C O N F I D E N T I A L 21 /205

23 3.2.2 Toxicology and nonclinical pharmacokinetics of cetuximab A series of nonclinical toxicity studies evaluated the single- and repeat-dose toxicity of cetuximab in laboratory animals. Detailed information can be found in the Investigator Brochure (1). The immunohistochemical studies described above showed that cetuximab does not recognize EGFR in hepatic tissues of standard animal models. However, immunohistochemistry data evaluated with cryosections of urinary bladder, skin and esophagus of Cynomolgus monkeys showed reactivity of the monoclonal antibody cetuximab with EGFRs of this primate species. The pharmacological action of the product was therefore considered to have been appropriately modeled in Cynomolgus monkeys Dose selection criteria and clinical pharmacokinetics of cetuximab When the clinical development of cetuximab started, the goal was to administer doses of the antibody that would be safe and would maintain serum cetuximab concentrations greater than those needed to saturate the binding of tumor-associated EGFR in murine models (approximately 20 nm). As early clinical development proceeded, this criterion for dose selection was revised based on a hypothesis that non-tumor-associated EGFR binding in patients (especially liver and skin) might represent a large sink for cetuximab which could limit availability of the antibody to tumor associated receptors. An extension of this hypothesis is that non-tumor binding of cetuximab and subsequent receptor internalization represented a major route of elimination for cetuximab that would theoretically become saturated. Thus at some point, systemic clearance of cetuximab may become stable which might be detected by estimation of patient serum pharmacokinetic parameters (total body clearance and half-life). Based on this hypothesis, the target criteria for dose selection were revised to identify a dose at which systemic clearance (as determined by serum pharmacokinetics) became stable. The initial clinical development program of cetuximab included 14 studies of which 13 contributed to the pharmacokinetic database. Across all dose-ranging studies, as the dose of cetuximab was increased from 5 to 500 mg/m 2, a trend to decreasing cetuximab clearance was reported. At doses of >200 mg/m 2, the clearance of cetuximab from the body appeared to level off and remained at approximately 0.02 L/h/m 2 through the highest dose tested of 500 mg/m 2. Estimates of mean serum cetuximab terminal half-life increased from 14 to 97 hours over the dose range of 5 to 300 mg/m 2, after which the half-life appeared to plateau. The mean serum cetuximab volume of distribution in the steady state was independent of cetuximab dose and ranged from 1.96 to 2.52 L/m 2, suggesting that cetuximab distributes into a volume equal to or slightly greater than that of the vascular space. Based on all of the above and the finding of increased incidence of skin toxicity at 500 mg/m 2, the cetuximab regimen chosen for phase II trials was an initial dose of 400 mg/m 2 followed by repeated weekly doses of 250 mg/m 2. With this regimen, it was proposed that EGFR occupancy and pharmacological activity would be sustained. Document No d18005aba0v1.0 C O N F I D E N T I A L 22 /205

24 When given as monotherapy in patients with EGFR-expressing solid tumors at an initial dose of 400 mg/m 2 followed by 2-weekly doses of 250 mg/m 2 (n=7), the mean C max for cetuximab in week 3 was 153 µg/ml (range: 112 to 225 µg/ml). The mean half-life of elimination in week 3 was 119 hours (range: 82 to 188 hours). The mean volume of distribution at steady state in week 3 was 3.6 L (range: 2.2 to 4.5 L). Concomitant administration of irinotecan (350 mg/m 2 ) in week 4 did not change the pharmacokinetic characteristics of cetuximab (13) Anti-cetuximab antibody response A total of 614 patients treated with cetuximab by 30 November 2002 were tested for the presence of anti-cetuximab antibodies by analyzing baseline and post-baseline sera. The overall incidence of an anti-cetuximab immune response in these patients was 3.7%. When it occurred, the anti-cetuximab response was generally found to be weak. The anticetuximab antibodies from 2 patients with the highest reactivity (4670 and 6516 ng/ml) were tested in an in vitro assay for neutralizing activity. The tested sera did not interfere with the ability of cetuximab to inhibit proliferation in a cetuximab-sensitive cell line, suggesting that the antibodies in these sera were non-neutralizing. Levels of reactivity in sera from other patients were not high enough to perform this type of analysis. In order to determine the specificity of the antibody response, sera from 15 patients who had a positive anti-cetuximab response were further studied in a double antigen radiometric assay using unlabeled cetuximab as a competitor. This analysis demonstrated that sera from 14 of the 15 patients contained cetuximab-specific antibodies Clinical efficacy Cetuximab clinical trials began in Cetuximab has been administered in phase I III clinical trials as a single agent or in combination with chemotherapy and/or radiation therapy. These trials have demonstrated antitumor activity in mcrc, squamous cell cancer of the head and neck, non-small-cell lung cancer, and pancreatic cancer. In cetuximab single-agent phase II studies and studies with cetuximab and irinotecan in combination, response rates of 11 and 23% were achieved in non-randomized studies and randomized studies (see Table 3.1). The tumor growth control rate ranged from 31 to 56%. Document No d18005aba0v1.0 C O N F I D E N T I A L 23 /205

25 Table 3.1 Efficacy of cetuximab in EGFR-expressing mcrc resistant to irinotecan-based chemotherapy Study Design Treatment N Partial response rate Saltz et al 2001 (14) Saltz et al 2002 (15) Cunningham et al 2003 singlearm singlearm randomized Cetuximab + irinotecan* Cetuximab monotherapy Cetuximab monotherapy Tumor growth control rate Median time to progression (months) Median overall survival (months) % 48% % 31% % 32% (16) Or Cetuximab % 56% irinotecan* *irinotecan was administered at the same dose and schedule that the patient failed on previously One phase I and 2 phase I/II studies used cetuximab in combination with irinotecan and 5- fluorouracil(fu)/folinic acid(fa) as first-line treatment in patients with EGFR-expressing mcrc. An overall response rate of 48% was achieved in 29/61 patients using the combination of cetuximab plus irinotecan and bolus 5-FU/FA (17). Two ongoing phase I/II studies investigated cetuximab in combination with irinotecan and infusional 5-FU/FA given as the modified Arbeitsgemeinschaft Internistischer Onkologie (AIO)regimen or as the modified, simplified de Gramont regimen (18, 19). Cetuximab in combination with weekly irinotecan plus an infusional 5 FU/FA regimen resulted in an overall response rate of 74% in 19 patients, with an acceptable safety profile (18). Raoul et al. used cetuximab in combination with a regimen of irinotecan 180 mg/m² and FA 400 mg/m² and 2 different doses of 5-FU (300 mg/m² bolus followed by 2000 mg/m² infusion over 46 hours, or 400 mg/m² bolus followed by 2400 mg/m² infusion over 46 hours) every second week (19). The combined response analysis of both dose levels showed a response in 59% of patients, with an acceptable safety profile Clinically relevant adverse events related to cetuximab Pooled safety data are available for 1473 patients treated with cetuximab in 26 clinical trials as of 30 November 2002 (1). AEs were reported for 94% of patients. At least 1 grade 3 or 4 AE was reported for 981 patients (66.6%). Cetuximab-related AEs were noted in 1284 patients (87.2%). In single-agent studies, 233 patients (82.9%) had a cetuximab-related AE of any grade. In combination with chemotherapy, 861 patients (87.3%) had a related AE of any grade. In combination with radiation therapy, 190 patients (92.2%) had a related AE of any grade. The incidence of the most common AEs related to cetuximab, is summarized in Table 3.2. Document No d18005aba0v1.0 C O N F I D E N T I A L 24 /205

26 Table 3.2: Most common adverse events related to cetuximab (n=1473) Number of patients N (%) Skin reaction Acne-like rash Fatigue/malaise Nausea/vomiting Fever/chills Mucositis/stomatitis Diarrhea Nail disorder Allergic/hypersensitivity reactions Data from 1473 patients in 26 trials receiving cetuximab alone or in combination with chemotherapy and radiation. Skin reactions are the most common AEs associated with cetuximab. They usually present as an acne-like rash or less frequently, as nail disorders. Acne-like rash usually occurs in the first 3 weeks of treatment on the face, upper chest and back, but occasionally extends to the extremities. It occurs as multiple follicular or pustular lesions characterized histologically as lymphocytic perifolliculitis or suppurative superficial folliculitis. It tends to resolve without sequelae over time following cessation of therapy. In patients who have received cetuximab in doses lower than 100 mg/m², the acne-like rash has been reported infrequently and has been restricted to grades 1 and 2. Several therapeutic interventions have been attempted, including oral and topical antibiotics, topical steroids, and rarely, oral steroids. The value of these measures is unknown since definite clinical trials have not been performed. The etiology of the acnelike rash is believed to be the result of cetuximab binding to the EGFR in the epidermis. Recent trials have shown that the occurrence of acne-like skin reactions were correlated with better efficacy outcomes (response, and time to progressive disease [PD], and survival). Nail disorders: Another typical but less frequently reported AE is nail disorder which presents as pain, tenderness and fissuring of the distal finger tufts to different degrees. The patients developed paronychial inflammation with associated swelling of the lateral nail folds of the toes and fingers. The most commonly affected digits are the great toes and thumbs. From investigator reports, it is known that nail disorders may persist for up to 3 months after discontinuation of cetuximab. Allergic/hypersensitivity reactions: Grade 3 or 4 hypersensitivity reactions (including allergic and anaphylactic reactions) characterized by the rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension, have been observed in 2.2% patients treated with cetuximab. Approximately 80% of all allergic/hypersensitivity reactions occurred during the first infusion of cetuximab and were observed during or within 1 hour of the completion of the infusion. Document No d18005aba0v1.0 C O N F I D E N T I A L 25 /205

27 Prior to the first administration of cetuximab, patients must be premedicated with an antihistamine (see Section 6.4.1). This premedication is also recommended prior to all subsequent infusions of cetuximab as approximately 15% of patients experienced their first severe allergic/hypersensitivity reaction during later infusions (see Section 7.3.2). In studies with cetuximab to date, patients who experienced severe reactions received standard treatment, and all but 1 patient recovered without sequelae and were withdrawn from the studies concerned. One patient died due to angioedema following the end of cetuximab infusion, which was recorded as being the result of a grade 4 reaction. The occurrence of allergic/hypersensitivity reactions does not appear to be related to singledrug therapy or combination therapy, underlying disease, or previous exposure to murine monoclonal antibodies. Mild to moderate allergic/hypersensitivity reactions can generally be managed by slowing the infusion rate of cetuximab (see Section ). 3.3 Study rationale CRC is the third most common cancer in men and the second most common cancer in women world-wide (20). Standard approaches to the first-line therapy of metastatic disease in Europe are, different combinations of infusional 5-FU/FA with either irinotecan or oxaliplatin as combination partners. All regimens have demonstrated statistically significant advantages over infusional 5-FU/FA alone in terms of response rate and median time to PD, but only the addition of irinotecan improved the median survival time statistically significantly (21 25). The regimen of irinotecan and infusional 5-FU/FA administered in the form of the simplified de Gramont regimen every 14 days is one of the most efficient first-line treatments in mcrc (23). Based on this, the combination of this regimen plus cetuximab was investigated in a phase I/II study, which demonstrated a promising overall response rate of 58%. In the light of this, in the present study, the combination of irinotecan plus infusional 5-FU/FA and cetuximab will be compared with the same irinotecan plus 5- FU/FA infusional regimen alone, in order to confirm the therapeutic value of cetuximab as a combination partner for this regimen in the first-line setting. 3.4 Risk/Benefit assessment The combination of cetuximab with irinotecan plus bolus 5-FU/FA, or of irinotecan plus infusional 5-FU/FA demonstrated acceptable safety profiles and promising results in 1 phase II study and 2 phase I/II studies. The regimen of irinotecan plus infusional 5-FU/FA every second 14 days demonstrated high efficacy as first-line treatment in metastatic disease in a randomized phase III study. The results of 1 phase I/II study showed that the full dose of irinotecan plus infusional 5-FU/FA can be combined with cetuximab at the recommended dose with only minimal additional grade 3 toxicity and promising response rates. (19). Document No d18005aba0v1.0 C O N F I D E N T I A L 26 /205

28 These findings suggest a favorable risk-benefit ratio of the combination of irinotecan, infusional 5-FU/FA and cetuximab over irinotecan plus 5-FU/FA alone, and support the comparison of both regimens in a randomized trial in order to confirm this assumption. A DSMB will be implemented to monitor AEs and ensure timely recognition of any unknown risks for the patient. Document No d18005aba0v1.0 C O N F I D E N T I A L 27 /205

29 4 Study objectives 4.1 Primary objective To assess whether the progression-free survival (PFS) time under 5-FU/FA plus irinotecan plus cetuximab is longer than that under 5-FU/FA plus irinotecan as first-line treatment for EGFR-expressing mcrc. 4.2 Secondary objectives To compare between the 2 treatment groups for: Overall survival time Response rate (modified World Health Organization [WHO] criteria) Disease control rate To determine: Duration of response Quality of life questionnaire (QoL; European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30 Questionnaire) Safety Document No d18005aba0v1.0 C O N F I D E N T I A L 28 /205

30 5 Investigational plan 5.1 Overall study design and plan This is an open, randomized, controlled, multicenter phase III study comparing 5-FU/FA plus irinotecan plus cetuximab versus 5-FU/FA plus irinotecan as first-line therapy for EGFR-expressing mcrc. It is planned to perform this study in about 140 centers in Europe, Australia, South Africa, Latin America and Asia. A center is defined as the primary institution of the clinical investigator. About 1300 patients will be screened for EGFR-expressing tumors to identify 1080 patients eligible for randomization: 540 in each group. Centers should not recruit more than 40 patients each. The study will start in May 2004 and run for 4 5 years. The recruitment period will be from May 2004 to November The planned treatment duration per patient will be until PD is observed. Eligible patients will be randomized 1:1 to treatment with the regimens given below. In addition to the chemotherapy regimen given in Table 5.2, the patients in Group A will receive cetuximab every 7 days. Cetuximab will be administered (1 hour) before chemotherapy. The dosage regimen is given in the following table: Table 5.1 Cetuximab regimen for patients in Group A Cetuximab every 7 days First infusion All subsequent infusions Cetuximab 400 mg/m² intravenous infusion over 120 min 250 mg/m² intravenous infusion over 60 min Groups A and B will receive the same chemotherapy regimen every 14 days. The regimen will be based on the simplified de Gramont regimen plus irinotecan (modified FOLFIRI regimen) (22, 26) and is given in the following table : Table 5.2 Chemotherapy regimen every 14 days in Groups A and B Order of administration Drug Dose First Second Third Irinotecan min infusion on day 1 Folinic acid 120-min infusion on day 1 5-Fluorouracil day mg/m² 400 mg/m² (racemic) or 200 mg/m² (L-form) before 5-FU bolus injection 400 mg/m² bolus on day 1 followed by a 46-hour continuous infusion of 2400 mg/m² Document No d18005aba0v1.0 C O N F I D E N T I A L 29 /205

31 Definition of treatment cycle and duration: The ideal treatment cycle in this study lasts 14 days and is determined by the chemotherapy dosage interval: Group A: 1 treatment cycle consists of dosing with cetuximab, irinotecan and 5-FU/FA on day 1 of the cycle, and of dosing of cetuximab on day 8 of the cycle, with follow-up through day 14 of the cycle. Group B: 1 treatment cycle consists of dosing with irinotecan and 5-FU/FA on day 1 of the cycle with follow-up through day 14 of the cycle. Treatment with either cetuximab or chemotherapy may be delayed due to toxicity. If treatment with cetuximab is delayed because of related toxicity, the 14-day rhythm of chemotherapy is retained. A maximum of 2 consecutive cetuximab infusions can be withheld (no more than 14 days). After this, the patient must withdrawn and all study treatments stopped. If treatment is delayed because of toxic effects of the chemotherapy, the 7-day rhythm of cetuximab infusions is retained. Chemotherapy can be delayed for a maximum of 28 days, after this, the patient must be withdrawn and all study treatments stopped. The patient may continue on cetuximab monotherapy if still benefiting). Thus, in the extreme case, a cycle may last 42 days. Duration of treatment: Treatment with the above regimens will be continued until PD is demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI), or unacceptable AEs occur in individual patients, or consent is withdrawn. Follow-up for survival: After the End-of-Study Visit, follow-up evaluations will be performed in all patients every 3 months to collect information on further anticancer treatment and overall survival time. Follow-up for AEs: The outcome of AEs ongoing when the study medication is discontinued will be assessed at the End-of-Study Visit. All cases of skin toxicity present at the End-of-Study Visit will be followed up until the outcome is known. The overall individual study duration may vary since patients will be treated until PD or unacceptable toxicity occurs or the patient withdraws consent. Patients who stop treatment before having developed PD will be assessed every 8 weeks for response until PD occurs. No further anti-tumor treatment will be initiated until progression of disease. After having developed PD, all study drugs should be discontinued (if still on therapy) and the Final Tumor Assessment Visit should then be performed. The End-of-Study Visit should be performed no earlier than 6 weeks after the discontinuation of the study medication. If second-line anticancer treatment will be given, the End-of Study Visit has to be performed before it starts and not earlier than 30 days after the end of study treatment. The patient will then enter the follow-up phase, where information on subsequent treatment, survival data and outcome of skin toxicities will be collected every 3 months. This is illustrated by Figure 5.1. Document No d18005aba0v1.0 C O N F I D E N T I A L 30 /205