Gefitinib versus Placebo in Completely Resected Non-Small Cell Lung Cancer, Results of the NCIC CTG BR19 Study

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1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: Gefitinib versus Placebo in Completely Resected Non-Small Cell Lung Cancer, Results of the NCIC CTG BR19 Study Goss, 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 NCI US RE-SUBMISSION TPD SUBMISSION AMENDMENT & REVISION: 02-NOV-14 AMENDMENT & REVISION #2: 2003-OCT-01 AMENDMENT& REVISION #3: 2003-DEC-17 AMENDMENT #4: 2005-JAN-03 NATIONAL CANCER INSTITUTE OF CANADA CLINICAL TRIALS GROUP (NCIC CTG) A PHASE III PROSPECTIVE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF THE EPIDERMAL GROWTH FACTOR RECEPTOR ANTAGONIST, ZD1839 (IRESSA) IN COMPLETELY RESECTED PRIMARY STAGE IB, II AND IIIA NON-SMALL CELL LUNG CANCER NCIC CTG Protocol Number: BR.19 CTSU Protocol Number: BR.19 STUDY CHAIR: STUDY CO-CHAIRS: TRIAL COMMITTEE: PROJECT COORDINATOR: BIOSTATISTICIAN: STUDY COORDINATOR: FELLOW: SPONSOR: Dr. Glenwood Goss (NCIC CTG) Dr. Timothy Winton (NCIC CTG) Dr. Greg Masters (ECOG)* Dr. Peter Roberts (SWOG)* Dr. James Jett (NCCTG)* Dr. Hak Choy (RTOG)* Dr. Fadlo Khuri (RTOG)* Dr. Katherine Pisters (ACOSOG)* Dr. Martin J. Edelman (CALGB)* Dr. Frances Shepherd Dr. Ming-Sound Tsao Dr. Ian Lorimer Dr. Chris O Callaghan Dr. Keyue Ding Ms. Nadine Magoski Dr. Naveed Alam NCIC CTG ZD1839 will be supplied by the NCI *All U.S. Cooperative Group enrolments and data submissions will be done via the Cancer Trials Support Unit (CTSU). (for NCI CTEP Use ONLY: VERSION DATE: 2005-JAN-03; UPDATE DATE: 2005-JAN-03) CONFIDENTIAL CONFIDENTIAL

3 REVISED: 02-NOV-14 AMENDMENT#2: 2003-OCT-01 Instructions for CTSU Investigators are inserted in the respective sections of the protocol: TABLE OF CONTENTS TREATMENT SCHEMA OBJECTIVES Primary Objective Secondary Objectives BACKGROUND INFORMATION AND RATIONALE BACKGROUND THERAPEUTIC INFORMATION Name and Chemical Information Chemical Structure Mechanism of Action Experimental Antitumour Activity Animal Toxicology Phase I Trials Phase II/III Trials Expected Possible Drug-Related Adverse Events Pharmacokinetic Studies... 11a 3.10 Pharmaceutical Data TRIAL DESIGN Stratification Randomization Inclusion of Women and Minorities STUDY POPULATION Eligibility Criteria Ineligibility Criteria PRE-TREATMENT EVALUATION ENTRY / RANDOMIZATION PROCEDURES Entry Procedures Stratification Randomization TREATMENT PLAN Chemotherapy Treatment Plan Surgical Treatment Plan Concomitant Therapy EVALUATION DURING AND AFTER PROTOCOL TREATMENT Evaluation During Protocol Treatment and for 6 Months Thereafter Evaluation After Protocol Treatment Evaluation After Relapse...30 CONFIDENTIAL i CONFIDENTIAL

4 10.0 CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS Evaluable for Toxicity Overall Survival Relapse-free Survival Evidence of Disease Recurrence Dating of First Recurrence Management Following Recurrence ADVERSE EVENT REPORTING Definition of a Reportable Serious Adverse Event Expedited Reporting Instructions for NCIC-CTG Investigators Expedited Reporting Instructions for CTSU Investigators NCIC CTG Responsibility for Reporting Serious Adverse Events to the NCI US NCIC CTG Responsibility for Reporting Serious Adverse Events to the Therapeutic Products Directorate (TPD) of Health Canada Reporting Serious Adverse Events to Local Research Ethics Boards PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING Criteria for Discontinuing Protocol Treatment Duration of Protocol Treatment Therapy After Protocol Treatment is Stopped Follow-up Off Protocol Treatment CENTRAL REVIEW PROCEDURES Central Pathology Review Tumour Blocks STATISTICAL CONSIDERATIONS Objectives and Design Primary Endpoints and Analysis Sample Size and Duration of Study Safety Monitoring Interim Analysis PUBLICATION POLICY Authorship of Papers, Meeting Abstracts, Etc Responsibility for Publication Submission of Material for Presentation or Publication ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES Institution Eligibility for Participation Retention of Patient Records and Study Files Regulatory Requirements REB (Research Ethics Board) Approval for Protocols Informed Consent Centre Performance Monitoring On-Site Monitoring/Auditing Case Report Forms Data Submission Data Reporting Cooperative Research and Development Agreement (CRADA) / Clinical Trials Agreement (CTA) REFERENCES...49 CONFIDENTIAL ii CONFIDENTIAL

5 AMENDMENT#3: 2003-DEC-17 APPENDIX I - PATIENT EVALUATION FLOW SHEET...52 APPENDIX II - PERFORMANCE STATUS (ECOG)...53 APPENDIX III - DOCUMENTATION FOR STUDY...54 APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS VERSION APPENDIX V - TNM STAGING AND NODE MAP...56 APPENDIX VI - CORRELATIVE STUDIES...59 APPENDIX VII - SAMPLE CONSENT FORMS...61 ENGLISH Sample Consent Form...61 FRENCH Sample Consent Form...72 LIST OF CONTACTS...Final Page CONFIDENTIAL iii CONFIDENTIAL

6 AMENDMENT#2: 2003-OCT-01; AMENDMENT#3: 2003-DEC-17; AMENDMENT #4: 2005-JAN-03 TREATMENT SCHEMA This is a multi-centre, prospective, randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor antagonist ZD1839 (IRESSA) in completely resected primary stage IB, II and IIIA non-small cell lung cancer patients. Stratification: Stage (IB, II, IIIA) Histological Subtype (squamous cell versus other) Post-operative radiotherapy (given versus not given) Gender (female versus male) Prior adjuvant platinum-based chemotherapy (given versus not given) Randomization (within 16 or 26 weeks** of surgical resection) ARM 1 - ZD1839 (IRESSA) ARM 2 - Placebo Dosage: 250 mg Route: po Schedule: Daily Duration: 2 years Dosage: 0 (zero) mg Route: po Schedule: Daily Duration: 2 years Planned Sample Size: 1242 ** Prior adjuvant platinum-based chemotherapy is allowed post-operatively: if given, patient must be randomized within 26 weeks of surgical resection if NOT given, patient must be randomized within 16 weeks of surgical resection Endpoints: Overall survival Disease-free survival Prognostic significance of EGFR expression, phosphorylation and mutations when present in the primary tumour Ability of the above to predict the impact of ZD1839 (IRESSA) on survival Toxicity CONFIDENTIAL 1 CONFIDENTIAL

7 1.0 OBJECTIVES 1.1 Primary Objective To assess, in comparison with placebo, the impact of adjuvant therapy with two years of daily oral ZD1839 (IRESSA) on the overall survival of patients with completely resected (T1N1-2, T2N0-2, T3N0-2) non-small cell lung cancer (NSCLC). 1.2 Secondary Objectives To compare the disease-free survival in the placebo arm to the ZD1839 (IRESSA) arm. To confirm the prognostic significance of EGFR expression, phosphorylation and mutations when present in the primary tumour. To assess the ability of EGFR expression, phosphorylation and mutations in the primary tumour to predict the relative impact of ZD1839 (IRESSA) on survival. To establish a comprehensive tumour bank linked to a clinical database for the further study of molecular markers in resected NSCLC. To further evaluate toxicity related to ZD1839 (IRESSA). CONFIDENTIAL 2 CONFIDENTIAL

8 2.0 BACKGROUND INFORMATION AND RATIONALE Lung Cancer Lung cancer is the second most common cancer in both men and women in North America, but is the most common cause of cancer-related mortality in both sexes. It accounts for approximately 30% of all cancer deaths, with 180,000 individuals in North America expected to develop lung cancer in year 2000, and 172,000 expected to die from this disease (1). Although incidence and death rates have stabilized and are falling slowly especially among males, death from lung cancer is still greater than that from the next three cancers (breast, colon and prostate) combined. It is expected that this pattern will remain for the next few decades. The development of lung cancer is clearly related to smoking. However, the absence of effective education and smoking cessation programs to date, and the increased use of tobacco by the teen-age population particularly young women, indicate that lung cancer will continue to be a health issue of critical importance well into the next decade. Based on clinicopathological features and treatment strategy, lung cancer can be broadly divided into two categories: small cell (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for 75-80% of all pulmonary neoplasms, and is composed of several histological subtypes. The major ones are squamous cell carcinoma (SQCC), adenocarcinoma (ADC) and large cell undifferentiated carcinoma (LCUC). Currently in North America, ADC is seen most frequently in up to 35% of patients followed by SQCC (30%) and LCUC (10-15%) (2). The primary treatment of early stage (I-II) NSCLC is curative surgery, but only ~30% of patients present at these stages. With intensive efforts being devoted to the improvement of early detection techniques, however, the percentage of early stage NSCLC patients is expected to increase (3). Stage is the most important determinant of survival in NSCLC. The 5-year survival rate for completely resected Stage I is ~70% (60% for Stage IB), but falls to 40% for patients who have first level nodal involvement (Stage II) (4). At this time, patients with Stages I and II NSCLC do not receive adjuvant therapy after surgery. Practice patterns vary in patients with stage IIIa disease, with many patients receiving neoadjuvant chemotherapy. Although some studies have demonstrated a definite biologic effect for adjuvant chemotherapy, the survival gains were modest at best, and frequently the benefit is reflected only in median survival, without a long-term benefit. However, a recent meta-analysis (4) showed that the addition of cisplatin-based chemotherapy to surgery contributes significantly to survival with a hazard ratio of 0.87, equal to an absolute benefit of 5% at 5 years. Despite this, the administration of adjuvant chemotherapy is not considered to be standard practice in North America. Adjuvant Chemotherapy for Non-Small Cell Lung Cancer The poor survival rates following surgical resection for patients with stage II and III disease have led several groups to investigate the usefulness of adjuvant chemotherapy after complete or partial resection of NSCLC. The likelihood of adjuvant therapy prolonging disease-free or overall survival is based on an number of hypotheses which include: 1) there is an inverse relationship between cell number and curability (5) ; 2) when a tumour is small the growth fraction is large and the fractional kill is greater than in larger tumours (6) ; 3) that drug-resistant cells emerge as tumour burden increases and therefore therapy is most likely to work in the setting of minimal tumour burden (7). There is data to support that clinically these hypotheses may be valid in the adjuvant treatment of NSCLC. It is known from numerous trials of induction chemotherapy in locally advanced NSCLC that response rates are higher in earlier stage disease than in metastatic (Stage IV) disease. Furthermore, in the meta-analyses mentioned below there was a survival advantage for patients receiving chemotherapy in early stage disease after chemotherapy. Finally, in patients with other solid tumours (breast, prostate, colon) chemotherapy and hormonal therapy, which may have low response rates and are not curative in metastatic disease, have been shown to improve disease-free and overall survival when given adjuvantly (8). CONFIDENTIAL 3 CONFIDENTIAL

9 AMENDMENT#2: 2003-OCT-01 The most active regimens result in responses in only 30 to 40 percent of patients with advanced disease, and complete clinical responses are rare. It is not surprising, therefore, that a major survival advantage has not been seen in most of the prospective randomized trials of adjuvant therapy to date. The results from several prospective trials of adjuvant chemotherapy are summarized in Randomized Trials of Adjuvant Chemotherapy in NSCLC Table below. The LCSG was formed in 1977 to evaluate the role of adjuvant therapy after surgery for NSCLC. The trials undertaken by this group are particularly important because all patients underwent meticulous mediastinal node sampling at the time of surgery to allow for precise staging. The first chemotherapy trial of the LCSG evaluated postoperative cyclophosphamide, doxorubicin, and cisplatin (CAP) or immunotherapy with bacillus Calmette-Guérin (BCG) in patients with completely resected stage II or III adenocarcinoma or large cell undifferentiated carcinoma (9). The recurrence rate was significantly lower in the chemotherapeutic arm. The median survival was approximately 7 months longer, and the 2-year survival rate was also greater, although this did not reach statistical significance by the two-sided logrank test. This trial has been criticized because it did not have a no-therapy control arm. Randomized Trials of Adjuvant Chemotherapy in NSCLC Author Stage Treatment No. of Median Survival Patients Survival 1 yr 2 yrs 3 yrs Holmes et al, 1986 (9) Lad et al, 1988 (10) Niiranen et al, 1992 (11) Feld et al, 1993 (12) Ohta et al, 1993 (13) Dautzenberg et al, 1995 (14) Wada et al, 1996 (15) Keller et al, 2000 (16) Le Chevalier et al, 2003 (40) Completely resected Stage II-III Incompletely resected Stage I-III Completely resected T1-3N0 Completely resected T2N0, T1N1 Completely resected Stage III Completely resected Stage I-III Completely resected Stage I-III Completely resected Stage II-III Completely resected Stage I-III CAP BCG CAP-RT RT CAP No Rx CAP No Rx VdsP No Rx COPAC and RT RT CVUft Uft No Rx EP-RT RT CEVVV No Rx mos 16 mos 20 mos 13 mos 5+ yrs 7+ yrs 76 mos 83 mos 31 mos 37 mos 1.3/1.2 yrs* 2.1/0.8 yrs* mos 39 mos % 64% 60% 54% % 88% % 30% 41% 32% % 73% /36%* 54/22%* % 67% % 20% 67% (5 yrs) 56% (5 yrs) 60% (5 yrs) 52% (5 yrs) 35% (5 yrs) 41% (5 yrs) 17/19%* 34/6%* 61% (5 yrs) 64% (5 yrs) 49% (5 yrs) 37% (5 yrs) 40% (5 yrs) 45% (5 yrs) 40% (5 yrs) CAP: Cyclophosphamide, doxorubicin, cisplatin BCG: Bacillus Calmette et Guerin RT: Radiotherapy No Rx: No treatment control arm VdsP: Vindesine, cisplatin COPAC: Cyclophosphamide, doxorubicin, cisplatin, vincristine, lomustine CVUft: Cisplatin, vindesine, tegafur, uracil Uft: Tegafur, uracil EP: Etoposide and cisplatin CEVVV: Cisplatin and etoposide or vinorelbine or vinblastine or vindesine *stage I-II/stage III CONFIDENTIAL 4 CONFIDENTIAL

10 AMENDMENT#2: 2003-OCT-01 In another trial, the LCSG also observed a benefit in patients with incompletely resected tumours who received postoperative CAP and radiotherapy compared with those treated with radiotherapy alone (10). Once again, the median survival time was prolonged by approximately 7 months, but the 3- year survival rate was equal in both arms. The last LCSG study evaluated the usefulness of CAP chemotherapy following complete resection of early stage tumours (T1N1 and T2N0) compared with no additional therapy. This study was disappointing because no improvement was seen for patients treated with CAP with respect to either the median survival or long-term survival time (12). The Finnish lung cancer group undertook a similar trial of adjuvant CAP chemotherapy in patients with early stage (T1-3N0) NSCLC (11). In contrast to the last LCSG study reported by Feld et al. (12), this study did demonstrate a survival advantage for patients in the chemotherapy arm at 5 and 10 years (P = 0.05). The greatest benefit was seen in patients with T2N0 tumours, but because of the small number of patients in this subgroup, the difference did not reach statistical significance (72.5 percent versus 50.3 percent; P = 0.15). The CAP regimen was expanded to include vincristine and lomustine (COPAC) in a multicentre French trial (14). At a minimum follow-up time of six years, no difference in either disease-free or overall survival was seen between the group who received thoracic radiotherapy alone, or three courses of COPAC followed by radiation. When these trials were designed up to 20 years ago, CAP chemotherapy was the most active regimen available for the treatment of non-small cell lung cancer. However, a National Cancer Institute of Canada (NCIC) study demonstrated a higher response rate and longer survival for patients with advanced disease who received vindesine and high-dose cisplatin compared to CAP (17). In a Japanese study (15), three cycles of vindesine and low-dose cisplatin, 50 mg/m 2 were administered, followed by one year of tegafur and uracil. The control arms received either one year of uracil alone or no therapy. The five-year survival rates for the chemotherapy and uracil groups were 60.6% and 64.1% respectively, compared to 49% for the no-treatment group (p=0.053, log-rank, and p=0.044, Wilcoxon). A comparison of the overall survival of the two treatment arms combined with that of the surgery alone group showed a significant advantage for treatment (p=0.022). In another Japanese trial limited to patients with completely resected stage III tumours, post-operative vindesine and cisplatin was compared to no further treatment (13). Their results were similar to those of the LCSG trials in that the median survival was prolonged by approximately six months, but long-term survival was not significantly improved (5-year rates 41% and 35%). In a US Intergroup study lead by the Eastern Cooperative Oncology group (16), 488 patients with completely resected Stage II or IIIA tumours were randomized to receive postoperative etoposide and cisplatin plus thoracic radiotherapy or radiotherapy alone. The median survival for the chemotherapy group was 38 months compared to 39 months for the radiation-alone group (P=0.56). Although some of the studies discussed above demonstrated a definite biologic effect for adjuvant chemotherapy, the survival gains were modest at best, and frequently the benefit was reflected only in median survival, without a long-term benefit. In addition, the CAP generation of studies encountered significant problems with both patient and physician compliance, with the result that only half of the intended chemotherapy was actually administered in most of the trials. Because, with the exception of the US Intergroup study (12), most of the trials were relatively small, they lacked the statistical power to show significant differences. To determine whether small but meaningful survival gains could actually be attributed to the administration of chemotherapy after surgery, a large meta-analysis was performed by the Non-small Cell Lung Cancer Collaborative Group (4). To evaluate the addition of chemotherapy to surgery, 14 trials, which included 4357 patients, were studied. The results for the use of long-term alkylating agents were negative with a combined hazard ratio of 1.15 (p= 0.005). However, for regimens which contained cisplatin, the overall hazard ratio was 0.87 (p=0.08), with an absolute benefit from chemotherapy of three percent at two years, and five percent at five years. When chemotherapy was added to surgery plus thoracic irradiation, the benefits were less, with an overall hazard ratio of 0.94 (p=0.46), and a two percent survival benefit at both two and five years. CONFIDENTIAL 5 CONFIDENTIAL

11 AMENDMENT#2: 2003-OCT-01 On the basis of the results of this meta-analysis, the International Adjuvant Lung Cancer Trial (40) was initiated by the lung cancer group at the Institut Gustave-Roussy in France. This trial spanned at least four continents, and was a trial of novel design. Patients with completely resected stages I, II, and selected IIIA must have received a platinum-based regimen, but the dose of cisplatin could range from mg/m 2, and the second drug could be vinblastine, vindesine, vinorelbine or etoposide according to availability of chemotherapeutic agents in the country where the patient was being treated. Patients must have received an adequate number of treatment cycles to receive a total cisplatin dose of mg/m 2. Radiotherapy could be administered at the discretion of the treating physicians. The trial closed in December, 2000 after accrual of 1867 patients and was recently analyzed at a median follow-up of 56 months. Overall survival was significantly different between the two arms: 2 and 5 year survival rates were 70% and 45% in the treatment arm versus 67% and 40% in the control arm respectively (RR=0.86; CI: , p<0.03). Disease-free survival was also significantly different: 61% and 39% in the treatment arm versus 55% and 34% in the control arm at 2 and 5 years respectively (RR=0.83; CI: , p<0.003). CONFIDENTIAL 5a CONFIDENTIAL

12 AMENDMENT#2: 2003-OCT-01 At least three more large randomized trials of adjuvant chemotherapy from Europe and North America have completed accrual and await analysis. A large European trial with a target accrual goal of 1500 patients was conducted by the EORTC and the Adjuvant Lung Project Italy (ALPI). Patients with completely resected stage I-IIIA tumours were randomized to receive three courses of adjuvant mitomycin C, vinblastine and cisplatin or follow-up alone; radiation was optional. In North America, NCIC-CTG, ECOG, SWOG and CALGB completed a trial of adjuvant cisplatin and vinorelbine for patients with stage I (T2N0), and stage II (excluding T3N0) NSCLC. This trial closed in Spring, Finally, another study of adjuvant vinorelbine and cisplatin was sponsored by Pierre Fabre in France. The trial has also closed, but results have not yet been analysed. While the results of these trials remain eagerly awaited, on the basis of a positive meta-analysis (4) and the apparent confirmatory results of the largest prospective randomized trial reported to-date (40), a change in standard treatment following complete resection of non-small cell lung cancer from observation to adjuvant chemotherapy may be anticipated. However, the poor long-term survival, even of early stage patients, and the modest improvements observed with cytotoxic chemotherapy suggests that novel approaches to adjuvant therapy should still be sought. Rationale for the use of Epidermal Growth Factor Receptor Inhibitors The control of cell growth is mediated by a complex network of signalling pathways responsive to external influences, such as growth factors, as well as internal controls and checks. Epidermal growth factor (EGF) was one of the first growth factors to be described, and was shown to be mitogenic, an effect mediated by the binding of EGF to a cell surface receptor (EGFR). The EGF receptor was the first receptor with a known non-oncogenic function to be described. Subsequent investigations revealed EGFR to be one of a group of closely related receptors now referred to as the EGFR family, which includes EGFR, HER2, HER3 and HER4. These family members are considered to be important in the development, progression and aggressive behaviour of human cancers. EGFR is a transmembrane glycoprotein with a single polypeptide chain of 1186 amino acids (170 kilodaltons) and consists of extracellular, transmembrane and extracellular regions. Known ligands for EGFR include EGF, TGF-α, amphiregulin, epiregulin, heregulin, heparin-binding EGF-like growth factor as well as betacellulin; EGF, TGF-α and amphiregulin bind exclusively to EGFR. The binding of a ligand to the EGFR initiates a cascade of events, the first of which is receptor dimerization, followed by receptor autophosphorylation. Autophosphorylation sites in turn become binding sites for SH2- containing signaling proteins. Dimerization consists of either homodimerization or heterodimerization between various members of the EGFR family of receptors. Signal transduction then proceeds, culminating in nuclear gene activation. Activated EGFR s are internalised and then either degraded or recycled, depending on the ligand bound to the receptor. Extensive cross talk and transactivation occurs between the members of the EGFR family, and the EGFR is believed to be important in multiple signal transduction pathways. EGFR appears to play a critical role in both tumourigenesis and tumour growth, with its effects mediated by receptor overexpression, mutation of receptors with resulting constitutive activation or the presence of autocrine loops with resultant auto-stimulation. EGFR and its ligands have been shown to be overexpressed or to be involved in autocrine growth loops in a number of tumour types, including NSCLC (18,19,20). It is known that overexpression of the EGF receptor in NIH3T3 cells confers a transformed phenotype if ligand for the receptor is present. CONFIDENTIAL 6 CONFIDENTIAL

13 AMENDMENT#2: 2003-OCT-01 Further, the expression of EGFR appears to correlate with radioresistance and lack of apoptosis of murine tumours expressing wild type p53. Increased EGFR expression is frequently noted in epithelial human tumours, most commonly due to gene amplification, but the increase in expression can also be mediated by increased transcription. A number of different deletions of EGFR mrna have been described, including 3 involving the extracellular domain; in type I the extracellular domain is deleted, the receptor cannot bind ligand, but is constitutively activated; type II contains a deletion in domain IV and remains capable of ligand binding and signal transduction; type III is the most common, lacks domains I and II, cannot bind ligand but is constitutively activated and is frequently overexpressed. Receptors that have undergone type III mutations are not internalised and may thus be overexpressed at the cell surface. A number of tumour types including non-small cell lung cancer (NSCLC) have been shown to express truncated EGFR (21). The truncated receptor, especially type III, may also arise through an alternate splicing mechanism in some tumours. The mutated receptor results in increased proliferation and decreased apoptosis in murine models and may confer drug resistance as well as altered sensitivity to some EGFR tyrosine kinase inhibitors. In addition to well-described growth stimulatory effects of EGFR activation (either by overexpression, mutation and constitutive activation or autocrine stimulation as described above), other effects have been described, such as the inhibition of apoptosis. Both EGF and TGF-α are known to induce angiogenesis, and promote invasion. As EGFR appears to play an important role in tumour growth, it has been widely investigated not only as a potential target, but also as a predictor of outcome for patients with early or late stage epithelial malignancies. An increase in EGFR expression appears to correlate with aggressive morphology and poor outcome in NSCLC (22). Other investigators have demonstrated an association between EGFR expression and poor response to therapy (23). Overall, EGFR is believed to play an important role in the development and progression of human epithelial malignancies and be a relevant target for chemotherapeutics. Inhibitors of EGFR tyrosine kinase activity have been in development for a number of years, and while earlier compounds lacked specificity and potency, newer compounds have proven active in preclinical and early clinical studies and are now in late phase clinical development. Reversible inhibitors of EGFR currently include quinazoline based compounds such as ZD1839 (IRESSA), PD and CP-358,774 (OSI-774), pyridopyrimidines (PD158780) and pyrrolopyrimidines such as CPG The quinazoline-based compounds are the most advanced in clinical development. Patients with minimal residual disease are generally considered to be the cohort of patients likely to achieve the most marked benefit with novel compounds such as ZD1839 (IRESSA) when used as monotherapy. Given the poor survival of patients with completely resected NSCLC, the modest improvements observed with adjuvant chemotherapy employing cytotoxic agents, the lack of any currently available effective therapy, the evidence of activity of ZD1839 in NSCLC coupled with an acceptable toxicity profile and an oral route of administration, a study of the compound in the adjuvant setting for patients with resected NSCLC appears appropriate. As the side effects of ZD1839 (IRESSA) are generally considered mild, assessment of quality of life was not felt to be necessary in this adjuvant patient population. CONFIDENTIAL 7 CONFIDENTIAL

14 3.0 BACKGROUND THERAPEUTIC INFORMATION 3.1 Name and Chemical Information ZD1839 (IRESSA ) Chemical name: N-(3-chloro-4-flurophenyl)-7-methoxy-6-(3-morpholiopropoxy)quinazoline-4-amine 3.2 Chemical Structure C 22 H 24 ClFN 4 O Mechanism of Action ZD1839 (IRESSA) has been developed as a signal transduction inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. 3.4 Experimental Antitumour Activity ZD1839 (IRESSA) is a quinazoline-based compound that potently inhibits EGFR tyrosine kinase invitro, and has demonstrable growth inhibitory effects in a number of preclinical models including A431, A549, HT29, LoVo and HX62 xenograft models (24). Interestingly, activity was seen in a murine A431 intracranial model, with significant tumour growth and survival benefit for treated mice (25). As for other EGFR-active agents, inhibition of VEGF, bfgf and angiogenesis has been reported in preclinical models (26). 3.5 Animal Toxicology ZD1839 (IRESSA) showed no genotoxic potential in vitro. The no-effect dose level after administration of ZD1839 (IRESSA) for up to 1 month is 10 mg/kg per day; at 6 months it is 1 mg/kg per day. The predominant and consistent form of toxicity was epithelial and included inflammation of eyelids, folliculitis, and degeneration of hair follicles. The findings at the lowest tested dose level were similar to those in the top and intermediate dose levels when given for longer but were less severe and had a lower incidence. Reversible ocular changes included granular/rough appearance to the cornea and corneal translucency without ulceration. Irreversible corneal opacities were seen only in the dog at the highest dose given chronically for 6 months. Renal papillary necrosis was seen in 7 out of 20 rats given 40 mg/kg/day for 1 month, and 1 out of 6 dogs given the same dose for a month. In addition, ECG recordings revealed a PR interval increase in 2 out of 12 dogs, with large variations between the individual PR interval measurements. A second-degree atrio-ventricular block occurred in one instance; ECG findings returned to normal when therapy was discontinued. The ophthalmologic, renal, and skin changes were considered to be related to the pharmacological activity of ZD1839 (IRESSA). Cardiac change was considered a possible effect of ZD1839 (IRESSA). CONFIDENTIAL 8 CONFIDENTIAL

15 AMENDMENT #4: 2005-JAN-03 Biochemical or hematological abnormalities included increased white blood cells, decreased red cells, reduced plasma albumin, increased plasma liver enzymes (alkaline phosphatase [ALP], alanine transaminase [ALT], and aspartate transaminase [AST]). They were generally reversible on discontinuation of the drug. The ovaries showed a reduction in the number of corporal lutea. In the 1month studies, a dose of 40mg/kg/day produced pathological changes in the ovaries of rats and in the eyes, kidneys and skin of both rats and dogs. Similar changes were detected in the 6-month studies and, in addition, minimal/mild hepatocellular necrosis was also detected, together with increased levels of circulating plasma liver enzymes. These effects showed signs of partial or full reversibility after drug withdrawal. There was evidence of reduced fertility in the female rat at 20 mg/kg/day, as well as slight maternal and fetotoxicity in the rabbit. These changes were all attributed to the pharmacological effects of ZD1839 (IRESSA) on EGF-dependent tissues. Reversible abnormalities of atrio-ventricular conduction were also seen in the dog, at 40 mg/kg/day in the 1- month study and at 15 mg/kg/day in the 6-month study. Data in dog Purkinje fibers indicates that ZD1839 (IRESSA) has a modest potential to affect to re-polarization and hence prolong QT at high plasma concentrations. There is some evidence for in vivo effects, however these were not clear even at the highest dose tested As part of the continuing nonclinical safety evaluation of ZD1839, AstraZeneca completed the in-life part and the necropsy of a 104-week oral carcinogenicity study in rats at doses of 1, 5, and 10 mg/kg/day. The necropsy and histopathogical results revealed an increased incidence of benign liver tumors and mesenteric lymph node hemangiosarcomas. A statistically significant increase in the incidence of hepatocellular adenomas in both male and female rats at 10 mg/kg/day was noted. Other findings included increased numbers of eosinophilic liver cell foci, increased pigment deposits, and decreased bile duct hyperplasia at this same dose level. In addition, a statistically significant increase in the incidence of hemangiosarcoma in the mesenteric lymph nodes was reported in female rats at the 10 mg/kg/day dose level. There was no evidence that either the benign liver cell tumor or mesenteric lymph node hemangiosarcoma were the cause of death of any study animal. Pharmacokinetic studies indicate that exposures achieved in rats given 10 mg/kg/day dose could be achieved in some patients treated with ZD mg daily. 3.6 Phase I Trials Phase I clinical trials have now confirmed the anti-tumour activity of ZD1839 (IRESSA) and its mild toxicity profile (27). Three trials treated 89 patients with advanced, recurrent, previously treated nonsmall cell lung cancer with ZD1839 (IRESSA) at doses ranging from 150mg to 1000 mg. (28,29,30). Durable objective partial responses in measurable disease were observed, as well as tumour reduction in evaluable sites, and stable or improved disease accompanied by rapid symptom relief. Radiographic response was evident in 8 patients: 8 patients (with doses of mg) showed partial responses in measurable disease for months, and 4 more patients had significant reductions of disease. Three patients had stable disease. No dose-response effect was seen for ZD1839 (IRESSA) as responses were seen at all doses, even those as low as 150 mg. Response and improvement were accompanied by improvement in symptoms such as cough and shortness of breath as measured by the Lung Cancer Symptom Scale in the FACT-L. These results are quite remarkable for two reasons. First, most of these patients had been heavily pre-treated, and response in this patient population is almost never expected. Secondly, agents such as ZD1839 (IRESSA) were expected to be cytostatic rather than cytotoxic. In view of these data and the frequency of EGFR over-expression, its clinical evaluation in non-small cell lung cancer is grounded in a strong biological rationale. CONFIDENTIAL 9 CONFIDENTIAL

16 AMENDMENT #4: 2005-JAN-03 To work most effectively, continuous receptor inhibition by ZD1839 (IRESSA) may be required. Available clinical data suggest that ZD1839 (IRESSA) administered at doses less than 600 mg daily for prolonged periods is well tolerated (27). Phase I/II clinical trials in over 250 patients have reported reversible follicular skin rash, and mild diarrhea. However, diarrhea is dose limiting at 1000 mg. Prolonged administration studies are still on going. One hundred and forty-four patients with a wide variety of cancers have received ZD1839 (IRESSA) for up to 3 months; 25 have been on treatment for 4-6 months, and 7 patients have been treated for longer than 1 year (27). Overall the types and frequencies of all adverse events of any causality reported while taking ZD1839 (IRESSA) included: diarrhea ~50%, rash~50%, tumour-related pain~35%, asthenia~35%, nausea~33%, vomiting~25% and anorexia~15%. There was no evidence of cumulative toxicity at any dose level. Skin toxicity consists mainly of a CTC grade 1-2 pustular rash on an erythematous base; gastrointestinal toxicity consists mainly of CTC grade 1-2 loose or watery, intermittent, non-bloody, non-mucoid stools, occasionally with nausea or isolated episodes of emesis. Overall, the frequency of skin or diarrheal toxicity is greater in the continuous daily dosing schedule compared to the 14-day intermittent schedule (48% versus 35% for skin, and 44% versus 31% for diarrhea, respectively). The majority of patients with rash at higher doses also experienced diarrhea. Skin, gastrointestinal, and the rare hepatic toxicity rapidly reverse with drug discontinuation and/or symptomatic support. Among 203 patients treated with continuous or intermittent monotherapy and monitored with ECG s and vital signs taken every 1-2 weeks, no significant or consistent cardiovascular finding was seen. Consistent or drug related hematopoietic, renal, and corneal toxicity have not occurred. Uveitis occurred in one patient. In 2 continuous monotherapy trials, 8.2% of the patients experienced mild, transient adverse events related to the eye which were considered to be possibly related to trial therapy (eg, transient redness or itchiness). Six patients developed ocular toxicity characterized by pain or erythema that was associated with aberrant lash growth in 4 patients. Removal of eyelash was associated with rapid reversal of symptoms and signs. CONFIDENTIAL 9a CONFIDENTIAL

17 AMENDED: 02-NOV-14; AMENDMENT #4: 2005-JAN Phase II/III Trials The efficacy of ZD1839 (IRESSA) alone and in combination with chemotherapy has been studied in phase II/III trials in patients with advanced NSCLC. In the second/third line setting, ZD1839 (IRESSA) resulted in 18% response at doses of 250 and 500 mg. Furthermore at the 250 mg dose, less than 2% of patients discontinued therapy because of adverse drug-related events (31). Studies of First-line Treatment in Combination with Chemotherapy - Two large randomized placebo trials were conducted in patients with stage III and IV non-small cell lung cancer who had not received chemotherapy. Two thousand on hundred thirty patients were randomized to receive ZD mg daily., ZD mg daily, or placebo in combination with platinum-based chemotherapy regimens. The chemotherapies given in these first-line trials were gemcitabine and cisplatin (N=1093 patients) or carboplatin and paclitaxel (N=1037 patients). The addition of ZD 1839 did not demonstrate any increase in tumour response rates, time to progression, or overall survival. Thus, results from the two large, controlled, randomized trials showed no benefit from adding ZD1839 to chemotherapy with platinum and one other chemotherapy drug in first-line treatment of non-small cell lung cancer. The adverse events ZD 1839 added to chemotherapy were comparable to chemotherapy alone with the exception of more frequent occurrences of skin rash, pruritus and diarrhea, which are expected adverse events associated with ZD1839. As of the end of 2001, over 9,500 patients have received ZD1839 (IRESSA). The majority of exposure has been in the expanded access programme (5,600) in the US, and as compassionate use in the rest of the world (820). A total of 960 patients (714 cancer patients, and 246 healthy volunteers) were exposed to ZD1839 (IRESSA) in the 20 completed monotherapy trials in advanced NSCLC. Over 2,000 patients were recruited into the Phase III NSCLC trials in combination with chemotherapy (either gemcitabine/cisplatin or paclitaxel/carboplatin) for previously untreated patients. The IRESSA Survival Evaluation in Lung cancer (ISEL) trial investigated the survival benefit of ZD1839 (IRESSA) 250 mg daily as monotherapy compared to placebo in patients with advanced NSCLC after failure of one or more lines of chemotherapy. The analysis of the primary endpoint of survival in 1692 randomized patients showed that ZD1839 (IRESSA) failed to significantly prolong survival in comparison to placebo in the overall population (HR 0.89, p=0.11, median 5.6 vs 5.1 months), or in patients with adenocarcinoma (HR 0.83, p=0.07, median 6.3 vs 5.4 months). There was a statistically significant improvement in tumour shrinkage (8.2% unconfirmed objective response rate for IRESSA), which did not translate into a statistically significant survival benefit. 3.8 Expected Possible Drug-Related Adverse Events The following table shows expected possible drug related adverse events with ZD1839 (IRESSA) as Monotherapy (27) CONFIDENTIAL 10 CONFIDENTIAL

18 AMENDED: 02-NOV-14; AMENDMENT#2: 2003-OCT-01; AMENDMENT #4: 2005-JAN-03 Frequency Body system Drug-related adverse event Very common (>10%) Common (>1 to 10%) Uncommon (> 0.1 to 1%) Rare (> 0.01 to 0.1%) Very Rare (<0.01%) Digestive Skin and appendages Digestive Metabolic and nutritional Diarrhea, mainly mild in nature (CTC grade 1), and less commonly, moderate (CTC grade 2). There have been isolated reports of severe (CTC grade 3) diarrhea with dehydration. Nausea, mainly mild in nature (CTC grade 1). Skin reactions, mainly a mild or moderate (CTC grade 1 or 2) pustular rash, sometimes itchy with dry skin, on an erythematous base. Vomiting, mainly mild or moderate in nature (CTC grade 1 or 2). Anorexia, mild or moderate in nature (CTC grade 1 or 2). Stomatitis, predominantly mild in nature (CTC grade 1). Dehydration, secondary to diarrhea, nausea, vomiting or anorexia. Liver function abnormalities, consisting mainly of asymptomatic mild or moderate elevations in transaminases (CTC grade 1 or 2). Skin and appendages Nail disorder. Alopecia Whole body Asthenia, predominantly mild in nature (CTC grade 1). Hemic and lymphatic Hemorrhage (such as epitaxis and hematuria) Ophthalmological Conjunctivitis and blepharitis, mainly mild in nature (CTC grade 1) Hemic and lymphatic Ophthalmological Interstitial Lung Disease Digestive Skin and appendages Renal INR elevations and/or bleeding events in some patients taking warfarin or other coumarin derivatives. Corneal erosion, reversible, and sometimes in association with aberrant eyelash growth. Acute onset of dyspnea, sometimes associated with cough or low grade fever. Radiology may show pulmonary infiltrates or shadowing in the absence of infection. Patients in respiratory distress may respond to corticosteroids, however distress may be fatal. Pancreatitis Isolated reports of toxic epidermal necrolysis and erythema multiforme and Stevens-Johnson syndrome Renal insufficiency with elevated serum creatinine and blood urea nitrogen Skin and appendages Allergic reactions, including angioedema and urticaria There have been a total of 12 incidences of CNS hemorrhage reported among patients on NCI sponsored studies of ZD1839. There have been five reports of CNS hemorrhage of the 48 patients enrolled in the pediatric studies, four events, including one fatality, occurred among 33 patients enrolled on a study of concurrent ZD1839 and radiation followed by ZD1839, and one event occurred in a patient with ependymoma receiving single agent ZD1839. There have been 7 patients with CNS hemorrhages into primary or metastatic tumours reported among 1355 patients enrolled in the adult studies. Four adult patients with hemorrhage had gliomas out of a total of 290 patients enrolled in the glioma studies. CONFIDENTIAL 11 CONFIDENTIAL

19 3.9 Pharmacokinetic Studies In healthy volunteers oral ZD1839 (IRESSA) is well absorbed, with an absolute bioavailability of about 60%, and has been shown to be both extensively distributed outside the central compartment and rapidly cleared. Absorption is moderately slow with plasma concentrations typically reaching a maximum at between 3 to 7 hours after dosing. Beyond the peak, the concentrations decline in a biphasic manner, with a terminal half-life of between 10 and 83 hours. Exposure has shown up to a 20-fold range at the same dose level and was not dose proportional over the dose range 50 to 500 mg with a greater than expected increase in exposure in some volunteers at the highest dose. However, the maximum degree of non-proportionality observed was only about 2 fold. On multiple dosing (utilising a double dose on day 1), exposure increased 1.3 to 2.8 fold with steady state achieved between day 3 and 5. In the fed state there was a small reduction in exposure that is not considered to be clinically significant. The major route of elimination for ZD1839 (IRESSA) and its metabolites is via the faecal route (<4% of a radiolabelled dose was excreted via the urinary route). CONFIDENTIAL 11a CONFIDENTIAL

20 In cancer patients, there was up to a 11-fold range in exposure was observed within a dose group. Despite this variability, exposure did show an increase with dose across the dose range studied of 50 to 700 mg. The terminal half-life in cancer patients ranged from 27 to 85 hours. Steady state was achieved within the first week of dosing with the variability in steady state trough concentrations within an individual patient being typically 4 to 35%. The metabolism of ZD1839 (IRESSA) has not yet been elucidated although in vitro data indicated the involvement of the cytochrome P450 CYP3A4. A trial in healthy volunteers, who received a low dose, 50 mg, of ZD1839 (IRESSA) alone and in combination with itraconazole (a potent CYP3A4 inhibitor), demonstrated that the mean AUC for ZD1839 (IRESSA) was increased by only 30% in the presence of itraconazole. However the combination of a single dose of 500 mg ZD1839 (IRESSA) with rifampicin, a potent CYP 3A4 inducer, resulted in a 6-fold reduction in mean AUC to ZD1839 (IRESSA) which was considered to be clinically significant. Steady-state plasma concentrations are achieved by Day 7 to 10, which is consistent with the mean terminal half-life of 48 hours. Inter-individual variability in exposure is in a 16-fold range whilst within an individual they span 1- to 3- fold. The exposure increases proportionally with dose. None of the 5 identified circulating metabolites is thought to contribute significantly to the overall pharmacological activity of ZD1839 (IRESSA). CYP3A4 is believed to be involved in the metabolism of ZD1839 (IRESSA). ZD1839 (IRESSA) does not induce any major cytochrome P450 enzymes. Interaction studies demonstrated that exposure was increased by approximately 80% in the presence of itraconazole, a potent CYP3A4 inhibitor. The increase may be clinically relevant since adverse experiences are related to dose and exposure. The combination of ZD1839 (IRESSA) with rifampicin, a potent CYP3A4 inducer, resulted in an 83% reduction in the exposure. Thus, co-administration with other CYP3A4 inducers (eg. Phenytoin, carbamazepine, barbiturates, or St John s Wort) may potentially reduce efficacy. In vitro data showed that ZD1839 (IRESSA) may weakly inhibit CYP2D6. An interaction study with metroprolol, a CYP2D6 substrate, demonstrated only a small effect on ZD1839 (IRESSA) on metroprolol exposure. The change is not considered to be clinically relevant and suggests little potential for interactions with drugs metabolized by this CYP Pharmaceutical Data Supplied: AstraZeneca (Pharmaceutical Company) will supply ZD1839 (IRESSA) (NSC / IND #61187) and matching placebo free-of-charge to study participants. This will be distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). The tablet is supplied as a brown capsule shaped tablet 14.5 x 7.25mm. Excipients present in ZD1839 (IRESSA) or Placebo tablets: Lactose monohydrate, cellulose microcrystalline, croscarmellose sodium, povidone, sodium lauryl sulphate, magnesium stearate and purified water. CONFIDENTIAL 12 CONFIDENTIAL