OWa 22 80) :IEZ

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1 Clinical Study Report: Part 2 Date: 22 September 2008 OWa 22 80) :IEZ Page 1 SYNOPSIS Name of the Sponsor: Name of Finished Product: Name of Active Ingredient: Immunex Corporation Panitumumab (ABX-EGF) rhumab-egfr Thousand Oaks CA USA Title of Study: A Clinical Trial of the Safety and Efficacy of ABX-EGF in Combination with Irinotecan, Leucovorin, and 5-Fluourouracil in Subjects with Metastatic Colorectal Cancer - Part 2 Investigator(s) and Study Center(s): Thirty-one investigators in the United States were recruited for participation, of whom 15 enrolled at least 1 subject in Part 2 of the study Publication(s): Patnaik A, Hecht JR, Meropol NJ, et al. Safety profile of panitumumab in metastatic colorectal cancer (mcrc) patients (pts). Abstract to the 1st Conference of the International Society of Gastrointestinal Oncology, July 2004, Washington DC. Berlin J, Posey J, Tchekmedyian S, et al. First line therapy of panitumumab, a fully human antibody, in combination with FOLFIRI for the treatment (txt) of metastatic colorectal cancer (mcrc). Eur J Cancer. 2005;3 su I 2:185a (Abstract 653). Study Period: 19 July 2002 (first subject enrolled) to Development Phase: 06 February 2008 (last subject ended treatment; subject Phase 2 did not return for safety follow-up) Introduction and Objectives: The overall objective of this study was to explore the safety and efficacy of panitumumab in combination with irinotecan/5-fu/leucovorin chemotherapy (the FOLFIRI regimen) as first-line treatment of subjects with metastatic colorectal cancer, complementing previous and ongoing studies using panitumumab as monotherapy. Because both 5-FU and irinotecan share diarrhea as a major side effect, it was of interest to explore the possible effects on the incidence or severity of diarrhea when anitumumab was administered with these drugs. Methodology: Open-label, multicenter, noncomparative study of panitumumab administered with FOLFIRI chemotherapy for untreated metastatic colorectal adenocarcinoma. Subjects received irinotecan, bolus and infusional 5-FU, and leucovorin every other week with panitumumab given at a dose of 2.5 mg/kg once weekly in 6-week cycles until disease progression or other reason for discontinuation. Number of Subjects Planned: 60 Number of Subjects Enrolled: 24 Sex: 14 men (58%), 10 women (42%) Age: Mean (SD) 61 (15) years Ethnicity Race : 18 white (75%), 3 black (13%), 3 other (13%) Diagnosis and Main Criteria for Eligibility: Metastatic adenocarcinoma of the colon or rectum with no prior treatment for disease other than surgery and 5-FU-based adjuvant chemotherapy; immunohistochemical proof of EGFr expression on tumor cells (sum of 1+, 2+, and 3+ staining on at least 10% of evaluated tumor cells); adequate hematologic and organ function; signed infnrmari r.nncant (continued)

2 Clinical Study Report: Part 2 Date: 22 September 2008 Page 2 Investigational Product, Dose and Mode of Administration Panitumumab (rhumab-egfr) 10 mg/ml in 5-mL single-use vials, dosed at 2.5 mg/kg IV using a 0.22-micron filter Duration of Treatment: Panitumumab was administered once weekly until progression of disease or other reason for removal from study Reference Therapy, Dose and Mode of Administration None Primary Endpoint: Incidence of grade 3 and 4 diarrhea Secondary Endpoints: Tumor response, time to progression, progression-free survival, overall survival, safety variables Statistical Methods: Analyses of efficacy and safety were conducted using the Subjects Treated Analysis Set (subjects who received at least 1 dose of panitumumab or I dose of chemotherapy). For the primary endpoint, incidence of grades 3 and 4 diarrhea, 2-sided 95% confidence intervals were calculated. Time-to-event endpoints were estimated using the Kaplan-Meier method. Standard analyses were used for pharmacokinetics. Descriptive statistics were conducted for extent of exposure, incidence of adverse events, laboratory analyte and vital signs changes, and antibody results. Ad hoc analyses and/or separate assessments were conducted on adverse events of special interest (ie, infusion reactions, integument/eye toxicities, cardiotoxicity, pulmonary toxicity, stomatitis, and h oma nesemia. Summary - Results: Subject Disposition: Twenty-four subjects were enrolled among 15 study sites, all of whom received at least 1 dose of panitumumab. Median follow-up time was 22 months (range: 4, 47). Enrollment was prematurely discontinued at 24 of the 60 originally planned subjects. Efficacy Results: The overall objective response rate was 42% (95% Cl: 22, 63). Median time to response was 11 weeks in the 10 subjects who responded, and median duration of response was 42 weeks (95% Cl: 14, NE). Median progression-free survival for the entire population was 47 weeks; time to progression was similar. Median overall survival was 23 months (95% Cl: 14.4, NE). Pharmacokinetic Results: Accumulation of panitumumab was observed after weekly administration of a 2.5 mg/kg dose. AUC was approximately 2.2-fold higher after the sixth dose compared with that after the first dose. Due to the limited sampling schedule, the exact time that panitumumab levels reached steady state cannot be determined. Based on data from week 13 and beyond, the mean panitumumab concentration at steady state was approximately 60 µg/ml before infusion (Ct,ou9h) and was approximately 130 pg/ml after infusion (Cmax). continue

3 Clinical Study Report: Part 2 Date: 22 September 2008 Page 3 Safety Results: Grade 3 and 4 diarrhea, the primary endpoint of the trial, occurred in 25% of subjects (95% Cl: 10, 47), lower than that observed in Part 1 (58%, 95% Cl: 34, 80), in which the IFL regimen was used (Saltz 2000). Overall, 19 subjects (79%) had 1 or more episodes of diarrhea. All 24 subjects experienced at least 1 adverse event; 18 subjects (75%) had an event that was grade 3 or 4. Eleven subjects (46%) experienced an adverse event considered serious. Adverse event was the primary reason or was contributory to treatment discontinuation in 10 subjects (42%). No subject died during the panitumumab treatment period or within 30 days of the last dose of panitumumab. All 24 subjects experienced a treatment-related adverse event; these were generally mild-to-moderate, consisting mainly of events in the Skin and Gastrointestinal system organ classes. No subject was reported to have an adverse event that the investigator described as an infusion reaction. Possible infusion reactions (based on a conservative analysis) occurred in 46% of subjects and in 4% of infusions; these were commonly nausea, vomiting, and dizziness. Only 1 of these reactions occurred in conjunction with the first infusion of panitumumab. Transient fluctuations were seen in vital signs during and postinfusion, particularly in diastolic blood pressure (both increases and decreases). Possible treatment-related laboratory trends included decreases in potassium, calcium, phosphorus, and magnesium. No postexposure serum sample tested seropositive for antibodies to panitumumab.

4 RZ41is/oq Product: Panitumumab Clinical Study Report: Part 1 Date: 4 November 2005 REZ Page 1 SYNOPSIS Name of the Sponsor: Name of Finished Product: Name of Active Ingredient: Immunex Corporation Panitumumab (ABX-EGF) rhumab-egfr Thousand Oaks CA USA Title of Study: A Clinical Trial of the Safety and Efficacy of ABX-EGF in Combination with Irinotecan, Leucovorin, and 5-Fluorouracil in Subjects with Metastatic Colorectal Cancer - Part 1 Investigator(s) and Study Center(s): Thirty-one investigators in the United States were recruited for participation in the study, of whom 8 enrolled at least 1 subject in Part 1. Publication(s): Berlin J, Malik I, Picus J, et al. Panitumumab therapy with irinotecan, 5-fluorouracil, and leucovorin (IFL) in patients (pts) with metastatic colorectal cancer (mcrc). Abstract to the 29th Congress of the European Society for Medical Oncology, October 2004, Vienna Austria. Yang BB, Hecht JR, Malik I, et al. Pharmacokinetics (PK) of panitumumab and irinotecan were not altered after first-line panitumumab therapy with irinotecan, 5-fluorouracil, and leucovorin (IFL) in metastatic colorectal cancer (mcrc) patients (pts). Abstract to the 29th Congress of the European Society for Medical Oncology, October 2004, Vienna Austria. Patnaik A, Hecht JR, Meropol NJ, et al. Safety profile of panitumumab in metastatic colorectal cancer (mcrc) patients (pts). Abstract to the 1 st Conference of the International Society of Gastrointestinal Oncology, July 2004, Washington DC. Study Period: Development Phase: First subject enrolled: 19 July 2002 Phase 2 Last subject completed safety follow-u : 22 January 2004 Introduction and Objectives: The overall objective of this study was to explore the safety and efficacy of panitumumab in combination with standard 5-FU-based chemotherapy as first-line treatment of subjects with metastatic colorectal cancer, complementing previous and ongoing studies using panitumumab as monotherapy. Because both 5-FU and irinotecan share diarrhea as a major side effect, it was of interest to explore the possible potentiation by panitumumab of the incidence or severity of diarrhea in this clinical setting. Methodology: Open-label, multicenter, noncomparative study of panitumumab in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL regimen) for untreated metastatic colorectal carcinoma. Subjects received irinotecan, 5-FU, and leucovorin in 6-week cycles, together with panitumumab 2.5 mg/kg once weekly for up to 48 weeks or until disease progression, intolerable adverse event, or other reason for discontinuation. Number of Subjects Planned: 84 Number of Subjects Enrolled: 19 Sex: 16 men (84%), 3 women (16%) Age: Mean (SD) 57 (12) years Ethnicity Race : 13 white (68%), 4 black (21%), 1 Asian (5%), 1 Hispanic 5% Diagnosis and Main Criteria for Eligibility: Metastatic adenocarcinoma of the colon or rectum with no prior treatment for disease other than surgery and 5-FU-based adjuvant chemotherapy; immunohistochemical detection of EGFr expression on tumor cells (sum of 2+ and 3+ staining on at least 10% of evaluated cells ; adequate hematologic and organ function; signed informed consent (continue

5 Clinical Study Report: Part I Date: 4 November 2005 Page 2 Investigational Product, Dose and Mode of Administration Panitumumab (rhumab-egfr) 10 mg/ml in 5-mL single-use vials, dosed at 2.5 mg/kg IV using a 0.22-micron filter Duration of Treatment: Once weekly for 48 weeks or until disease progression or other reason for treatment discontinuation Reference Therapy, Dose and Mode of Administration None Primary Endpoint: Incidence of grade 3 and grade 4 diarrhea Secondary Endpoints: Tumor response, time to progression, progression-free survival, overall survival, safety variables Statistical Methods: Analyses of efficacy and safety were conducted using the Subjects Treated Analysis Set (all subjects who received at least 1 dose of panitumumab or chemotherapy). For the primary endpoint, incidence of grades 3 and 4 diarrhea, 2-sided 95% confidence intervals were calculated. Time-to-event efficacy endpoints were estimated using the Kaplan-Meier method. Standard analyses were used for pharmacokinetics. Descriptive statistics were calculated for extent of exposure, incidence of adverse events, laboratory analytes, vital signs changes, and antibody results. Ad hoc analyses and/or separate assessments were conducted on adverse events of special interest (ie, infusion reactions, integument/eye toxicities, cardiotoxicity, pulmonary toxicity, stomatitis, and h oma nesemia. Summary - Results: Subject Disposition: Nineteen subjects were enrolled among 8 study sites, all of whom received at least 1 dose of panitumumab. Four subjects (21 %) completed the maximum of 48 weeks of treatment. Major reasons for treatment discontinuation included disease progression (7 subjects, 37%) and adverse event (6 subjects, 32%). Median follow-up time was 16 months (range: 1, 25). Efficacy Results: The overall objective response rate was 47.4% (95% Cl: 24.4, 71.1). Median time to response was 6 weeks in the 9 subjects who responded, and median duration of response was 25 weeks. Median progression-free survival was 24 weeks and median overall survival was 17 months. Pharmacokinetic Results: Due to the limited sampling schedule in this study, the time to PK steady state cannot be accurately measured. Based on data from weeks 13 and beyond, the mean panitumumab concentration at steady state was 40 pg/ml before infusion (trough) and 110 pg/ml after infusion (peak). Panitumumab had no apparent effect on the PK profiles of irinotecan or SN-38 (its major metabolite), which were similar at week 1 (first dose and at week 3 (third dose) and approximated those previously reported. (continued)

6 Clinical Study Report: Part 1 Date: 4 November 2005 Page 3 Safety Results: All 19 subjects experienced at least 1 adverse event during the study. Twelve subjects (63%) had a serious adverse event. Grade 3 or 4 diarrhea was experienced by 58% of subjects (95% Cl: 34, 80). Two subjects died during the panitumumab treatment period for reasons unrelated to study drug. Six subjects (32%) had treatment discontinued due to an adverse event; 5 (26%) were considered related to panitumumab. No subject was reported to have an adverse event that the investigator described as an infusion reaction. Six possible infusion reactions (mostly nausea) occurred in the study (based on a conservative post hoc analysis), representing an incidence of 26% of subjects and 1% of infusions. Transient fluctuations were seen in vital signs during and postinfusion, particularly in diastolic blood pressure (both increases and decreases). However, in only 2 infusions did a clinically significant vital sign change coincide with clinical symptoms of an infusion reaction. Possible treatment-related laboratory trends included decreases in potassium, calcium, and magnesium. No pre- or postdose blood sample tested seropositive for human antibodies to panitumumab.