abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of.
Trial Report Afatinib (BIBW 2992) 1 of 6 Disclosure Synopsis 06 Aug 2013 Trial No. / U No.: 1200.44 / Date of trial: 30 SEP 2009 28 AUG 2011 Date of revision: Proprietary confidential information 2013 International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Title of trial: A neoadjuvant, randomized, open-label Phase II trial of BIBW 2992 versus trastuzumab versus lapatinib in patients with locally advanced HER2 positive breast cancer Coordinating Investigator: MD Trial sites: Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: planned: Total of 16 centers: 15 centers in Latin America (Brazil, Colombia, and Peru) and 1 center in the United States Not applicable II To evaluate the efficacy and safety of afatinib versus trastuzumab and lapatinib in women with HER2 - positive treatment-naïve Stage IIIa, b, or c locally advanced breast cancer Open-label, randomized, multicenter study consisting of a screening period (Day -14 to Day -1), followed by a 6-week treatment period (two continuous 21-day courses of afatinib or lapatinib, or weekly infusions of trastuzumab), and a follow-up visit (28 ±7 days after end-of-treatment [EOT] visit). Up to 120 (40 per treatment group) actual: Screened (Enrolled): 73; Randomized: 29 Diagnosis and main criteria for inclusion: Afatinib: 10 randomized; 10 treated (analyzed for primary endpoint) Lapatinib: 8 randomized; 8 treated (analyzed for primary endpoint) Trastuzumab: 11 randomized; 11 treated (analyzed for primary endpoint) Women 18 years of age with locally advanced, non-metastatic, HER2 positive, Stage III breast cancer (including Stage IIIa, b, and c and inflammatory breast cancer), with ECOG score of 0 or 1, and no prior treatment
Afatinib (BIBW 2992) 2 of 6 Test products: Afatinib (BIBW 2992) dose: mode of admin.: batch no.: Reference therapy: dose: mode of admin.: Afatinib: 50 mg daily oral tablet Afatinib: B093000368, B093000369, B103000456 Trastuzumab 2 mg/kg weekly, following an initial loading dose of 4 mg/kg intravenous infusion batch no.: B093000372, B093000396, B093000397, B093000423, B093000442, B093000456 Reference therapy: dose: mode of admin.: batch no.: Duration of treatment: Criteria for evaluation: Efficacy / clinical pharmacology: Lapatinib 1500 mg daily oral tablet (250 mg per tablet) B093000371, B093000826, B103000457, R453421 (commercial source), R477992 (commercial source) 6 weeks Primary endpoint: Objective Response (OR; Complete response [CR] or Partial Response [PR]) Secondary endpoints: Clinical benefit (Complete Response, Partial Response, and Stable Disease [SD] as determined by RECIST 1.0 criteria) The sum of the longest diameters of the target lesions at three and at six weeks Biomarkers (from biopsy tissue): Phospho-MAP-Kinase (MAPK) Total MAPK expression EGFR, HER2 Phospho-EGFR and -HER2 Proliferation marker (Ki67 and p27)
Afatinib (BIBW 2992) 3 of 6 Safety: Statistical methods: SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: Apoptotic index (cleaved caspase 3) Phosphate and tensin homolog (PTEN) HER2 homodimerisation by HERmark assay Phospho AKT Afatinib pharmacokinetics (PK) Adverse events (AE), NCI common terminology criteria for AEs (CTCAE Version 3.0), laboratory evaluation, patient performance, cardiac left ventricular function The OR according to the RECIST 1.0 criteria was estimated along with the exact 95% Clopper-Pearson confidence interval for each treatment regiment. Fisher s exact test was used to compare overall response rate (ORR) between treatment groups: afatinib vs. trastuzumab and afatinib vs. lapatinib. Because the trial was exploratory, no adjustment was made for the multiple treatment comparisons. The sample size calculation (40 patients per group) was based on Sargent and Goldberg design to have a 90% chance of observing afatinib ORR larger than trastuzumab or lapatinib. (sponsor) terminated the trial due to a high screen-failure rate and challenges with recruitment. Due to the small sample size, the results were interpreted with caution; however, findings are provided below. All 29 randomized patients (10 afatinib, 8 lapatinib, and 11 trastuzumab) with locally advanced breast cancer were treated and included in the primary efficacy analysis, safety analyses, biomarker, and PK analyses. Efficacy results Eight patients (80.0%) treated with afatinib experienced an OR at any time during the study compared with 6 (75.0%) lapatinib and 4 (36.4%) trastuzumabtreated patients. Of the patients with an OR, all had a PR as the best overall tumor response; no patients presented with a CR at any time during the 6-week study. All remaining patients had SD as the best overall response (afatinib [2 (20.0%)], lapatinib [2 (25.0%)], trastuzumab [7 (63.6%)]). All patients experienced a clinical benefit (CR, PR, or SD) as the best overall response at any time during the study. Objective response according to RECIST 1.0 criteria was also determined at
Afatinib (BIBW 2992) 4 of 6 Safety results: Week 3 and Week 6 to assess tumor response over time. Five (50.0%) patients treated with afatinib had a PR at Week 3 compared with 2 (25%) lapatinib and 2 (18.2%) trastuzumab-treated patients. At Week 6, 7 (70.0%) patients treated with afatinib had a PR compared with 6 (75.0%) lapatinib and 4 (36.4%) trastuzumab-treated patients. One afatinib-treated patient was not included in the Week 6 analysis after permanently discontinuing study medication on Day 11 due to an adverse event; the EOT tumor assessment showed a PR. There was no evidence of progressive disease in any afatinib-treated patient at any time during the study. One (12.5%) lapatinib and 1 (9.1%) trastuzumabtreated patient showed evidence of progressive disease at Week 6. The lapatinibtreated patient, who had stable disease at Week 3, presented with an increase in size of the primary lesion at Week 6. The trastuzumab-treated patient, who had stable disease at Week 3, presented with a new lesion at the EOT visit. Biomarkers The small number of available biomarker samples in this study did not allow for a correlation analysis between EGFR expression and clinical response to ErbB targeting agents. Assessment of HER2 dimerization as a surrogate for functional activation demonstrated that dimerization was increased 2 to 10-fold in the lapatinib group and consistently decreased in the afatinib group; no trend was observed in the trastuzumab group. No correlation was noted between pher2 status and dimerization status, and no meaningful differences were observed for any of the additional biomarkers probably due to the small sample size as well as the inter-patient variability on the baseline expression for some of the markers. Pharmacokinetics Pharmacokinetics were examined for afatinib only. Steady state seemed to be reached at Day 8 in patients who received afatinib 50 mg, and pre-dose plasma concentrations appeared to remain stable over the observed treatment periods. The overall variability of pre-dose plasma concentrations of patients receiving 50 mg was moderate to high, with gcv values of 35.6% to 74.7%. Exposure All but one patient (afatinib) completed study treatment; the overall median exposure to study medication was 45 days. Adverse events Adverse events were reported for all patients treated with afatinib and lapatinib; 72.7% of patients treated with trastuzumab reported AEs. Adverse events
Afatinib (BIBW 2992) 5 of 6 considered to be related to study medication were reported for all 10 patients treated with afatinib compared with 6 (75.0%) lapatinib and 5 (45.5%) trastuzumab-treated patients. No serious adverse events or fatal events were reported in any treatment group during the study. Adverse events in the gastrointestinal disorders system organ class (SOC) (100%), skin and subcutaneous tissue disorders SOC (100%), and infections and infestations SOC (80%) were reported more frequently with afatinib therapy. Diarrhea (100%), dermatitis acneiform (60.0%), paronychia (50.0%), mucosal inflammation (40.0%), and rash (30.0%) were the most frequently occurring AEs with afatinib therapy. A lower proportion of lapatinib and trastuzumab-treated patients experienced these events (diarrhea: 37.5% lapatinib, 9.1% trastuzumab; dermatitis acneiform: 0% lapatinib, 0% trastuzumab; paronychia: 0% lapatinib, 0% trastuzumab; mucosal inflammation: 0% lapatinib, 9.1% trastuzumab; rash: 12.5% lapatinib, 0% trastuzumab). Patients treated with afatinib reported fewer headaches (20.0%), nausea (10.0%) and arthralgia (0%) compared with patients treated with trastuzumab (headache 36.4%; nausea 27.3%; arthralgia 36.4%); patients treated with lapatinib also reported fewer of these events (headache 12.5%; nausea 25.0%; arthralgia 0%). The most frequently occurring drug-related AEs for afatinib therapy included diarrhea (100%), dermatitis acneiform (60.0%), paronychia (50.0%), mucosal inflammation (40.0%), rash (30.0%), and hypocalcaemia (20.0%). Fewer patients treated with lapatinib experienced these drug-related AEs (diarrhea [37.5%], dermatitis acneiform [0%], paronychia [0%], mucosal inflammation [0%], rash [12.5%], and hypocalcaemia [0%]). Arthralgia (18.2%) and vomiting (18.2%) were the AEs most frequently related to trastuzumab therapy. The majority of AEs were assessed as Grade 1 or 2 across all treatment groups. Three (30.0%) patients treated with afatinib experienced events of Grade 3 (diarrhea, dermatitis acneiform, and mucosal inflammation). Two (25.0%) patients treated with lapatinib experienced Grade 3 events (leukopenia, diarrhea); 2 patients treated with lapatinib experienced Grade 4 events of neutropenia. No Grade 4 or 5 adverse events were reported for afatinib or trastuzumab therapies. Adverse events leading to dose reduction were reported in 2 (20.0%) afatinib patients (diarrhea and rash); an additional afatinib-treated patient experienced Grade 3 mucosal inflammation that resulted in dose reduction based on the protocol-specified dose-reduction AE criteria. An AE leading to permanent discontinuation of study medication was reported for one patient treated with
Afatinib (BIBW 2992) 6 of 6 afatinib (dermatitis acneiform). Conclusions: Clinical laboratory and other safety assessments Five patients had Grade 4 decreases in neutrophil counts (absolute) during the study (1 afatinib, 2 lapatinib, and 2 trastuzumab patients); 3 patients had Grade 4 decreases in lymphocytes (absolute) (1 afatinib and 2 trastuzumab). There was no indication of drug-induced liver injury and no patient met the criteria for Hy's law. There were no notable changes from baseline in mean values for vital signs or LVEF. No AEs associated with changes in ECG or physical examinations were reported. Overall, afatinib showed a similar efficacy profile compared to lapatinib, yet better than trastuzumab when comparing best response and objective response at 3 and 6 weeks. However, this conclusion is limited by the small sample size overall and within each treatment group. All three treatments were generally well tolerated, with few drug-related Grade 3 events and no drug-related Grade 4 or 5 events. Overall, more AEs were reported for afatinib; however, no unexpected events were observed for any treatment. No SAEs or deaths were reported. Few dose reductions or discontinuations due to AEs occurred with afatinib therapy. Based on the limited available PK data for afatinib, steady state for afatinib seemed to be attained by Day 8; pre-dose plasma concentrations remained stable over the observed treatment period. The overall variability in plasma concentrations was moderate to high.
BI trial number 1200.44 Trial Synopsis - Appendix Trial Synopsis - Appendix The result table on the following page supplements the trial results presented in the Trial Synopsis. The appended table provides additional results for a secondary endpoint, as summarised below. Results for presented in Change in primary target lesion Table 15.2.3: 1
Page 148 BI Trial No.: 1200.44 1. - 15. CTR Main Part Table 15.2.3: 1 ANCOVA of maximum decrease from baseline in the primary target lesion by Treatment treated set Afa, 50mg Lap, 1500mg Tra, 4mg/kg Number of patients treated 10 (100.0) 8 (100.0) 11 (100.0) Patients with tumor measurements 10 (100.0) 8 (100.0) 11 (100.0) [N (%)] Adjusted mean (mm) decrease from 27.5 ( 5.90) 31.0 ( 6.63) 20.9 ( 5.63) baseline (SE) Adjusted mean difference compared 3.48 6.65 to Afatinib 95% CI 24.4, 17.39 12.5, 25.78 Source data: Appendix 16.2, Listing 6.1.2 ctr15\ancova_max_dfb.sas 13DEC2011