[PDF] Deckblatt für Report - DIMDI

25482_8O__626_01_2_0_C2362A_20150416123843.pdf

Report according to § 42b (2) German Drug Law

Protocol-No.: BO20906 (BETH)

Study Title: A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients with HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab with Chemotherapy Plus Trastuzumab Plus

Bevacizumab

Date of Report: Final Clinical Study Report 1061423 (December 2014) Primary Clinical Study Report 1056851 (April 2014) Study Sponsor(s) F. Hoffmann-La Roche Ltd, Switzerland (Sponsor in Europe) Study Date: Final Clinical Study Report 1061423 (December 2014):

First Patient Entered: 01 May, 2008

Last Patient Entered: 10 December, 2010

LPLV: 17 April 2014

Database lock: 10 July, 2014

This CSR covers the period from 30 June, 2013 (cut-off for the primary analysis) until LPLV on 17 April 2014. Primary Clinical Study Report 1056851 (April 2014):

First Patient Entered: 01 May, 2008

Last Patient Entered: 10 December, 2010

Clinical Cut

-off: 30 June, 2013

Trial Phase: III

Indication: breast cancer

Name of Finished Product: Avastin

®

Herceptin

® Taxotere ®

Name of Active Substance: Bevacizumab

Trastuzumab Docetaxel

Number of Patients: Planned: 3500

Randomised: 3509 Chemotherapy + Herceptin: N = 1757 ĺ (ĺĺ Chemotherapy + Herceptin + Bevacizumab: N = 1752 ĺ ĺĺ

Disposition of Patients (ITT Population):

Study Interruptions/

Premature end: Study was prematurely ended:

The BO20906 (BETH) study did not meet its primary endpoint of demonstrating a benefit from the addition of bevacizumab to THC (docetaxel, carboplatin, trastuzumab). All patients have been off treatment since December 2011 or before. There were no efficacy benefits accrued to patients with use of bevacizumab and there were no new safety concerns found when examining the study data. For these reasons Roche has decided to close the study early effective immediately.

Synopsis of final report

1061423 (December 2014)

Study BO2090

6

Data cut-off:

LPLV: 17 April 2014

Period covered by

this report:

30 June 2013 (cut-off for the primary

analysis) to LPLV on 17 April 2014. SYNOPSIS OF RESEARCH REPORT 1061423 (PROTOCOL BO20906)

COMPANY:

NAME OF FINISHED PRODUCT:

NAME OF ACTIVE SUBSTANCE(S):

TITLE OF THE STUDY / REPORT No. /

DATE OF REPORT Final Clinical Study Report - BO20906 - A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients with HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab with Chemotherapy Plus Trastuzumab Plus Bevacizumab. Report No. 1061423. December, 2014.

INVESTIGATORS / CENTERS AND

COUNTRIES Western Europe: Austria, Belgium, Germany, France, Greece, Ireland, Italy, Portugal, Spain, Sweden, United

Kingdom

Eastern Europe: Bosnia-Hercegovina, Bulgaria, Croatia, Estonia, Hungary, Latvia, Poland, Romania, Russia, Serbia,

Slovenia

North America: Canada, United States

Central and South America: Argentine, Brazil, Mexico, Peru Asia and Pacific: Australia, China, Korea, Philippines,

Thailand, Taiwan

Other: Egypt, Israel, South Africa

PUBLICATION (REFERENCE)

None

PERIOD OF TRIAL

First Patient Entered: 01 May, 2008

Last Patient Entered: 10 December, 2010

LPLV: 17 April 2014

Database lock: 10 July, 2014

This CSR covers the period from 30 June, 2013 (cut-off for the primary analysis) until LPLV on 17 April 2014.

CLINICAL PHASE III

OBJECTIVES

Primary objective: To determine whether the addition of bevacizumab to the two designated regimens of chemotherapy + trastuzumab (TCHBHB; THBFECHB) improves invasive disease-free survival relative to the two designated regimens of chemotherapy + trastuzumab (TCHH; THFECH).

STUDY DESIGN

International, multi-center, open-label, randomized, Phase

III trial

NUMBER OF SUBJECTS

Planned: 3500 patients overall.

Enrolled: 3509 patients overall.

Chemotherapy + Herceptin: N = 1757

(Group 1A: TCHH; N = 1617) (Group 2A: THFECH; N = 140)

Chemotherapy + Herceptin + Bevacizumab: N = 1752

(Group 1B: TCHBHB; N = 1614) (Group 2B: THBFECHB; N = 138)

DIAGNOSIS AND MAIN CRITERIA FOR

INCLUSION

Pre- and postmenopausal female patients with HER2- positive, node-positive or high risk node-negative invasive adenocarcinoma of the breast.

Age 18 years old

Unilateral invasive primary pT1T3 breast carcinoma, node positive or high-risk node negative (at least one of the following: >2cm; ER and PgR negative; grade 2 or 3; age <35 years) Centrally tested HER2-positive disease (FISH+ or IHC3+) Undergone total mastectomy or breast-conserving surgery completed 412 weeks before randomization

LVEF 55%

ECOG PS 0/1

TRIAL DRUG / STROKE (BATCH) No.

Bevacizumab:

Batch Numbers. See Primary CSR (Roche Report No.

1056851).

DOSE / ROUTE / REGIMEN / DURATION 15 mg/kg IV every 3 weeks (q3w) for 1 year.

REFERENCE DRUG / STROKE (BATCH)

No. Trastuzumab; Docetaxel: Carboplatin: 5-FU; Epirubicin;

Cyclophosphamide

DOSE / ROUTE / REGIMEN / DURATION

Trastuzumab: Group 1A and 1B - 1st dose 8 mg/kg IV, subsequent doses 6 mg/kg IV / q3w x 1 year; Group 2A and

2B - 1st dose 8 mg/kg IV, doses 2 and 3 - 6 mg/kg IV; dose

4 - 8 mg/kg IV, subsequent doses 6 mg/kg IV / q3w x 1 year.

Docetaxel; Group 1A and 1B - 75 mg/m2 IV / q3w x 6 cycles; Group 2A and 2B - 100 mg/m2 IV / q3w x 6 cycles. Carboplatin: Group 1A, 1B, 2A, 2B: AUC = 6 mg/mL/min IV / q3w x 6 cycles.

5-FU: 600 mg/m2 IV; Epirubicin: 90 mg/m2 IV;

Cyclophosphamide: 600 mg/m2 IV / q3w x 3 cycles.

CRITERIA FOR EVALUATION

EFFICACY: Primary parameter: Invasive Disease Free Survival (IDFS). Secondary parameters: IDFS within the chemotherapy cohorts, disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI).

Biomarkers

SAFETY: Adverse events (cardiac and non-cardiac toxicity), laboratory tests, vital signs, ECOG PS.

STATISTICAL METHODS

The statistical methods used for the analysis of the primary and secondary efficacy endpoints are shown in the Primary

CSR (Roche Report No. 1056851).

METHODOLOGY

Patients in study BO20906 were enrolled in one of two chemotherapy groups. One group received 6 cycles of docetaxel/carboplatin plus trastuzumab with or without bevacizumab (TCHH or TCHBHB); the other group received 3 cycles of docetaxel plus trastuzumab given with or without bevacizumab followed by 3 cycles of FEC (THFECH or THBFECHB). With both regimens, patients continued trastuzumab with or without bevacizumab following chemotherapy to complete 1 year of targeted therapy. Following completion of chemotherapy, patients received adjuvant radiotherapy and endocrine therapy as clinically indicated. Adverse events were reported in two safety cohorts: Cohort1 (standard reporting): Until 18 months post randomization - first 300 patients enrolled in each group - all grades of AEs reported. Cohort 2 (limited reporting): Until 18 months post randomization - patients enrolled after the first 300 patients in each group - AESIs; Grade 1 and 2 AEs requiring change in treatment; all grade 3 & 4 AEs. Both cohorts: After 18 months and for the remainder of the follow-up - ongoing and newly occurring treatment related Grade 3 & 4 AEs, s regardless of causality and SAEs considered to be related to study treatment/procedures. Results of the efficacy (primary and secondary endpoints) and safety data up to the clinical cut- off date of 30 June, 2013 were reported in the Primary CSR (Roche Report No. 1056851) dated

April 2014.

Study BO20906 did not meet its protocol specified primary endpoint of Invasive Disease-Free Survival (IDFS). Bevacizumab when combined with chemotherapy plus trastuzumab and continued for a treatment duration of one year did not prolong IDFS compared to chemotherapy plus trastuzumab in the adjuvant treatment of HER2-positive node positive or high risk node- negative breast cancer. This final CSR has been prepared in an abbreviated format as it primarily reports the safety data collected between the clinical cut off for the primary analysis (30 June, 2013) and LPLV (17 April, 2014). During this period, patients were in post-study treatment follow-up and were not receiving study treatment (i.e., bevacizumab, trastuzumab or chemotherapy). Since special attention was focused on the cardiac safety of the combination treatments used in

this trial, the data presented in this report covers the entire duration of the trial (01 May, 2008 to

17 April, 2014).

This report does not include any efficacy data in addition to that reported in the Primary CSR (Roche Report No. 1056851). SAFETY RESULTS The safety data reported during the period from June 30, 2013 to 17 April, 2014 resulted in the following: The overall incidence of AEs in both treatment arms was low during the period covered by this report. The proportion of patients with at least one AE (all grades) was similar in the two treatment arms (Chemo+H, 1.1%; Chemo+H+Bv, 1.3%). The proportion of patients with a SAE was similar in the two treatment arms (Chemo+H,

0.1%; Chemo+H+Bv, 0.2%).

The proportion of patients with Grade 3 AEs was the same in the two treatment arms (Chemo+H arm, 0.3%;

Chemo+H+Bv arm, 0.3%).

Grade 5 AEs were not reported in either treatment arm. AESIs were reported at a similar frequency in both treatment arms.

Overview of Safety (Safety Population)

______________________________________________________________________________ Chemo+H Chemo+H+Bv (N=1750) (N=1722) n (%) n (%) Adverse Event ______________________________________________________________________________ General Adverse Events #: Pts w. AE 20 ( 1.1%) 23 ( 1.3%) Pts w. Serious AE 1 ( 0.1%) 3 ( 0.2%) Pts w. Grade 3/4/5 AE 5 ( 0.3%) 6 ( 0.3%) Pts w. Grade 5 AE (Outcome Death) 0 ( 0.0%) 0 ( 0.0%) Pts who Disc. Bev Treatment due to AE ## 0 ( 0.0%) 0 ( 0.0%) Pts who Disc. Trial Treatment due to AE ## 0 ( 0.0%) 0 ( 0.0%) All Deaths 14 ( 0.8%) 14 ( 0.8%) Deaths not due to Recurrence 4 ( 0.2%) 3 ( 0.2%) AE of Special Interest for Bevacizumab ###: Pts w. AE of Special Interest 20 ( 1.1%) 16 ( 0.9%) Pts w. AE of Special Interest Grade 3/4/5 5 ( 0.3%) 5 ( 0.3%) Pts w. Serious AE of Special Interest 1 ( 0.1%) 2 ( 0.1%) Pts w. Bleeding 0 ( 0.0%) 0 ( 0.0%) Pts w. Congestive Heart Failure 3 ( 0.2%) 4 ( 0.2%) Pts w. Abscesses and Fistulae 0 ( 0.0%) 0 ( 0.0%) Pts w. Gastrointestinal Perforations 0 ( 0.0%) 0 ( 0.0%) Pts w. Hypertension 13 ( 0.7%) 7 ( 0.4%) Pts w. Proteinuria 0 ( 0.0%) 0 ( 0.0%) Pts w. PRES 0 ( 0.0%) 0 ( 0.0%) Pts w. Arterial Thromboembolic Events 4 ( 0.2%) 5 ( 0.3%) Pts w. Venous Thromboembolic Events 0 ( 0.0%) 0 ( 0.0%) Pts w. Wound Healing Complication 0 ( 0.0%) 0 ( 0.0%) ______________________________________________________________________________ #,### Includes AEs that started after the last clinical cut-off for the primary analysis, 30th June 2013 ## Note that there were no patients on study treatment during the period covered by this table. Hence, no patients could be withdrawn from bevacizumab or trial treatment Program : $PROD/cdp10044/i20906b/saefu_11.sas Output : $PROD/cdp10044/i20906b/reports/saefu_11_S001.lst 06AUG2014 12:14

In this study where special attention was focused on the cardiac safety of the treatment combinations administered, the overall frequency of cardiovascular events from the start of treatment was higher in the Chemo+H+Bv arm (51% patients) than in the Chemo+H arm (26% patients). This was mainly driven by an increased incidence in hypertension (43% vs. 15%). The rate per 100 patient years for hypertension events was higher in the Chemo+H+Bv arm (20.0) than in the Chemo+H arm (4.8), and to a lesser extent for left ventricular dysfunction events (3.4 in the Chemo+H+Bv arm vs. 2.5 in the Chemo+H arm). Declines in LVEF of 10% and to below 55% and LVEF decreases of more than 5% to less than the lower limit of normal were more apparent in the Chemo+H+Bv arm (13.3% patients and

23.0% patients, respectively), than in the Chemo+H arm (10.3% patients and 18.3% patients,

respectively). CONCLUSIONS Overall, no new or unexpected safety signals were observed when compared with those reported during the treatment phase of the study. The cardiac safety profile was consistent with that observed in prior studies with bevacizumab. The overall safety profile was consistent with other studies in which patients with breast cancer had received bevacizumab therapy.

Synopsis of

primary report 1056851 (April 2014)

Study BO2090

6

Data cut-off:

30 June 2013 (primary analysis)

SYNOPSIS OF RESEARCH REPORT 1056851 (PROTOCOL BO20906)

COMPANY:

NAME OF FINISHED PRODUCT:

NAME OF ACTIVE SUBSTANCE(S):

TITLE OF THE STUDY / REPORT No. /

DATE OF REPORT Primary Clinical Study Report - BO20906 - A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients with HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab with Chemotherapy Plus Trastuzumab Plus Bevacizumab. Report No. 1056851. April 2014 INVESTIGATORS / CENTERS AND COUNTRIES Western Europe: Austria, Belgium, Germany, France, Greece, Ireland, Italy, Portugal, Spain, Sweden, United

Kingdom

Eastern Europe: Bosnia-Hercegovina, Bulgaria, Croatia, Estonia, Hungary, Latvia, Poland, Romania, Russia, Serbia,

Slovenia

North America: Canada, United States

Central and South America: Argentine, Brazil, Mexico, Peru Asia and Pacific: Australia, China, Korea, Philippines,

Thailand, Taiwan

Other: Egypt, Israel, South Africa PUBLICATION (REFERENCE) None

PERIOD OF TRIAL

First Patient Entered: 01 May, 2008

Last Patient Entered: 10 December, 2010

Clinical Cut-off: 30 June, 2013

CLINICAL PHASE III

OBJECTIVES

Primary objective: To determine whether the addition of bevacizumab to the two designated regimens of chemotherapy + trastuzumab (TCHB HB; THBFECHB) improves invasive disease-free survival relative to the two designated regimens of chemotherapy + trastuzumab (TCHH; THFECH). STUDY DESIGN International, multi-center, open-label, randomized, Phase

III trial

NUMBER OF SUBJECTS

Planned: 3500 patients overall.

Enrolled: 3509 patients overall.

Chemotherapy + Herceptin: N = 1757

(Group 1A: TCHH; N = 1617) (Group 2A: THFECH; N = 140)

Chemotherapy + Herceptin + Bevacizumab: N = 1752

(Group 1B: TCHBHB; N = 1614) (Group 2B: THBFECHB; N = 138)

DIAGNOSIS AND MAIN CRITERIA FOR

INCLUSION

Pre- and postmenopausal female patients with HER2- positive, node-positive or high risk node-negative invasive adenocarcinoma of the breast.

Age 18 years old

Unilateral invasive primary pT1-T3 breast carcinoma, node positive or high-risk node negative (at least one of the following: >2cm; ER and PgR negative; grade 2 or 3; age <35 years) Centrally tested HER2-positive disease (FISH+ or IHC3+) Undergone total mastectomy or breast-conserving surgery completed 4-12 weeks before randomization

LVEF 55%

ECOG PS 0/1

TRIAL DRUG / STROKE (BATCH) No.

Bevacizumab:

Batch Numbers. See Clinical Study Report text

DOSE / ROUTE / REGIMEN / DURATION 15 mg/kg IV every 3 weeks (q3w) for 1 year.

REFERENCE DRUG / STROKE (BATCH)

No. Trastuzumab; Docetaxel: Carboplatin: 5-FU; Epirubicin;

Cyclophosphamide

DOSE / ROUTE / REGIMEN / DURATION

Trastuzumab: Group 1A and 1B - 1st dose 8 mg/kg IV, subsequent doses 6 mg/kg IV / q3w x 1 year; Group 2A and

2B - 1st dose 8 mg/kg IV, doses 2 and 3 - 6 mg/kg IV; dose

4 - 8 mg/kg IV, s

ubsequent doses 6 mg/kg IV / q3w x 1 year.

Docetaxel; Group 1A and 1B - 75 mg/m

2 IV / q3w x 6 cycles; Group 2A and 2B - 100 mg/m 2 IV / q3w x 6 cycles. Carboplatin: Group 1A, 1B, 2A, 2B: AUC = 6 mg/mL/min IV / q3w x 6 cycles.

5-FU: 600 mg/m

2 IV; Epirubicin: 90 mg/m 2 IV;

Cyclophosphamide: 600 mg/m

2 IV / q3w x 3 cycles.

CRITERIA FOR EVALUATION

EFFICACY: Primary parameter: Invasive Disease Free Survival (IDFS): Time from randomization to local recurrence or second primary cancer (other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, colon carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Secondary parameters: IDFS within the chemotherapy cohorts, disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI).

Biomarkers

SAFETY: Adverse events (cardiac and non-cardiac toxicity), laboratory tests, vital signs, ECOG PS.

STATISTICAL METHODS

The Kaplan-Meier product limit method was used to estimate the IDFS. The log-rank test at the 5% alpha level, stratified for background chemotherapy regimen, nodal status (N0 versus N13 versus N4), and hormonal receptor status (estrogen and/or progesterone receptor positive versus negative), was used to perform all comparisons between treatment arms with respect to IDFS. Confidence intervals of the median IDFS was calculated using the Brookmeyer and Crowley method.

METHODOLOGY

Patients in study BO20906 were enrolled in one of two chemotherapy groups. One group received 6 cycles of docetaxel/carboplatin plus trastuzumab with or without bevacizumab (TCHH or TCHBHB); the other group received 3 cycles of docetaxel plus trastuzumab given with or without bevacizumab followed by 3 cycles of FEC (THFECH or THBFECHB). With both regimens, patients continued trastuzumab with or without bevacizumab following chemotherapy to complete 1 year of targeted therapy. Following completion of chemotherapy, patients received adjuvant radiotherapy and endocrine therapy as clinically indicated. Adverse events were reported in two safety cohorts: Cohort1 (standard reporting): Until 18 months post randomization - first 300 patients enrolled in each group - all grades of AEs reported. Cohort 2 (limited reporting): Until 18 months post randomization - patients enrolled after the first 300 patients in each group - Grade 2 AESI; Grade 1 and 2 AEs requiring change in treatment; all grade 3 & 4 AEs. Both cohorts: After 18 months and for the remainder of the follow-up - ongoing and newly occurring treatment related Grade 3 & 4 AEs, Grade 2 AESI regardless of causality. Results of the primary and secondary efficacy data reported in this CSR are presented in an abbreviated form as data will not be used to support an efficacy claim. Safety data from this study are reported in full in this CSR.

EFFICACY RESULTS

Study BO20906 did not meet its protocol specified primary endpoint of Invasive Disease-Free Survival (IDFS). Bevacizumab when combined with chemotherapy plus trastuzumab and continued for a treatment duration of one year in combination with trastuzumab did not prolong IDFS in the adjuvant treatment of HER2-positive node positive or high risk node-negative breast cancer. The hazard ratio for IDFS was 0.99 (95% CI [0.79; 1.25]). The stratified log-rank test p-value was 0.9610. The KaplanMeier estimated median duration of IDFS was not reached in either treatment arm. In the unstratified analysis, the hazard ratio for IDFS was 1.02 (95% CI [0.81; 1.28]); log-rank test p-value was 0.8796. In the analysis in which patients with a second primary malignancy were excluded (U.S. analysis), the hazard ratio for IDFS was 1.06 (95% CI [0.83; 1.35]). The stratified log-rank test p-value was 0.6428. The KaplanMeier estimated median duration of IDFS was not reached in either treatment arm. Treatment with Chemo+H+Bv compared with Chemo+H did not prolong the secondary efficacy parameters of disease-free survival, overall survival (interim analysis), recurrence-free interval or distant recurrence-free interval. Summary of Key Primary and Secondary Efficacy Results by Trial Treatment (ITT)

__________________________________________________________________________________________ Chemo+H Chemo+H+Bv (N=1757) (N=1752) __________________________________________________________________________________________ Primary Efficacy parameter Invasive Disease-Free Survival (IDFS) Patients with event 145 ( 8.3 %) 147 ( 8.4 %) Patients without events** 1612 ( 91.7 %) 1605 ( 91.6 %) Time to event (months) Median### . . p-Value (Log-Rank Test, Stratified $) 0.9610 Hazard Ratio (Stratified $) 0.99 95% CI [0.79;1.25] __________________________________________________________________________________________

Summary of Key Primary and Secondary Efficacy Results by Trial Treatment (ITT) (Cont)

__________________________________________________________________________________________ Chemo+H Chemo+H+Bv (N=1757) (N=1752) __________________________________________________________________________________________ IDFS, Excl. Sec. Prim. Non-BIC Patients with event 126 ( 7.2 %) 136 ( 7.8 %) Patients without events** 1631 ( 92.8 %) 1616 ( 92.2 %) Time to event (months) Median### . . p-Value (Log-Rank Test, Stratified $) 0.6428 Hazard Ratio (Stratified $) 1.06 95% CI [0.83;1.35] Secondary Efficacy parameters Disease-Free Survival Patients with event 145 ( 8.3 %) 151 ( 8.6 %) Patients without events** 1612 ( 91.7 %) 1601 ( 91.4 %) Time to event (months) Median### . . p-Value (Log-Rank Test, Stratified $) 0.8402 Hazard Ratio (Stratified $) 1.02 95% CI [0.81;1.29] Overall Survival Patients with event 62 ( 3.5 %) 54 ( 3.1 %) Patients without events** 1695 ( 96.5 %) 1698 ( 96.9 %) Time to event (months) Median### . . p-Value (Log-Rank Test, Stratified $) 0.5147 Hazard Ratio (Stratified $) 0.89 95% CI [0.61;1.28] Recurrence-Free Interval Patients with event 111 ( 6.3 %) 125 ( 7.1 %) Patients without events** 1646 ( 93.7 %) 1627 ( 92.9 %) Time to event (months) Median### . . p-Value (Log-Rank Test, Stratified $) 0.4331 Hazard Ratio (Stratified $) 1.11 95% CI [0.86;1.43] Distant Recurrence-Free Interval Patients with event 94 ( 5.4 %) 103 ( 5.9 %) Patients without events** 1663 ( 94.6 %) 1649 ( 94.1 %) Time to event (months) Median### . . p-Value (Log-Rank Test, Stratified $) 0.5829 Hazard Ratio (Stratified $) 1.08 95% CI [0.82;1.43] __________________________________________________________________________________________ Time to CSIDFS [months] (TTMIDFS) - Censoring: Invasive Disease Free Survival (CSIDFS) Time to CSIDFSM [months] (TTMIDFSM) - Censoring: IDFS, Excl. Sec. Prim. Non-BIC (CSIDFSM) Time to CSDFS [months] (TTMDFS) - Censoring: Disease Free Survival (CSDFS) Time to Death [months] (TTMDIED) - Censoring: Overall survival (CSDIED) Time to RFI [months] (TTMRFI) - Censoring: Recurrence Free Interval (CSRFI) Time to CSDRFI [months] (TTMDRFI) - Censoring: Distant Recurrence Free Survival (CSDRFI) ** censored ### Kaplan-Meier estimates Program : $PROD/cdp10044/bo20906/eoeff0_10.sas Output : $PROD/cdp10044/i20906a/reports/eoeff0_10_I001.lst 30OCT2013 18:57

SAFETY RESULTS

Cohort 1

The safety data reported during the period from randomization to 18 months for Cohort 1 patients resulted in the following: The proportion of patients with at least one AE (all grades) was similar in the two treatment arms (Chemo+H, 97.9%; Chemo+H+Bv, 97.6%). The proportion of patients with a SAE was higher in the Chemo+H+Bv arm (34.3%) than in the Chemo+H arm (22.1%). The proportion of patients with Grade 3 AEs was higher in the Chemo+H+Bv arm (72.7%) than in the Chemo+H arm (63.3%). Grade 5 AEs were reported with a low frequency in both treatment arms (Chemo+H, 0.7%;

Chemo+H+Bv, 0.3%).

More patients in the Chemo+H+Bv arm (19.2%) discontinued trial treatment due to an AE than in the Chemo+H arm (7.6%). Adverse events of special interest were reported more frequently in patients in the Chemo+H+Bv arm (83.9%) than in the Chemo+H arm (46.4%), as were Grade 3 AESIs (Chemo+H+Bv, 31.1%; Chemo+H 8.7%) and serious AESIs (Chemo+H+Bv, 5.9%; Chemo+H 2.1%). The increase in the overall incidence of AESIs in the Chemo+H+Bv arm compared with the Chemo+H arm was mainly due to a higher incidence of bleeding events (56.6% vs. 24.2%), hypertension (50.3% vs. 17.0%) and proteinuria (13.3% vs. 1.4%). Overview of Safety: Cohort 1- Patients With all Adverse Events Reported With any Grade

Until 18 Months After Randomization (SAP)

______________________________________________________________________________ Chemo+H Chemo+H+Bv (N=289) (N=286) n (%) n (%) Adverse Event ______________________________________________________________________________ General Adverse Events #: Pts w. AE 283 ( 97.9%) 279 ( 97.6%) Pts w. Serious AE 64 ( 22.1%) 98 ( 34.3%) Pts w. Grade 3/4/5 AE 183 ( 63.3%) 208 ( 72.7%) Pts w. Grade 5 AE (Outcome Death) 2 ( 0.7%) 1 ( 0.3%) Pts who Disc. Bev Treatment due to AE 1 ( 0.3%) 47 ( 16.4%) Pts who Disc. Trial Treatment due to AE 22 ( 7.6%) 55 ( 19.2%) All Deaths 5 ( 1.7%) 1 ( 0.3%) Deaths not due to Recurrence 2 ( 0.7%) 1 ( 0.3%) AE of Special Interest for Bevacizumab ##: Pts w. AE of Special Interest 134 ( 46.4%) 240 ( 83.9%) Pts w. AE of Special Interest Grade 3/4/5 25 ( 8.7%) 89 ( 31.1%) Pts w. Serious AE of Special Interest 6 ( 2.1%) 17 ( 5.9%) Pts w. Bleeding 70 ( 24.2%) 162 ( 56.6%) Pts w. Congestive Heart Failure 29 ( 10.0%) 40 ( 14.0%) Pts w. Abscesses and Fistulae 0 ( 0.0%) 0 ( 0.0%) Pts w. Gastrointestinal Perforations 1 ( 0.3%) 5 ( 1.7%) Pts w. Hypertension 49 ( 17.0%) 144 ( 50.3%) Pts w. Proteinuria 4 ( 1.4%) 38 ( 13.3%) Pts w. PRES 0 ( 0.0%) 1 ( 0.3%) Pts w. Arterial Thromboembolic Events 2 ( 0.7%) 6 ( 2.1%) Pts w. Venous Thromboembolic Events 8 ( 2.8%) 12 ( 4.2%) Pts w. Wound Healing Complication 6 ( 2.1%) 8 ( 2.8%) ______________________________________________________________________________ #,## AE onset between time of very first drug intake and 18 months plus 28 days Program : $PROD/cdp10044/bo20906/sae_11.sas Output : $PROD/cdp10044/i20906a/reports/sae_11_S001_ALL.lst 06FEB2014 11:00 Page 1 of 1

Cohort 2

The safety data reported during the period from randomization to 18 months after randomization for Cohort 2 patients resulted in the following: The proportion of patients with at least one AE was higher in the Chemo+H+Bv, arm (90.7%) than in the Chemo+H arm (80.0%). The proportion of patients with a SAE was higher in the Chemo+H+Bv arm (33.0%) than in the Chemo+H arm (23.5%). The proportion of patients with Grade 3 AEs was higher in the Chemo+H+Bv arm (72.9%) than in the Chemo+H arm (61.5%). Grade 5 AEs were reported with a low incidence in both treatment arms (Chemo+H, 0.3%;

Chemo+H+Bv, 0.6%).

More patients in the Chemo+H+Bv arm (23.9%) discontinued trial treatment due to an AE than in the Chemo+H arm (5.7%). Adverse events of special interest were reported more frequently in patients in the Chemo+H+Bv arm (57.7%) than in the Chemo+H arm (20.7%), as were Grade 3 AESIs (Chemo+H+Bv, 25.2%; Chemo+H, 7.2%). The increase in the overall incidence of AESIs in the Chemo+H+Bv arm compared with the Chemo+H arm was mainly due to a higher incidence of hypertension (40.0% vs. 11.2%), bleeding events (11.8% vs. 2.0%), and proteinuria (6.7% vs. 0.6%). Overview of Safety: Cohort 2 - Patients With AESIs Grade 2 and all AEs Grade 3 Until

18 Months After Randomization (SAP)

______________________________________________________________________________ Chemo+H Chemo+H+Bv (N=1461) (N=1436) n (%) n (%) Adverse Event ______________________________________________________________________________ General Adverse Events #: Pts w. AE 1169 ( 80.0%) 1302 ( 90.7%) Pts w. Serious AE 344 ( 23.5%) 474 ( 33.0%) Pts w. Grade 3/4/5 AE 899 ( 61.5%) 1047 ( 72.9%) Pts w. Grade 5 AE (Outcome Death) 5 ( 0.3%) 8 ( 0.6%) Pts who Disc. Bev Treatment due to AE 3 ( 0.2%) 317 ( 22.1%) Pts who Disc. Trial Treatment due to AE 84 ( 5.7%) 343 ( 23.9%) All Deaths 10 ( 0.7%) 13 ( 0.9%) Deaths not due to Recurrence 6 ( 0.4%) 8 ( 0.6%) AE of Special Interest for Bevacizumab ##: Pts w. AE of Special Interest 303 ( 20.7%) 829 ( 57.7%) Pts w. AE of Special Interest Grade 3/4/5 105 ( 7.2%) 362 ( 25.2%) Pts w. Serious AE of Special Interest 35 ( 2.4%) 53 ( 3.7%) Pts w. Bleeding 29 ( 2.0%) 169 ( 11.8%) Pts w. Congestive Heart Failure 83 ( 5.7%) 112 ( 7.8%) Pts w. Abscesses and Fistulae 3 ( 0.2%) 3 ( 0.2%) Pts w. Gastrointestinal Perforations 2 ( 0.1%) 13 ( 0.9%) Pts w. Hypertension 163 ( 11.2%) 574 ( 40.0%) Pts w. PRES 0 ( 0.0%) 0 ( 0.0%) Pts w. Proteinuria 9 ( 0.6%) 96 ( 6.7%) Pts w. Arterial Thromboembolic Events 6 ( 0.4%) 14 ( 1.0%) Pts w. Venous Thromboembolic Events 34 ( 2.3%) 30 ( 2.1%) Pts w. Wound Healing Complication 15 ( 1.0%) 44 ( 3.1%) ______________________________________________________________________________ #,## AE onset between time of very first drug intake and 18 months plus 28 days Program : $PROD/cdp10044/bo20906/sae_11.sas Output : $PROD/cdp10044/i20906a/reports/sae_11_S001_NALL.lst 24JAN2014 17:35 Page 1 of 1

CONCLUSIONS

The primary objective of study BO20906 was not met. Bevacizumab when combined with chemotherapy plus trastuzumab and continued for a treatment duration of one year did not prolong IDFS in the adjuvant treatment of HER2-positive node positive or high risk node- negative breast cancer. Bevacizumab in combination with chemotherapy and trastuzumab in the adjuvant setting resulted in: No difference in IDFS between the Chemo+H+Bv and Chemo+H arms (HR 0.99, 95% CI [0.79; 1.25], p=0.9610). No difference between the two treatment arms in the secondary objectives of disease-free survival, overall survival (interim analysis), recurrence-free interval or distant recurrence- free interval as well as for the U.S. definition of IDFS. A lack of treatment effect on IDFS in most of the subgroups analyzed that was generally consistent with that of the overall study population. Overall, no new or unexpected safety signals were observed when compared with the established safety profile of bevacizumab in other cancer indications, including breast cancer, and with the known toxicities of trastuzumab and the chemotherapy regimens used in this study.

The safety analyses showed:

Higher rates of Grade 3 AEs, SAEs, and AEs leading to study drug discontinuation in the Chemo+H+Bv arm than in the Chemo+H arm, mainly driven by the known bevacizumab related events. A similarly low rate of fatal AEs reported in both treatment arms. A cardiac safety profile consistent with that observed in prior studies. An overall safety profile consistent with other studies of bevacizumab in breast cancer patients with no new or unexpected toxicities seen.

Batch details

Study BO2090

6

Product NameBatch Number

Bevacizumab 400mg703976

Bevacizumab 400mg755462

Bevacizumab 400mg755474Bevacizumab 400mg762145

Bevacizumab 400mg762146

Bevacizumab 400mg781040

Bevacizumab 400mg800076

Bevacizumab 400mg815836

Bevacizumab 400mg B5025

Bevacizumab 400mg B6007

Bevacizumab 400mgB2001

Bevacizumab 400mgB2016Bevacizumab 400mgB3349

Bevacizumab 400mgB3387

Bevacizumab 400mgB5011B01

Bevacizumab 400mgB5011B02 Bevacizumab 400mgB5017

Bevacizumab 400mgB5018

Bevacizumab 400mgB5020

Bevacizumab 400mgB5021

Bevacizumab 400mgB5023

Bevacizumab 400mgB5025

Bevacizumab 400mgB5027

Bevacizumab 400mgB6004

Bevacizumab 400mg

B6005Bevacizumab 400mgB6007

Bevacizumab 400mgB6014

Please note, that the IMP Bevacizumab 25 mg/ml is available in two formulations (vial with 100 mg/4 ml and vial with 400 mg/16 ml). In the

BO20906 study only Bevacizumab 400 mg/16 ml was used, although both presentations had been authorized.

Product NameBatch Number

Trastuzumab 150mg B1341

Trastuzumab 150mg B1569

Trastuzumab 150mg B2085Trastuzumab 150mg B2089

Trastuzumab 150mg B2091

Trastuzumab 150mgB1341

Trastuzumab 150mgB1372Trastuzumab 150mgB1440

Trastuzumab 150mgB1559

Trastuzumab 150mgB1561

Trastuzumab 150mgB1569Trastuzumab 150mgB1574

Trastuzumab 150mgB1578

Trastuzumab 150mgB1579

Trastuzumab 150mg

B1581Trastuzumab 150mgB1586

Trastuzumab 150mgB2085

Trastuzumab 150mgB2086

Trastuzumab 150mg

B2088Trastuzumab 150mgB2089

Trastuzumab 150mgB2091

Trastuzumab 150mgB2096

Trastuzumab 150mg

B2097Trastuzumab 150mgB2098

Trastuzumab 150mgB2099

Trastuzumab 150mgH0724

Trastuzumab 150mg

H0738

Product NameBatch Number

Docetaxel 20mgD0A143/D0A141

Docetaxel 80mgD0A152/D0A142

Docetaxel 80mgD0C308/D0C300

Docetaxel 20mgD7D757/D7D758

Docetaxel 80mgD7D759/D7D760

Docetaxel 80mgD7D759/D8C545

Docetaxel 20mgD8C543/D8C541

Docetaxel 20mgD8C543/D8C675

Docetaxel 80mgD8C547/D8C545

Docetaxel 80mgD8C547/D9A362

Docetaxel 80mgD8C548/D8C545

Docetaxel 80mgD8C718/D8C676

Docetaxel 20mgD8C757/D8C675

Docetaxel 20mgD9A001/D8C675

Docetaxel 80mgD9A274/D9A362

Docetaxel 20mgD9A361/D9A110

Docetaxel 20mgD9C465/D9C463

Docetaxel 80mgD9C467/D9C464

List of Amendments

Study BO2090

6

Protocol Amendments

This summary reflects the changes made from the February 1, 2008 version (Version 1) of the CIRG (TRIO) 011 / NSABP B-44-I / BO20906 protocol to the version dated May 6, 2009 (Version 2).

Many of the revisions made in Amendment #1

were for the purpose of providing clarifications, instructions for consistency with CRF completion guidelines, and minor corrections that were identified during the first year after study activation. Amendment #1 changes of greater significance include the following: · At the investigator's discretion, expansion of tissue expanders can continue during bevacizumab therapy. Instructions regarding the minimum time required for replacing the expander with a permanent breast implant have been provided. · The option of using PET-CT scan as a substitute for CT and PET scans has been provided.

· An additional option for proteinuria testing has been provided. UPC ratio may be used for proteinuria screening and as a follow-uctions for

calculation of UPC ratio have been provided. · Text has been added to specify that patients with synchronous or metachronous contralateral in situ breast cancers are eligible. · The LVEF assessment schedule has been revised to make the assessments more consistent between Groups 1A/1B and 2A/2B. Specifically, the assessments at 8, 15, and 24 months after randomization have been changed to 7, 10, and 18 months following randomization. · Instructions have been addressed for reporting the LVEF as a whole number when the cardiac imaging facility provided the LVEF with a decimal point or as a range. · The definition of grade 1 LVEF decrease for the BETH Trial has been added. · Acceptable timeframes for follow-up visits, testing, and specimen collections were added to the study schedules to allow added flexibility following completion of therapy. · Hypertension assessment and related bevacizumab treatment instructions have been provided to enhance the accuracy of BP assessments and to address treatment decisions when elevated

BP is detected on the treatment day.

· Improved instructions and a tool (dosing graphs) have been provided to illustrate the duration of targeted therapy and number the maximum number of targeted therapy doses. · Additional instructions have been added to improve the clarity and consistency of the carboplatin dose calculations. Related to this, a recommendation has also been added for adjustment of the creatinine value (for use in the Cockcroft-Gault formula) if the lab performing creatinine testing utilizes Isotope Dilution Mass Spectrometry (IDMS)-traceable calibration methods. · When appropriate, instructions for supportive therapies, such as dexamethasone, G-CSF, fluoroquinilones, and erythropoiesis-stimulating agents have been updated and clarified to allow investigators to follow their usual clinical management practices.

· Instructions regarding the documentation requirements for cancer recurrence have been provided in greater detail.

List of

Study Sites

Study BO2090

6

Site #Center

123972Universitätsklinikum Erlangen; Frauenklinik, Universitätsstraße 21-23,

91054, Erlangen, GERMANY

123973Friedrich-Schiller-Uni Jena; Klinik für Frauenheilkunde & Geburtshilfe,

Bachstraße 18, 07740, Jena, GERMANY123974HSK Dr.-Horst-Schmidt-Kliniken; Klinik für Gynäkologie und

gynäkologische Onkologie, Ludwig-Erhard-Str. 100, Station A52, room

19/20, 65199, Wiesbaden, GERMANY

123975Rotkreuzklinikum München; Frauenklinik, Taxisstrasse 3, 80637,

Muenchen, GERMANY

123977KLINIK SCHAUMBURG, KREISKRANKENHAUS; GYNAEKOLOGIE & GEBURTSHILFE, AM KREISKRANKENHAUS 1, 31655, STADTHAGEN, GERMANY

123978HOCHWALDKRANKENHAUS, Chaumont Platz 1, 61231, Bad

Nauheim, GERMANY

123979JOHANNITER-KRANKENHAUS GENTHIN-STENDAL; KLINIK FÜR

FRAUENHEILKUNDE & GEBURTSHILFE, Bahnhofstraße 24-26,

39576, Stendal, GERMANY123981Klinikum der Johann Wolfgang von Goethe Universität, Frauenklinik,

Theodor-Stern-Kai 7, 60596, Frankfurt, GERMANY

123982Asklepios Klinik; Abt. Gynäkologie und Geburtshilfe, Goethestrasse 4,

35423, Lich, GERMANY

123985Gesundheitszentrum St. Marien GmbH; Med. II,

Hämatologie/Onkologie, Mariahilfbergweg 7, 92224, Amberg, GERMANY123987St. Vincenz-Elisabeth-Hospital; Katholisches Klinikum Mainz; Frauenklinik, An der Goldgrube 11, 55131, Mainz, GERMANY

123990CLINICA ONCOLOGICA DE ROSARIO, Córdoba 2457 . CP

S2000KZE, S2000DSK, Rosario, ARGENTINA

123991Policlinica Privada Site la Plata SA; Oncology, Avenida 7 nº 505,

B1902CMK, La Plata, ARGENTINA

123993Mount Medical Center, 146 MOUNTS BAY ROAD, 6000, PERTH,

Western Australia, AUSTRALIA

123994SOUTHERN MEDICAL DAY CARE; CLINICAL TRIALS UNIT, 410

CROWN STREET, 2500, WOLLONGONG, New South Wales,

AUSTRALIA123996Royal Brisbane and Women's Hospital (RBWH); ONCOLOGY DEPARTMENT, Butterfield Street, 4029, BRISBANE, Queensland,

AUSTRALIA

123997Ashford Cancer Center Research, 520 South Road, Tennyson Centre,

520 South Road, 5037, Kurralta Park, South Australia, AUSTRALIA

123999ALFRED HOSPITAL; MEDICAL ONCOLOGY, COMMERCIAL ROAD,

3181, MELBOURNE, Victoria, AUSTRALIA

Listing of Investigators by Site

Protocol : BO20906

Sites: All sites that have enrolled a patient

124002PRIVATE PRACTICE, PA, 6400 W Newberry Rd, SUITE 208,

Gainsville, FL, 32605, UNITED STATES

124003CANCER CARE CENTER, INC., 2210 GREEN VALLEY ROAD,

SUITE 1, NEW ALBANY, IN, 47150, UNITED STATES

124004überörtl. Mammazentrum Hamburg Schlotfeldt, Frauenthal 7, 20149,

Hamburg, GERMANY

124005HOSPITAL BRITANICO; ONCOLOGIA, Perdriel 74, 2nd Floor, office #

61, Servicio de Oncologia, C1280AEB, Buenos Aires, ARGENTINA

124007UAB COMPREHENSIVE CANCER CENTER, 1824 6TH AVENUE

SOUTH, WALLACE TOWER INSTITUTE, BIRMINGHAM, AL, 35294-

3300, UNITED STATES

124009UNI OF TENNESSEE CANCER INST., 1331 UNION AVENUE, SUITE

800, MEMPHIS, TN, 38104, UNITED STATES

124010TEXAS CANCER ASSOCIATES, 8220 WALNUT HILL LANE, SUITE

600, DALLAS, TX, 75231, UNITED STATES

124011AUGUSTA ONCOLOGY ASSOCIATES, 1348 WALTON WAY, SUITE

4300, AUGUSTA, GA, 30901, UNITED STATES

124012MCLEOD CANCER AND BLOOD CENTER, 310 N. STATE OF

FRANKLIN ROAD, SUITE 401, JOHNSON CITY, TN, 37604, UNITED

STATES

124015CANCER SPECIALISTS OF TIDEWATER, 110 WIMBLEDON

SQUARE, SUITE E, CHESAPEAKE, VA, 23320, UNITED STATES

124016BETH ISRAEL MEDICAL CENTER, 10 Nathan D. Perlman Place,

New York, NY, 10003, UNITED STATES

124019Carolina Oncology Specialists, PA - Hickory, 2406 Century Place, SE,

Hickory, NC, 28602, UNITED STATES

124020Mercy Medical Center; Medical Oncology & Hematology, 227 St. Paul

Place, 4th Floor, Baltimore, MD, 21202, UNITED STATES

124022Cone Health Cancer Center, 501 NORTH ELAM AVENUE,

GREENSBORO, NC, 27403, UNITED STATES

124025FRANKSTON HOSPITAL; ONCOLOGY/HAEMATOLOGY,

HASTINGS ROAD, 3199, FRANKSTON, Victoria, AUSTRALIA

124026ST GEORGE HOSPITAL; CANCER CARE CENTRE, 1 SHORT

STREET, 2217, SYDNEY, New South Wales, AUSTRALIA

124027FLINDERS MEDICAL CENTER; MEDICAL ONCOLOGY, FLINDERS

DRIVE, 5041, ADELAIDE, South Australia, AUSTRALIA

124028SHARP HEALTHCARE; ONCOLOGY RESEARCH PROGRAM, 7901

Frost Street, San Diego, CA, 92123, UNITED STATES

124031North County Oncology, 3617 Vista Way, Suite C, Oceanside, CA,

92056-4506, UNITED STATES

124032CENTRAL GEORGIA HEMATOLOGY ONCOLOGY ASSOCIATES,

1062 FORSYTH STREET, SUITE 1B, MACON, GA, 31201, UNITED

STATES

124033WEST CLINIC, 100 N Humphreys Blvd, Memphis, TN, 38120,

UNITED STATES

124034UPSTATE NY CANCER RESEARCH & EDUCATION FOUNDATION,

211 WHITE SPRUCE BLVD, ROCHESTER, NY, 14623, UNITED

STATES

124036UNI OF TEXAS - MD ANDERSON CANCER CENTER; DEPT OF

BREAST MEDICAL ONCOLOGY, 1155 Pressler Street, BOX 424,

Houston, TX, 77030, UNITED STATES

124037Aptium Oncology, 21020 STATE ROAD 7, BOCA RATON, FL, 33428,

UNITED STATES

124038ASSOCIATES IN ONCOLOGY/HEMATOLOGY P.C., 9707 Medical

Center Dr, SUITE 300, Rockville, MD, 20850, UNITED STATES

124039St. Luke's Mountain States Tumor Inst., 100 East Idaho Street, Boise,

ID, 83712, UNITED STATES

124040NORTHWEST ONCOLOGY/ HEMATOLOGY ASSOC., 8170 ROYAL

PALM BLVD, CORAL SPRINGS, 33065-5701, UNITED STATES

124041HEMATOLOGY & ONCOLOGY OF NORTHEAST GEORGIA, PC,

3320 OLD JEFFERSON ROAD, BLDG. 700, ATHENS, GA, 30607,

UNITED STATES

124042Grand Hôpital De Charleroi, Site Notre Dame; Oncology, 3 Grandrue,

B6000, Charleroi, BELGIUM

124044MEDISCH INSTITUUT ST. AUGUSTINUS; ONCOLOGY,

OOSTERVELDLAAN 24, CTO departement, 2610, WILRIJK,

BELGIUM

124045A.Z. KLINA, AUGUSTIJNSLEI 100, 2930, BRASSCHAAT, BELGIUM

124049UMHAT Tsaritsa Yoanna - ISUL; Clinic of Oncotherapy, 8 BJALO

MORE STREET, 1527, SOFIA, BULGARIA

124051FSBI Research Oncology Institute n.a. N.N.Petrov of Ministry of

Health of Russian Federation, Persochny , Leningradskaya Str., bld.

68, 197758, Saint-Petersburg, RUSSIAN FEDERATION

124053Republican Clinical Oncologic Dispensary of Republic Of Tatarstan,

SIBIRSKY TRACT, 29, 420029, KAZAN, RUSSIAN FEDERATION

124056ST. PETERSBURG ONCOLOGY HOSPITAL, BERESZOVAYA

ALLEYA 3/5, 197022 ST PETERSBURG, RUSSIAN FEDERATION

124057Papageorgiou General Hospital; Medical Oncology, Ring Road of

Thessaloniki, Nea Efkarpia, 56429, Thessaloniki, GREECE

124060HOPITAL SAINT ANTOINE; SCE ONCOLOGIE, 184 Rue Du

Faubourg Saint Antoine, 75571, PARIS, FRANCE

124061IPO do Porto; Servico de Oncologia Medica, RUA DR. ANTONIO

BERNARDINO DE ALMEIDA, 4200-319, PORTO, PORTUGAL

124063NOTTINGHAM CITY HOSPITAL; ONCOLOGY, Hucknall Road,

HAYWOOD HOUSE, Nottingham, NG5 1PB, UNITED KINGDOM

124064CH Dptal Les Oudairies; Hematologie Oncologie, Boulevard Stephane

Moreau, 85925, La Roche Sur Yon, FRANCE

124065BRISTOL ONCOLOGY CENTRE; CLINICAL TRIALS UNIT; R & D

department, Grange Road Uphill, Weston Super Mare, BS23 4TQ,

UNITED KINGDOM

124067IPSWICH HOSPITAL; CLINICAL ONCOLOGY, HEATH ROAD,

IPSWICH, IP4 5PD, UNITED KINGDOM

124068CLINIQUE HENRY HARTMANN; Institut d`ONCOLOGIE, 4 rue

Kléber, 92300 Levallois-Perret, France

124072ROYAL BOURNEMOUTH GENERAL HOSPITAL; ONCOLOGY, NHS

Foundation Trust Castle Lane East, Bournemouth, BH7 7DW,

UNITED KINGDOM

124074PETERBOROUGH CITY HOSPITAL; ONCOLOGY WARD, Edith

Cavell Campus; Bretton Gate, PETERBOROUGH, PE 3 9GZ,

UNITED KINGDOM

124076ROYAL CORNWALL HOSPITAL; DEPT OF CLINICAL ONCOLOGY,

CHY HOWLEK (SUNRISE BUILDING), TRURO, TR1 3LJ, UNITED

KINGDOM

124078KRANKENHAUS DER STADT WIEN-HIETZING; ABT. FÜR GYNÄKOLOGIE U. GEBURTSHILFE, WOLKERSBERGENSTRASSE

1, 1130, WIEN, AUSTRIA

124080LKH SALZBURG - Universitätsklinikum der PMU; III. MEDIZINISCHE

ABT., Müllner Hauptstrasse 48, 5020, Salzburg, AUSTRIA

124081LHK VÖCKLABRUCK; II. INTERNE ABT., Dr. Wilhelm-Bock-Strasse

1, 4840, Vöcklabruck, AUSTRIA

124084UNIVERSITÄTSKLINIK FÜR FRAUENHEILKUNDE; KLINIK FÜR

GYNÄKOLOGIE IV, WÄHRINGER GÜRTEL 18-20, 1090, WIEN,

AUSTRIA

124085LKH-UNIV. KLINIKUM GRAZ; KLINIK FÜR GYNÄKOLOGIE,

AUENBRUGGERPLATZ 15, 8036, GRAZ, AUSTRIA

124086CENTRE CATHERINE DE SIENNE; CHIMIOTHERAPIE, 2 RUE ERIC

TABARLY, 44202, NANTES, FRANCE

124087TIROLER LANDESKRANKENANSTALTEN GES.M.B.H.; ABT. FÜR GYNÄKOLOGIE, ANICHSTRASSE 35, 6020, INNSBRUCK, AUSTRIA

124088KH DER BARMHERZIGEN SCHWESTERN; NEUROLOGISCHE

ABT., ELANGGASSE 16, 4010, LINZ, AUSTRIA

124089UNIVERSITÄTSKLINIK FÜR INNERE MEDIZIN I; ABT. INNERE

MEDIZIN I., WÄHRINGER GÜRTEL 18-20, 1090, WIEN, AUSTRIA

124090KLINIKUM KREUZSCHWESTERN WELS; III. INTERNE ABT.,

GRIESKIRCHNERSTRASSE 42, 4600, WELS, AUSTRIA

124091A.Ö. BEZIRKSKRANKENHAUS KUFSTEIN; INNERE MEDIZIN X,

Endach 27, 6330, KUFSTEIN, AUSTRIA

124093LION'S GATE HOSPITAL, 231 EAST 15TH STREET, Suite 270, V7L

2L7, NORTH VANCOUVER, British Columbia, CANADA

124094CROSS CANCER INSTITUTE ; DEPT OF MEDICAL ONCOLOGY,

11560 UNIVERSITY AVENUE, T6G 1Z2, EDMONTON, Alberta,

CANADA

124095Hopital Louis Pasteur; Medecine B, 39 Avenue De La Liberte, 68024,

Colmar, FRANCE

124100HOPITAL DU SACRE COEUR DE MONTREAL; ONCOLOGY, 5400

BOUL. GOUIN OUEST, H4J 1C5, MONTREAL, Quebec, CANADA

124102William Osler Health System Brampton Civic Hospital, 2100 Bovaird

Drive East, L6R 3J7, Brampton, Ontario, CANADA

124104HUMBER RIVER HOSPITAL, 200 Church Street, Weston, M9N 1N8,

Toronto, Ontario, CANADA

124105SOUTHLAKE REGIONAL HEALTH CENTER; COMMUNITY CARE

CLINIC / ONCOLOGY, 596 DAVIS DRIVE, L3Y 2P9, NEWMARKET,

Ontario, CANADA

124107ST. MICHAEL'S HOSPITAL, 30 Bond Street, B1 002, M5B 1W8,

TORONTO, Ontario, CANADA

124108University Health Network; Princess Margaret Hospital; Medical

Oncology, 610 University Ave, Room 4-115, Suite 5-222, M5G 2M9,

Toronto, Ontario, CANADA

124110WINDSOR REGIONAL CANCER CENTRE, 2220 Kildare Road, N8W

2X3, Windsor, Ontario, CANADA

124111Institut Daniel Hollard, 12 Rue Docteur Calmette, 38000, Grenoble,

FRANCE

124113HUC; Servico de Ginecologia A, AVDA. DR. BISSYA BARRETO,

3000-075, COIMBRA, PORTUGAL

124114ST VINCENT'S UNI HOSPITAL; MEDICAL ONCOLOGY, ELM PARK,

DUBLIN, 4, IRELAND

124115Beaumont Hospital; Cancer Clinical Trials Unit, BEAUMONT ROAD,

PO Box 1297, DUBLIN, 9, IRELAND

124118ST. JAMES HOSPITAL; ONCOLOGY, JAMES' STREET, DUBLIN, 8,

IRELAND

124119ST. VINCENT'S WARD MATER MISERICORDIAE HOSP. & MATER

PRIV. HOSP., ECCLES STREET, DUBLIN, 7, IRELAND

124120MERCY UNI HOSPITAL; DEPARMENT OF MEDICAL ONCOLOGY,

GRENVILLE PLACE, CORK, IRELAND

124121OSPEDALE MATER SALUTIS; DEPT OF ONCOLOGY, VIA

GIANELLA 1, 37045, LEGNAGO, Lombardia, ITALY

124122OSPEDALE S.S. TRINITÀ NUOVO; DIVISIONE ONCOLOGIA,

LOCALITÀ SAN MARCIANO, 03039, SORA, Lazio, ITALY

124124IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia

Medica A, Via Mariano Semmola, 80131, Napoli, Campania, ITALY

124125Ospedale Calvi di Noale; U.O. Complessa di Oncologia ed Ematologia

Oncologica, Largo San Giorgio, 2, 30035, Mirano, Veneto, ITALY

124126CENTRO CATANESE DI ONCOLOGIA; ONCOLOGIA MEDICA, VIA

DA BORMIDA 64, 95100, CATANIA, Sicilia, ITALY

124129AZIENDA OSPEDALIERO UNIVERSITARIA DI

SASSARI;ONCOLOGIA, VIALE S. PIETRO 8, 07100, SASSARI,

Sardegna, ITALY

124130OSPEDALE S. VINCENZO; ONCOLOGIA MEDICA, Contrada Sirina,

98030, Taormina, Sicilia, ITALY

124132POLICLINICO OSPEDALIERO SS ANNUNZIATA; U.O. DI CLINICA

ONCOLOGICA, VIA DEL VESTINI, 66100, CHIETI, Abruzzo, ITALY

124133OSPEDALE VITO FAZZI; DIV. ONCOEMATOLOGIA, PIAZZA

FILIPPO MURATORE, 73100, LECCE, Puglia, ITALY

124134IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia, VIALE

CAPPUCCINI, 71013, SAN GIOVANNI ROTONDO, Puglia, ITALY

124135AZ. OSP. S. ORSOLA MALPIGHI; ISTITUTO DI ONCOLOGIA

SERAGNOLI, 15 VIA ALBERTONI, 40138, BOLOGNA, Emilia-

Romagna, ITALY

124143CLINIQUE CHENIEUX; ONCOLOGY, 18 Rue Du General Catroux,

87039, Limoges, FRANCE

124146POLYCLINIQUE DU PARC; ONCOLOGIE MEDICALE, 105 RUE

ACHILLE VIADIEU, 31078, TOULOUSE, FRANCE

124148CENTRE PAUL STRAUSS; ONCOLOGIE MEDICALE, 3 RUE DE LA

PORTE DE L'HOPITAL, 67065, STRASBOURG, FRANCE

124149HOPITAL JEAN MINJOZ; Oncologie, 3 Boulevard Alexander Fleming

Niveau 1, Cedex, 25030, Besancon, FRANCE

124150HOTEL DIEU; HEMATOLOGIE- ONCOLOGIE, 1 place du Parvis

Notre-Dame, 75004 Paris, FRANCE

124151HOPITAL MORVAN; ONCOLOGIE - RADIOTHERAPIE, 5 AVENUE

DU MARECHAL FOCH, 29609, BREST, FRANCE

124152Semmelweis Egyetem, Altalanos Orvostudomanyi Kar I. sz.

Belgyogyaszati Klinika Onkologiai Reszleg, Tomo u. 25-29, 1083,

Budapest, HUNGARY

124153DEBRECENI EGYETEM ORVOS ES EGESZSEGTUDOMANYI

CENTRUM; ONKOLOGIAI TANSZEK, NAGYERDEI KRT. 98, 4032,

DEBRECEN, HUNGARY

124165NATIONAL CANCER INST., 268/1 RAMA VI ROAD, RAJATHEVEE,

10400, BANGKOK, THAILAND

124166CHULALONGKORN HOSPITAL; MEDICAL ONCOLOGY, RAMA IV

ROAD, PATUMWAN, 10400, BANGKOK, THAILAND

124167PRINCE OF SONGKLA UNI ; UNIT OF MEDICAL ONCOLOGY,

PRINCE OF SONGKLA UNIV; UNIT OF MED ONC, HATYAI, 90110,

SONGKHLA, THAILAND

124170Clinic of Oncology - Clinical Center University of Sarajevo, BOLNICKA

25, 71000, SARAJEVO, BOSNIA AND HERZEGOVINA

124172NATIONAL HOSPITAL; ONCOTHERAPY DEPT, Roth Avenue, 9301,

Bloemfontein, SOUTH AFRICA

124173University of Witwatersrand/Johannesburg Hospital; Dept. of ocnology,

7 York Road, PARKTOWN, 2193, Johannesburg, SOUTH AFRICA

124174CHINESE ACADEMY OF MEDICAL SCIENCE; CANCER INST. &

HOSPITAL, 17 PAN JIA GARDEN, CHAOYANG DISTRICT, 100021,

BEIJING, CHINA

124175307 Hospital of The Chinese PLA; The First Medical Dept of

Oncology Dept, No.8, East street, Fengtai District, Beijing, 100071,

Beijing, CHINA

124176The First Affiliated Hospital of Soochow University, No.188 Shizi

Street, 215004, Suzhou, CHINA

124177QUEEN ELIZABETH HOSPITAL; CLINICAL ONCOLOGY, 30

Gascoigene Road, Hong Kong, CHINA

124178The 81st Hospital of P.L.A., No.34, 34 Biao, Yanggongjing, Nanjing,

Nanjing, CHINA

124179Tongji Hosp, Tongji Med. Col, Huazhong Univ. of Sci. & Tech, 1095

Jie Fang Da Dao, 430030, Wuhan, CHINA

124180TRI-SERVICE GENERAL HOSPITAL; HEMATOLOGY AND

ONCOLOGY, NO.325, SEC.2, CHENGGONG RD., NEIHU DISTRICT,

114, TAIPEI, TAIWAN

124181KOO FOUNDATION SUN YAT-SEN CANCER CENTER; HEMATO-

ONCOLOGY, 125 LIH-DER RD., PEI-TOU DISTRICT, 112, TAIPEI,

TAIWAN

124182NATIONAL CHENG KUNG UNI HOSPITAL; DEPT OF

HEMATOLOGY & ONCOLOGY, 138 SHENG-LI ROAD, 704, TAINAN,

TAIWAN

124183CHANG GUNG MEDICAL FOUNDATION - LINKOU; DEPT OF

SURGERY, 5, FU-Hsin Street, Kweishan, 333, Taoyuan, TAIWAN

124185CHANGHUA CHRISTIAN HOSPITAL; DEPT OF SURGERY, 135

NANSHIAU STREET, 500, CHANGHUA, TAIWAN

124187NATIONAL TAIWAN UNI HOSPITAL; DEPT OF ONCOLOGY, 7,

Chung-Shan South Road, 100, Taipei, TAIWAN

124188VETERANS GENERAL HOSPITAL; Department of General Surgery,

201 SHIH-PAI ROAD SECTION 2, 00112, TAIPEI, TAIWAN

124189SEOUL NATIONAL UNI HOSPITAL; DEPT. OF INTERNAL MEDICINE/HEMATOLOGY/ONCOLOGY, 101, Daehak-ro, Jongno-gu,

110-744, Seoul, KOREA, REPUBLIC OF

124190SAMSUNG MEDICAL CENTRE; DIVISION OF

HEMATOLOGY/ONCOLOGY, 81, Irwon-ro, Gangnam-gu, 135-710,

Seoul, KOREA, REPUBLIC OF

124191ASAN MEDICAL CENTER, UNI ULSAN COLLEGEMEDICINE;

DEPT.INTERNAL MEDICINE /

DIVISIONHEMATOLOGY/ONCOLOGY, 88, Olympic-ro 43-gil, Songpa- gu, 138-736, Seoul, KOREA, REPUBLIC OF

124192YONSEI UNI COLLEGE OF MEDICINE, SEVERANCE HOSPITAL;

INTERNAL MEDICINE DEPT., 134 Shinchon-Dong, CPO BOX 8044,

120-752, Seoul, KOREA, REPUBLIC OF

124193BUNDANG SEOUL UNI HOSPITAL; MEDOCAL ONCOLOGY, 82,

Gumi-ro 173-gil, Bundang-gu, Seongnam-si, 463-802, Bundang City,

KOREA, REPUBLIC OF

124194ZAKLAD OPIEKI ZDROWOTNEJ MSWIA; ODDZIAL CHEMIOTERAPII, AL. WOJSKA POLSKIEGO 37, 10-228, OLSZTYN,

POLAND

124195CENTRUM ONKOLOGII - INST.IM. MARII SKLODOWSKIEJ-CURIE;

KLINIKA NOWOTWOROW PLUCA I KLATKI PIERSIOWEJ, UL.

ROENTGENA 5, 02-781, WARSZAWA, POLAND

124197Bialostockie Centrum Onkologii; Oddzial Onkologii Klinicznej, UL.

OGRODOWA 12, 15-027, BIALYSTOK, POLAND

124198CENTRUM ONKOLOGII, INST.IM M. CURIE-SLODOWSKIEJ;

KLINIKA ONKOLOGII KLINICZNEJ, WYBRZEZE ARMII KRAJOWEJ

15, 44-101, GLIWICE, POLAND

124199ĔĞ

KOPERNIKA 30, 10-513, OLSZTYN, POLAND

124201Clinical Hospital Centre Zagreb, Kispaticeva 12, 10000, Zagreb,

CROATIA

124205UNI HOSPITAL FOR TUMOURS; DEPT OF MEDICAL ONCOLOGY,

ILLICA 197, 10000, ZAGREB, CROATIA

124206UNI HOSPITAL SPLIT; ONCOLOGY & RADIOTHERAPY,

SPINCICEVA 1, 21000, SPLIT, CROATIA

124207Veterans Memorial Medical Center; Department of General Surgery,

201 SHIH-PAI ROAD SECTION 2, 00112, TAIPEI, Taiwan

124209CEBU DOCTORS UNIVERSITY HOSPITAL, Rm. 203A, MAB 1,

Osmena Boulevard, 6000, CEBU City, PHILIPPINES

124211HOPELANDS CANCER CENTRE; ONCOLOGY, 28 HOPELANDS

ROAD, OVERPORT, 4001, DURBAN, SOUTH AFRICA

124212Russian Oncology Research Center n.a. N.N. Blokhin Dpt of Clinical

Pharmacology and Chemotherapy, KASHIRSKOYE SHOSSE, 24,

115478, MOSCOW, RUSSIAN FEDERATION

124213HOSPITAL NACIONAL CARLOS ALBERTO SEGUIN ESCOBEDO-

ESSALUD; ONCOLOGY & HAEMATHOLOGY, Calle Peral y

Ayacucho S/N Cercado - Arequipa, 04001, Arequipa, PERU

124214HOSPITAL NACIONAL EDGARDO REBAGLIATI MARTINS;

ONCOLOGIA, Avenida Edgardo Rebagliati No 490, Piso 8º A, Jesus

Maria, 11, Lima, PERU

124215CLINICAL CENTER BEZANIJSKA KOSA; ONCOLOGY, AUTOPUT

BB, 11080, BELGRADE, SERBIA

124216CLINICAL CENTER NIS; INSTITUTE OF ONCOLOGY, BUL ZORANA

DJINDJICA, 18000, NIS, SERBIA

124223KAPLAN MEDICAL CENTER; ONCOLOGY INST., Bilu Junc., PO

BOX 1, 7610001, Rehovot, ISRAEL

124224CHAIM SHEBA MEDICAL CENTER; ONCOLOGY DEPT, Sheba

Medical Center, 52620-00, Ramat Gan, ISRAEL

124225SOURASKY / ICHILOV HOSPITAL; ONCOLOGY DEPARTMENT, 6

Weitzman Street, 64239-06, Tel Aviv, ISRAEL

124226CARMEL HOSPITAL; ONCOLOGY UNIT, 7, MICHAL STR., 34362,

HAIFA, ISRAEL

124227Rabin Medical Center; Oncology Dept, Rabin \Belinson

M.C,JABOTINSKI 39 Street, PO BOX 85, 49100, PETACH TIKVA,

ISRAEL

124228ASSAF HAROFEH; ONCOLOGY, Assaf Harofe Medical Center,

Tsrifin, 70300, ISRAEL

124229MEIR MEDICAL CENTER; ONCOLOGY, 59 Tschernichovsky,

4428164, Kfar-Saba, ISRAEL

124232Hospital del Mar; Servicio de Oncologia, Paseo Maritimo 25-29,

08003, Barcelona, BARCELONA, SPAIN

124233Hospital Ruber Internacional;Servicio de Oncologia, LA MASO 38,

28034, MADRID, MADRID, SPAIN

124234Hospital Universitario Miguel Servet; Servicio Oncologia, PASEO

ISABEL LA CATOLICA 1-3, 50009, ZARAGOZA, ZARAGOZA, SPAIN

124235Hospital de Terrassa; Servicio de Oncologia, CARRETERA DE

TORREBONICA S/N, 08227, BARCELONA, BARCELONA, SPAIN

124236Hospital de la Santa Creu i Sant Pau; Servicio de Oncologia, C/ Mas

Casanovas nº 90, 08041, Barcelona, BARCELONA, SPAIN

124237Hospital Universitario de Canarias;servicio de Oncologia, Ofra S/N La

Cuesta, 38320, La Laguna, TENERIFE, SPAIN

124238Chi De Creteil; Radiotherapie Oncologie, 40 AVENUE DE VERDUN,

94010, CRETEIL, FRANCE

124240Hospital de Torrevieja; Servicio de Oncologia, Ctra. CV-95 Partida La

Ceñuela, 03186, Torrevieja, ALICANTE, SPAIN

124241Corporacio Sanitaria Parc Tauli; Servicio de Oncologia, Edificio Santa

Fe, Planta Principal, Investigación Oncológica, 08208, Sabadell,

Barcelona, BARCELONA, SPAIN

124242Complejo Hospitalario de Jaen-Hospital Universitario Medico

Quirurgico; Servicio de Oncologia, AVDA. DEL EJERCITO ESPANOL

S/N, 23007, JAEN, JAEN, SPAIN

124243Instituto Valenciano Oncologia; Oncologia Medica, C/ Profesor Beltrán

Báguena,8, 46009, Valencia, VALENCIA, SPAIN

124244Hospital Universitario Virgen del Rocio; Servicio de Oncologia,

AVENIDA MANUEL SIUROT S.N., 41013, SEVILLA, SEVILLA, SPAIN

124245Hospital Clinico Universitario de Salamanca; Servicio de Oncologia, PASEO DE SAN VICENTE 182, 37007, SALAMANCA, SALAMANCA,

SPAIN

124246Hospital General Universitario de Elche; Servicio de Oncologia,

Hospital de día, 1ªplanta Camí de la Almazara, 11, 03203, ELCHE,

ALICANTE, SPAIN

124247Hospital Clinico Universitario Virgen de la Victoria; Servicio de

Oncologia, CAMPUS UNIVERSITARIO DE TEATINOS S/N., 29010,

Malaga, MALAGA, SPAIN

124248Centro Oncológico Gallego José Antonio Quiroga y Piñeiro, Servicio

de Oncologia, C/ Dr Camilo Veiras s/n, 15009, La Coruña, LA

CORUÑA, SPAIN

124249IInstituto Oncologico de San Sebastian, Oncologikoa; Servicio de

Oncologia, Paseo Dr. Beguiristain, 121, Planta primera, 20014, SAN

SEBASTIAN, GUIPUZCOA, SPAIN

124250Hospital de C

Politique de confidentialité -Privacy policy