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Backup Slides. Physiology of Anemia. J&J Breast Cancer (EPO-ANE-3010). Design Features Excludes patients who ever had hormonal Rx or who are on anticoagulants Tumor Assessments and Follow Up are adequate Routine Assessment for TVEs included Dosing of epoetin alfa=Procrit label

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j j breast cancer epo ane 3010
J&J Breast Cancer (EPO-ANE-3010)
  • Design Features
    • Excludes patients who ever had hormonal Rx or who are on anticoagulants
    • Tumor Assessments and Follow Up are adequate
    • Routine Assessment for TVEs included
    • Dosing of epoetin alfa=Procrit label
    • Stratified Randomization by
      • Prior adjuvant anthracycline
      • Her-2 Neu status
      • DFS Interval between initial diagnosis and metastatic disease
slide4

GBR-7 (H/N)

RTOG 9903 (H/N)

GER-22 (NSCLC)

CAN-20 (NSCLC)

CAN-17 (Breast)

AGO (Cervical)

BEST

(Breast)

Supportive Safety Studies from J&J

ODAC 2004

N93-004

(J&J PMC; SCLC)

EPO-ANE-3010

(J&J PMC; Breast)

2001-0145 (SCLC)

PREPARE (Breast)

ARA-03 (Breast)

DAHANCA (H/N)

GELA (NHL)

PMC Studies from Amgen

Henke

(Head/Neck)

ago neoadjuvant breast prepare
AGO Neoadjuvant Breast (PREPARE)

Aranesp

1° Objectives

RFS, OS

EC→T q 21

SURGERY

Transfusion Support

Breast Cancer >2 cm

N=720

2° Objectives

pCR, LN status, in breast recurrence, remission rate

Aranesp

Dose Dense + Intense

E→T→CMF

Transfusion Support

  • Randomized, Open Label, Multifactorial
  • 1° and 2° Endpoints:
    • Q 21 vs Q 14 Dose Intense chemo
  • Influence of Aranesp vs Supportive Care on 1° and 2° endpoints is also a 2° endpoint

Target Hgb 12-13

Study DE2001-0033

E=epirubicin, C=cyclophosphamide, T=paclitaxel, M=MTX, F=5FU

ago neoadjuvant breast prepare6
AGO Neoadjuvant Breast (PREPARE)
  • Trial presented at ODAC 2004
  • Accrual June 2002 - March 2005
  • Results not available
  • Limitations
    • Primary Data not provided to FDA
    • Open Label
    • Multifactorial
    • M0 status confirmed by CXR, Abd US, Bone Scan
    • Inadequate follow up surveillance for recurrence
    • Off-label Aranesp dose + dose adjustments
    • No routine assessment of TVEs

Study DE2001-0033

wsg adjuvant breast ara 03
WSG Adjuvant Breast (ARA-03)

1° Endpoint: EFS

TAC or CEF x 6

Aranesp

Breast Cancer T1-3 and >3 + LN

N=690 of planned 1234

RT+

Hormones

2° Endpoints: OS, Local Relapse

TAC or CEF x 6

Transfusion Support

Target Hgb >14

Randomized, Open Label

Trial presented at ODAC 2004

Accrual began January 2004; currently ongoing

TAC=Docetaxel, Doxirubicin, Cyclophosphamide CEF=Cyclophosphamide, Epirubicin, 5-FU

Study DE 2002-0015

wsg adjuvant breast ara 038
WSG Adjuvant Breast (ARA-03)
  • Limitations
    • Heterogeneous chemotherapy regimens; no attempt to stratify
    • Open Label
    • M0 status confirmed by CXR, Abd US, Bone Scan
    • Inadequate follow up surveillance for recurrence
    • Off-label Aranesp dose + dose adjustments
    • No routine assessment of TVEs

Study DE 2002-0015

gela dlbcl lnh03 6b
GELA DLBCL (LNH03-6B)

1° Objective

EFS (Q 14 vs Q 21)

Aranesp

R-CHOP Q 14 x 8 + MTX IT x 4

Transfusion or Aranesp if Hgb≤9

DLBCL

N=328 of planned 600

2° Objectives

RR, DFS, OS, Progression rate, Relapse Rate

Aranesp

R-CHOP Q 21 x 8 + MTX IT x 4

Transfusion or Aranesp if Hgb≤9

  • Randomized, Open Label, Multifactorial
  • 1° Endpoint:
    • Q 21 vs Q 14 Dose Intense chemo
  • Control arm could receive Aranesp

Target Hgb 13-15

Study FR 2003-2005

gela dlbcl lnh03 6b10
GELA DLBCL (LNH03-6B)
  • Accrual began December 2003; ongoing
  • Interim results on 130 patients-1 yr OS, 1 yr EFS no difference observed
  • Design Problems
    • Control arm could receive Aranesp
    • Multifactorial
    • Open Label
    • Response Rate and DFS not clearly defined
    • Criteria for tumor response or progression not provided
    • Off-label Aranesp dose + dose adjustments
    • No routine assessment of TVEs

Study FR 2003-2005

slide11

GBR-7 (H/N)

RTOG 9903 (H/N)

GER-22 (NSCLC)

CAN-20 (NSCLC)

CAN-17 (Breast)

AGO (Cervical)

BEST

(Breast)

Supportive Safety Studies from J&J

ODAC 2004

N93-004

(J&J PMC; SCLC)

EPO-ANE-3010

(J&J PMC; Breast)

2001-0145 (SCLC)

PREPARE (Breast)

ARA-03 (Breast)

DAHANCA (H/N)

GELA (NHL)

PMC Studies from Amgen

Henke

(Head/Neck)

common limitations
Common Limitations
  • Excessively high Target Hgb
  • Off Label Epoetin alfa dosage and dose adjustments
  • Inadequate radiological assessments to assess for recurrence
  • No routine assessment for TVEs
  • Open Label
  • Primary data not submitted to FDA on trials that have finished enrollment
epo gbr 7 head neck
EPO-GBR-7 Head/Neck

1° Endpoint: 2 yr Local DFS

Definitive RT

Eprex

Head/Neck Cancer (Stage II/III)

N=301

2° Endpoint: 1, 2, 5 yr OS

Definitive RT

Transfusion Support

Target Hgb 14.5-15

Randomized, Open Label

Trial presented at ODAC 2004

Accrual August 1999 – April 2002

Terminated early due to slow accrual (goal = 800 pts)

epo gbr 7 head neck14
EPO-GBR-7 Head/Neck

Result summary from J&J, April 2006

  • No significant differences for local recurrence in or outside the RT field, 1 yr OS, RR
epo gbr 7 head neck15
EPO-GBR-7 Head/Neck
  • Limitations
    • Primary Data not given to FDA
    • No result for Primary Endpoint, 2 yr local DFS
    • Assessment method and the frequency of testing for local recurrence was inadequate
    • Suspected recurrences did not need biopsy
    • Assessment of Survival was not required for subjects withdrawn from study
    • Response judged from clinical assessments only
    • Dose and dose adjustments off-label
    • Target Hgb excessively high
    • No routine TVE assessments
rtog 99 03 head neck
RTOG 99-03 Head/Neck

1° Endpoint: 2 yr LRF

Definitive RT or chemoRT

Procrit

Head/Neck Cancer (Stage I-IV)

N=148

2° Endpoint: OS

Definitive RT or chemoRT

Transfusion Support

Target Hgb 13.5-16 M, 12.5-14 F

Randomized, Open Label

Trial presented at ODAC 2004

Accrual June 2000-October 2003

Terminated early due to DMC trend to lower LRC and OS in Procrit arm (goal = 372 pts)

LRF-loco regional failure; LRC-loco regional control

rtog 99 03 head neck17
RTOG 99-03 Head/Neck

Result summary (abstract 2004):

  • Limitations
    • Primary Data not given to FDA
    • No result for Primary Endpoint, 2 yr LRF
    • Dose adjustments off-label
    • Frequency of testing for local recurrence inadequate
    • Target Hgb excessively high
    • No routine TVE assessments
epo ger 22 nsclc
EPO-GER-22 NSCLC

1° Endpoint: 2 yr OS

Weekly chemo→RT

Eprex

NSCLC (Stage IIIA/IIIB)

N=389

2° Endpoint: Remission Rate, Local Control

Weekly chemo→RT

Transfusion Support

Target Hgb: 12-13

Randomized, Open Label

Trial presented at ODAC 2004

Accrual August 2001-December 2005

Terminated early due to slow accrual (Target = 612 patients)

epo ger 22 nsclc19
EPO-GER-22 NSCLC

Result summary from J&J, April 2006

  • Limitations
    • Primary Data not given to FDA
    • No result for Primary Endpoint, 2 yr OS
    • Dose and dose adjustments off-label
    • Target Hgb excessively high
    • No routine TVE assessments
epo can 17 breast
EPO-CAN-17 Breast

1° Endpoint: QOL

Chemo

Eprex

Breast Ca (Stage I-IV)

N=354

2° Endpoint: RR, OS

Chemo

Transfusion Support

Target Hgb: 12-14

Randomized, Open Label

Trial presented at ODAC 2004

Accrual February 2002 – May 2003

epo can 17 breast21
EPO-CAN-17 Breast
  • Results (J&J summary 4/06)

Limitations

  • Primary Tumor Outcome or Survival data not given to FDA
  • Primary Endpoint: QOL
  • Open Label
  • Systematic tumor restaging in Stg IV dz not required post treatment
  • Length of f/u inadequate
  • Dose adjustments off-label
  • Target Hgb excessively high
  • No routine TVE assessments
ago noggo cervical
AGO/NOGGO Cervical

1° Endpoint: 5 yr RFS

Chemo→RT

Eprex

SURGERY

Cervical Ca (Stage Ib-IIb)

N=264

2° Endpoint: OS, TTF

Chemo→RT

Transfusion Support

Target Hgb: 13

Randomized, Open Label

Trial presented at ODAC 2004

Accrual January 1999 – March 2001

RFS: Relapse Free Survival TTF: Time to Treatment Failure

ago noggo
AGO/NOGGO

Results (J&J summary 4/06)

5 year RFS (primary endpoint), OS, TTF: not reported

  • Limitations
    • Primary Data not given to FDA
    • Open Label
    • Dose adjustments off-label
    • Target Hgb excessively high
    • No routine TVE assessments
slide24

Supportive Safety Studies from J&J

GBR-7 (H/N)

RTOG 9903 (H/N)

GER-22 (NSCLC)

CAN-20 (NSCLC)

CAN-17 (Breast)

AGO (Cervical)

BEST

(Breast)

ODAC 2004

N93-004

(J&J PMC; SCLC)

EPO-ANE-3010

(J&J PMC; Breast)

Other Studies

2001-0145 (SCLC)

PREPARE (Breast)

ARA-03 (Breast)

DAHANCA (H/N)

GELA (NHL)

PMC Studies from Amgen

Henke

(Head/Neck)

Anemia of Cancer

Lymphoid Malignancy

Non-Myeloid Malignancy

Moebus

non myeloid malignancy 2003 0232
Non-Myeloid Malignancy (2003-0232)

Chemo

Aranesp

1° Endpoint: % transfusion

Non-Myeloid Ca

N=391

Chemo

Placebo

Target Hgb: 12-13

Randomized, Double-Blind, Placebo Controlled

Stratified by Tumor Type

Accrual February 2004 – October 2004

Primary Data submitted March 2007

non myeloid malignancy 2003 023226
Non-Myeloid Malignancy (2003-0232)
  • Results (FDA review of primary data)
    • No significant difference in OS ( HR 0.82 [95% CI 0.43, 1.57]).
  • Limitations
    • Primary endpoint: % transfusions
    • Data collection not adequate
    • No long term follow-up plan
    • Dosing was off-label in dose (300 µg Q3W) and adjustments
    • Heterogeneous cancer types
    • Target Hgb excessively high
    • No routine TVE assessments
brave breast
BRAVE (Breast)

1° Endpoint: OS

Chemo

Epoetin beta

Breast Ca (Stage IV)

N=463

2° Endpoint: PFS

Chemo

Transfusion Support

Target Hgb: 13-15

Randomized, Open Label

Stratified by chemo type and hormonal status

Accrual November 2002 – June 2004

brave breast28
BRAVE (Breast)
  • Results (summary results)
    • OS no significant difference (HR 1.07, 95% CI 0.87, 1.33; p=0.522)
    • PFS no significant difference (HR 1.07, 95% CI 0.89, 1.30; p=0.448)
    • TVE higher in ESA arm (13% v 6%, RR 2.36, 95% CI 1,23, 4.55; p=0.01)
  • Limitations
    • Primary data not supplied to FDA
    • Protocol not submitted to FDA
    • Target Hgb 13-15
    • No routine TVE assessments
moebus breast
Moebus (Breast)

1° Objective: EFS (Q14 v Q21) ∆Hgb

Eprex

Dose Dense/Intense ETC + GCSF

2° Objectives: 5 yr OS and DFS (Q14 v Q21), Intramammary recurrence (ESA v control)

Transfusion Support

Breast Ca (Adjuvant Node +)

N=1284

Standard EC->T

  • Multifactorial
  • Accrual January 1999 – March 2001

Target Hgb 12.5-13

Study

moebus breast30
Moebus (Breast)
  • Results
    • 5 yr OS and DFS: no significant difference
    • ↑ TVE in ESA arm (3.0% vs 1.7%)
  • Limitations
    • Primary data not submitted to FDA
    • Inadequate study endpoints
    • Multifactorial
    • Inadequate frequency of radiographic assessments
    • Dosing adjustments off label
    • No routine TVE assessments
tve risks
TVE Risks
  • There are increased risks of TVE with the use of ESAs
  • Evidence:
    • EPO-CAN-15 (SCLC)
    • PR00-03-006 (Gastric/Rectal cancer)
    • GOG 191 (Cervical cancer)
    • Rosenzweig (Breast)
    • Bohlius meta-analysis JNCI April 2006
    • SPINE Study
  • With the exception of EPO-ANE-3010, tumor promotion studies discussed do not routinely assess patients for TVE, & did not specify TVE as prespecified endpoint.
    • Safety signals for increased risk may be missed
epo can 15 sclc
EPO-CAN-15 (SCLC)

1° Endpoint: PFS

Chemo

Epoetin

SCLC (Limited Stg)N=106

2° Endpoints: RR, OS, median survival, LC

Chemo

Placebo

Target Hgb: 14-16

Terminated early due to TVEs

TVE OR 7.74 (ESA vs Control)

↑ Mortality (40% vs 19%) in ESA arm

pr 00 03 006 gastric rectal
PR 00-03-006 (Gastric/Rectal)

1° Endpoint: % transfusion

ChemoRT→surgery

Epoetin

Gastric/Rectal Ca

N=59

2° Endpoints: RR, pCR

ChemoRT →surgery

Placebo

Target Hgb: 14-15

Terminated early due to TVEs

TVE OR 3.79 (ESA vs Control)

gog 191 cervical
GOG 191 (Cervical)

1° Endpoint: PFS

ChemoRT

Epoetin

Cervical Ca

N=113

2° Endpoints: OS, LC

ChemoRT

Transfusion Support

Target Hgb: 13-14

Terminated early due to TVEs

TVE OR 2.65 (ESA vs Control)

rosenzweig breast
Rosenzweig (Breast)

1° Endpoint: Unclear

Unclear

Epoetin

Breast Ca (Stg 4)

N=27

2° Endpoints: Unclear

Unclear

Transfusion Support

Target Hgb: Unclear

Terminated early due to TVEs

TVE 29% vs 0% (ESA vs Control)

jnci meta analysis
JNCI Meta Analysis
  • 2005 OS: HR 0.81 (95% CI: 0.67 to 0.99)
  • 2006 OS: HR 1.08 (95% CI: 0.99 to 1.18)
slide39

Final Data/Study Report not received

2008

2007

2003

2006

2009

2001

2012

2004

2002

2010

2005

2011

GBR-7

RTOG 9903*

GER-22

CAN-17†

AGO*

232‡

PREPARE

ARA-03

GELA

*=Data never submitted to FDA

=Last pt accrued

†=Received limited safety data (no efficacy data)

‡=Received primary data

=Final Data/Study Report Anticipated

final data study report not received
Final Data/Study Report not received

*=Data never submitted to FDA

†=Received limited safety data (no efficacy data)

‡=Received primary data

non inferiority trials
Non Inferiority Trials
  • Purpose is to rule out a prespecified margin of inferiority between ESA and control
  • In trials with ESAs in cancer pts specifically designed to look for safety signals, non-inferiority design preferable over superiority design

Prespecified Margin

Inferior

Non-inferior

1.0

Worse for Control

Worse for ESA

Hazard Ratio

slide42

Studies Initiated by Amgen or J&J

Epoetin alfa Studies

ODAC 2004

EPO-ANE-3010

(J&J PMC; Breast)

N93-004

(PMC; SCLC)

Other Studies

Aranesp Studies

completed studies w summary results no reported safety signal
Completed studies w/summary results + no reported safety signal
  • 5 epoetin alfa studies have been completed, and have had summary results submitted to FDA either by a J&J report or by literature publication, and have not reported safety signals
  • Both FDA and J&J have not analyzed data from these trials
  • Study Limitations
    • 3 of the 5 studies have inadequate design to address risk of tumor promotion
slide44

Completed studies w/summary results + no reported safety signal

Epoetin alfa Studies

ODAC 2004

Other Studies

Aranesp Studies

meta analysis results
Meta-Analysis results
  • Amgen meta analysis used Peto odds ratio, which:
    • Is based solely on the # of known deaths and total # of pts in each arm
    • Does not consider pt follow-up and survival times
    • Is not interpretable since study patients do not have the same study start day