# Presentation: 516425

## Backup Slides

## Physiology of Anemia

**Notes:**
What should be noted from the picture is the sigmoid shape of the curve.  The curve is sigmoidal due to the fact that hemoglobin can bind 4 heme groups and due to interaction between these 4 heme groups.  As each heme group acquires O2, subsequent heme groups bind O2 with greater affinity.  As O2 leaves the first heme molecule, subsequent molecules can disassociate even easier.
The PO2 of blood as it leaves the lung is 80-100 (CLICK), while the PO2 in the body cells is approximately 40 (CLICK).  (CLICK) so now you can see the difference in the percent saturation of oxyhemoglobin, which is the amount of oxygen that is given up by hemoglobin to the tissues.  (CLICK).  Now you will examine what happens when the precious to the right.  This is a way that the oxygen dissociation curve can introduced increase oxygen to tissues when it is needed.  This occurs with decreased pH, or increased DPG or temperature.  (CLICK) so again, we’ll look at a typical PO2 for body tissue.  With the standard sigmoid curve, this is the % saturation of oxyhemoglobin (CLICK).  When the curve shifts to the right, this is now the % saturation of oxyhemoglobin (CLICK).  So this difference (point to the vertical axis) is the increased amount of oxygen release to tissues when the curve shifts to the right.  The shifting of the curve to the right is one way the body can compensate for a decreased hemoglobin.  

2,3-diphosphoglycerate = DPG

## 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

## ODAC 2004

- BEST
- (Breast)

- N93-004
- (J&J PMC; SCLC)

- Henke
- (Head/Neck)

- Supportive Safety Studies from J&J

- EPO-ANE-3010
- (J&J PMC; Breast)

- PMC Studies from Amgen

- 2001-0145 (SCLC)
- PREPARE (Breast)
- ARA-03 (Breast)
- DAHANCA (H/N)
- GELA (NHL)

- GBR-7 (H/N)
- RTOG 9903 (H/N)
- GER-22 (NSCLC)
- CAN-20 (NSCLC)
- CAN-17 (Breast)
- AGO (Cervical)

**Notes:**
State that these trials were intended to answer safety ?s of ESAs

## AGO Neoadjuvant Breast (PREPARE)

- AGO Neoadjuvant Breast (PREPARE)

- 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

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

- Breast Cancer >2 cm
- N=720

- EC→T       q 21

- Dose Dense + Intense
- E→T→CMF

- Aranesp

- Aranesp

- Transfusion Support

- Transfusion Support

- SURGERY

- 1° Objectives
- RFS, OS

- 2° Objectives
- pCR, LN status, in breast recurrence, remission rate

- Target Hgb 12-13

- Study DE2001-0033

## AGO Neoadjuvant Breast (PREPARE)

- 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

**Notes:**
Note after 2nd bullet that accrual ongoing as of ODAC 2004

## WSG Adjuvant Breast (ARA-03)

- WSG Adjuvant Breast (ARA-03)

- Breast Cancer T1-3 and >3 + LN
- N=690 of planned 1234

- TAC or CEF x 6
- Aranesp

- TAC or CEF x 6
- Transfusion Support

- 1° Endpoint: EFS

- Target Hgb >14

- Randomized, Open Label
- Trial presented at ODAC 2004
- Accrual began January 2004; currently ongoing

- Study DE 2002-0015

- RT+
- Hormones

- 2° Endpoints: OS,          Local Relapse

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

**Notes:**
Look up WSG study, and find what “events” were.

## WSG Adjuvant Breast (ARA-03)

- 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

**Notes:**
Note after 2nd bullet that Accrual ongoing as of ODAC 2004

## GELA DLBCL (LNH03-6B)

- GELA DLBCL (LNH03-6B)

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

- DLBCL
- N=328 of planned 600

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

- Aranesp

- Aranesp

- Transfusion or Aranesp if Hgb≤9

- Transfusion or Aranesp if Hgb≤9

- 1° Objective
- EFS             (Q 14 vs Q 21)

- 2° Objectives
- RR, DFS, OS, Progression rate, Relapse Rate

- Target Hgb       13-15

- Study FR 2003-2005

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

## GELA DLBCL (LNH03-6B)

- 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

**Notes:**
Note 1st bullet that Accrual ongoing as of ODAC 2004

## ODAC 2004

- BEST
- (Breast)

- N93-004
- (J&J PMC; SCLC)

- Henke
- (Head/Neck)

- Supportive Safety Studies from J&J

- EPO-ANE-3010
- (J&J PMC; Breast)

- PMC Studies from Amgen

- 2001-0145 (SCLC)
- PREPARE (Breast)
- ARA-03 (Breast)
- DAHANCA (H/N)
- GELA (NHL)

- GBR-7 (H/N)
- RTOG 9903 (H/N)
- GER-22 (NSCLC)
- CAN-20 (NSCLC)
- CAN-17 (Breast)
- AGO (Cervical)

**Notes:**
State that these trials were intended to answer safety ?s of ESAs

## 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

- Head/Neck Cancer            (Stage II/III)
- N=301

- Definitive RT
- Eprex

- Definitive RT
- Transfusion Support

- 1° Endpoint: 2 yr Local DFS

- 2° Endpoint: 1, 2, 5 yr OS

- Randomized, Open Label
- Trial presented at ODAC 2004
- Accrual August 1999 – April 2002
- Terminated early due to slow accrual (goal = 800 pts)

- Target Hgb       14.5-15

## EPO-GBR-7 Head/Neck

| N=301 | Eprex | Control |  |
| --- | --- | --- | --- |
| 12 wk ORR | 99% | 99% |  |
| Local Relapse in RT field | 25% | 29% |  |
| Local Relapse outside RT field | 13% | 15% |  |
| 1 yr OS | 77.3% | 79.9% | 95 % CI (-12.1% to 6.8%), p=0.867 |
| TVE | 3% | 1% |  |

- 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/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

**Notes:**
Results based on 4/06 update

## RTOG 99-03 Head/Neck

- Head/Neck Cancer            (Stage I-IV)
- N=148

- Definitive RT or chemoRT
- Procrit

- Definitive RT or chemoRT
- Transfusion Support

- 1° Endpoint: 2 yr LRF

- 2° Endpoint: OS

- 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)

- Target Hgb 13.5-16 M,  12.5-14 F

- LRF-loco regional failure; LRC-loco regional control

## RTOG 99-03 Head/Neck

- 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

- Result summary (abstract 2004):

**Notes:**
Results based on 4/06 update

## EPO-GER-22 NSCLC

- NSCLC            (Stage IIIA/IIIB)
- N=389

- Weekly chemo→RT
- Eprex

- Weekly chemo→RT
- Transfusion Support

- 1° Endpoint: 2 yr OS

- 2° Endpoint: Remission Rate, Local Control

- Randomized, Open Label
- Trial presented at ODAC 2004
- Accrual August 2001-December 2005
- Terminated early due to slow accrual (Target = 612 patients)

- Target Hgb:   12-13

## EPO-GER-22 NSCLC

|  | Eprex | Control |  | Based on  |
| --- | --- | --- | --- | --- |
| ORR | 55% | 47% |  | 177/389 pts |
| Median Survival 
(days) | 338+/-49
(95% CI 242-434) | 299+/-33
(95% CI 234-364) | P=0.61 | 215/389 pts |
| TVE | 17.7% | 8.5% | P=0.097 | 230/389 pts |

- 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

- Result summary from J&J, April 2006

## EPO-CAN-17 Breast

- Breast Ca            (Stage I-IV)
- N=354

- Chemo
- Eprex

- Chemo
- Transfusion Support

- 1° Endpoint: QOL

- 2° Endpoint: RR, OS

- Randomized, Open Label
- Trial presented at ODAC 2004
- Accrual February 2002 – May 2003

- Target Hgb:   12-14

## EPO-CAN-17 Breast

| N=354 | Eprex | Control |  |
| --- | --- | --- | --- |
| ORR (74 pts w/Stg IV dz) | 36% | 30% | p=0.586 |
| # deaths at 24 months | 27 | 28 | P=0.82 |
| Deep Thrombophlebitis | 6.3% | 0.6% |  |
| TVEs (FDA Analysis) | 7.1% | 3.6% |  |

**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

- Results (J&J summary 4/06)

## AGO/NOGGO Cervical

- Cervical Ca            (Stage Ib-IIb)
- N=264

- Chemo→RT
- Eprex

- Chemo→RT
- Transfusion Support

- 1° Endpoint: 5 yr RFS

- 2° Endpoint: OS, TTF

- Randomized, Open Label
- Trial presented at ODAC 2004
- Accrual January 1999 – March 2001

- Target Hgb:  13

- SURGERY

- RFS: Relapse Free Survival  TTF: Time to Treatment Failure

## AGO/NOGGO

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

|  | ESA | Control |  |
| --- | --- | --- | --- |
| Relapse Rates @ median 105 wks | 17% | 25% | P=0.074 |
| 2 yr RFS | 70% | 81% | P=0.058 |
| 1 yr RFS | 86% | 91% |  |

- Results (J&J summary 4/06)

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

## ODAC 2004

- BEST
- (Breast)

- N93-004
- (J&J PMC; SCLC)

- Henke
- (Head/Neck)

- Supportive Safety Studies from J&J

- EPO-ANE-3010
- (J&J PMC; Breast)

- PMC Studies from Amgen

- 2001-0145 (SCLC)
- PREPARE (Breast)
- ARA-03 (Breast)
- DAHANCA (H/N)
- GELA (NHL)

- GBR-7 (H/N)
- RTOG 9903 (H/N)
- GER-22 (NSCLC)
- CAN-20 (NSCLC)
- CAN-17 (Breast)
- AGO (Cervical)

- Other Studies

- Anemia of Cancer
- Lymphoid Malignancy
- Non-Myeloid Malignancy
- Moebus

## Non-Myeloid Malignancy (2003-0232)

- Non-Myeloid Malignancy (2003-0232)

- Non-Myeloid Ca
- N=391

- Chemo
- Aranesp

- Chemo
- Placebo

- 1° Endpoint: % transfusion

- Randomized, Double-Blind, Placebo Controlled
- Stratified by Tumor Type
- Accrual February 2004 – October 2004
- Primary Data submitted March 2007

- Target Hgb:    12-13

**Notes:**
2nd bullet: Note: state “Among the stratification factors, was stratification by ...”

## Non-Myeloid Malignancy (2003-0232)

- 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)

- Breast Ca    (Stage IV)
- N=463

- Chemo
- Epoetin beta

- Chemo
- Transfusion Support

- 1° Endpoint: OS

- 2° Endpoint: PFS

- Randomized, Open Label
- Stratified by chemo type and hormonal status
- Accrual November 2002 – June 2004

- Target Hgb: 13-15

**Notes:**
Emphasize that this was a superiority study, and 1⁄2 the size of the BEST Trial

## 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)

- Multifactorial
- Accrual January 1999 – March 2001

- Breast Ca (Adjuvant Node +)
- N=1284

- Dose Dense/Intense ETC + GCSF

- Eprex

- Transfusion Support

- 1° Objective:     EFS (Q14 v Q21) ∆Hgb

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

- Target Hgb     12.5-13

- Study

- Standard EC->T

## 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

- 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

**Notes:**
This slide should go at the end.  U may not need to list the evidence-there are really too many trials showing this
Make sure you  remind the audience what EPO-ANE-3010 is

## EPO-CAN-15 (SCLC)

- SCLC       (Limited Stg) N=106

- Chemo
- Epoetin

- Chemo
- Placebo

- 1° Endpoint: PFS

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

- Terminated early due to TVEs
- TVE OR 7.74 (ESA vs Control)
- ↑ Mortality (40% vs 19%) in ESA arm

- Target Hgb:   14-16

**Notes:**
Emphasize that this was a superiority study, and 1⁄2 the size of the BEST Trial

## PR 00-03-006 (Gastric/Rectal)

- Gastric/Rectal Ca
- N=59

- ChemoRT→surgery
- Epoetin

- ChemoRT →surgery
- Placebo

- 1° Endpoint: % transfusion

- 2° Endpoints: RR, pCR

- Terminated early due to TVEs
- TVE OR 3.79 (ESA vs Control)

- Target Hgb:   14-15

**Notes:**
Emphasize that this was a superiority study, and 1⁄2 the size of the BEST Trial

## GOG 191 (Cervical)

- Cervical Ca
- N=113

- ChemoRT
- Epoetin

- ChemoRT
- Transfusion Support

- 1° Endpoint: PFS

- 2° Endpoints: OS, LC

- Terminated early due to TVEs
- TVE OR 2.65 (ESA vs Control)

- Target Hgb:   13-14

**Notes:**
Emphasize that this was a superiority study, and 1⁄2 the size of the BEST Trial

## Rosenzweig (Breast)

- Breast Ca       (Stg 4)
- N=27

- Unclear
- Epoetin

- Unclear
- Transfusion Support

- 1° Endpoint: Unclear

- 2° Endpoints: Unclear

- Terminated early due to TVEs
- TVE 29% vs 0% (ESA vs Control)

- Target Hgb:   Unclear

**Notes:**
Emphasize that this was a superiority study, and 1⁄2 the size of the BEST Trial

## JNCI Meta Analysis 2006: TVE

## JNCI Meta Analysis 2006: OS

## 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)

## Final Data/Study Report not received

- 2001

- 2002

- 2003

- 2004

- 2005

- 2006

- 2007

- 2008

- 2009

- *=Data never submitted to FDA

- †=Received limited safety data (no efficacy data)

- ‡=Received primary data

- GBR-7

- RTOG 9903*

- GER-22

- CAN-17†

- AGO*

- 232‡

- PREPARE

- ARA-03

- GELA

- 2010

- 2011

- 2012

- =Last pt accrued

- =Final Data/Study Report Anticipated

**Notes:**
Focus on the *, cross, and daggers

## Final Data/Study Report not received

| Study | Date Last Pt accrued | Final Data or Study Report Anticipated |
| --- | --- | --- |
| GBR-7 (H/N) | April 2002 | 4Q 2007-1Q 2008 |
| RTOG 99-03 (H/N) | Nov 2003 | 2004* |
| GER-22 (NSCLC) | Dec 2005 | 1Q-2Q 2008 |
| CAN-17 (Breast) | May 2003 | 2007† |
| AGO (Cervical) | Mar 2001 | 2006* |
| 232 (Non-myeloid) | Oct 2004 | 2007‡ |
| PREPARE (Breast) | Mar 2005 | Q4 2007 |
| ARA-03 (Breast) | Ongoing | Q2 2011 |
| GELA (DLBCL) | Ongoing | Q3 2010 |

- *=Data never submitted to FDA

- †=Received limited safety data (no efficacy data)

- ‡=Received primary data

**Notes:**

FYI
The date listed for RTOG is the date listed in ODAC 2004.  Otherwise all dates r derived from Feb 07 correspondence w/companies.

## 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

- Hazard Ratio

- 1.0

- Worse for Control

- Worse for ESA

- Prespecified Margin

- Non-inferior

- Inferior

## ODAC 2004

**N93-004**
**(PMC; SCLC)**

- Epoetin alfa Studies

**EPO-ANE-3010**
**(J&J PMC; Breast)**

- Aranesp Studies

** ****Studies Initiated by Amgen or J&J **

- Other Studies

| Anemia of Cancer (103) |
| --- |
| Lymphoid Ca (161) |
| Non-Myeloid Ca (232) |

| 2001-0145 (SCLC) |
| --- |
|  |
|  |
|  |
|  |

| GBR-7 (H/N) |
| --- |
|  |
| GER-22 (NSCLC) |
|  |
| CAN-17 (Breast) |
|  |

**Notes:**
Highlighted in yellow are studies have been initiated by Amgen or J&J.  These r studies that the companies have full rights of data access.  The other 7 studies (Empty boxes) are cooperative group studies and the companies may have legal problems accessing the data.  Now again, referring back to slides, FDA has received primary data from only one of studies on the right-hand side of the slide, study 145.  EPO-ANE-3010 (POINT) is still ongoing.  The three studies highlighted in yellow at the top right hand side of the slide (POINT)  have closed as long as five years ago, but not have had primary data submitted.  These three studies have only had summary results submitted to the FDA.

## 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

**Notes:**
Now I will mention completed studies that only have summary results available and have no reported safety signal
(CLICK) There are 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
(CLICK) Both FDA and J&J have not analyzed data from these trials
(CLICK) These Studies have limitations.  3 of the 5 studies have inadequate design to address risk of tumor promotion

FYI
Of these 5 studies, 3 of them are not adequate in design to address the risk of tumor promotion [GBR-7, RTOG, CAN-17], and none of them are able to adequately address the risk of TVEs.

## ODAC 2004

- Epoetin alfa Studies

- Aranesp Studies

** ****Completed studies w/summary results +                     no reported safety signal**

- Other Studies

|  |
| --- |
|  |
|  |

|  |
| --- |
|  |
|  |
|  |
|  |

| GBR-7 (H/N) |
| --- |
| RTOG 9903 (H/N) |
| GER-22 (NSCLC) |
|  |
| CAN-17 (Breast) |
| AGO (Cervical) |

**Notes:**
Highlighted in yellow are these studies have been completed and have provided summary results but not primary data.  The studies have no reported safety signals. Detection of safety signals may be limited by the design of the studies.  

## Hazards Ratios for Overall Survival by Studies

## 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

**Notes:**
Quote slide