# Presentation: 290375

## Safety 

**Safety **

**Nausea/Vomiting**
**Mild to moderate severity**
**Grade 3 incidence**
**  ****8% of patients**
**<1% of infusions**
**Anti-emetics**
**Oral 5HT3 antagonists were most ****	****commonly used anti-emetics**

## Weight Loss During Treatment 

**Percent Weight Loss*******

**None****	****<5%****	****5%-10%****	****>10%**

**Amifostine + RT****(N=150)**

**24%****29%****30%****17%**

***Normalized to pre-treatment baseline**

## Hypotension 

**PO/IV hydration 30 minutes prior****	****to administration **
**Overall incidence**
**15% of patients**
**  ****1% of infusions**
**Moderate**
**  ****3% of patients (transient)**
**<1% of infusions**
**No sequelae **

## Safety 

**Safety **

## Reasons for Discontinuation of Amifostine

**Number of Patients****(n = 29)**

**15**
**4**
**3**
**2**
**2**
**1**
**1**
**1**

**Nausea/vomiting**
**Allergy/rash**
**Hypotension**
**Fever**
**Patient request (unspecified) **
**Drowsiness**
**Cachexia**
**Other**

## Hospitalizations

**	****	****	****	****Amifostine + RT****	****RT Alone**
**	****	****	****	****      ****(N=150)                       (N=153)**
**	****	**
**   ****Patients****	****	****	****	****42****	****	****       23**
**   ****Hospitalizations****	****	****	****50****	****                  31**
**   ****Amifostine-related****	****	****  6****	****	****       n/a **
**   **
**   **

## Safety 

**Safety **

**Amifostine generally well tolerated**
**No new or cumulative toxicities**
**Nausea, vomiting, and hypotension****	****most frequent adverse events**

## Overall Conclusions 

**Amifostine reduces the incidence****	****of ********Grade 2 **
**Acute xerostomia (RTOG) **
**Late xerostomia (RTOG)**
**Amifostine preserves greater saliva flow**
**Amifostine provides clinical benefit to ****	****	****patients (PBQ)**
**Amifostine does not reduce anti-tumor ****	****	****efficacy (LRC, DFS, and OS)**
**Amifostine is safe at the recommended ****	****	****dose **

## Statistical Evidence of Effectiveness and Preservation of Anti-tumor Efficacy

**Gary Koch, PhD**
**Chapel Hill, NC**

## Preservation of Anti-tumor Efficacy (LRC)

****	**p*-Value based on Fisher’s Exact test
- **Local/regional control ratio >1.0 favors Amifostine + RT

**Local/regional control rate****	****Amifostine + RT****	****RT Alone**
**	*****p*****-Value***
**Local/regional control ratio****
**Lower limit of 95% one-sided****	****confidence interval**
**95% confidence****	****interval (2 sided)**

**12 Months**

**18 Months**

**91/127 (72%)****96/135 (71%)**
**1.000**
**1.008**
**(0.886)**
**(0.864, 1.175)**

**77/126 (61%)****85/133 (64%)**
**0.700**
**0.956**
**(0.816)**
**(0.792, 1.155)**

## Point Rate and RatiosKaplan-Meier Estimates (LRC)

**100**

**Percent local-regional control**

**Months**

**0**

**90**

**80**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**Log-rank P:  0.776**
**Hazard ratio:  0.946 (0.643-1.392)**
**26 month median follow-up**

**                               ****RT + Amifostine****	****	****52****	****150****	****	**
**                         ****RT Alone****	****	****51****	****153****	**

**Failures**

**Total**

**76%**

**75%**

**65%**

**68%**

**12 Months**
**	****Ratio:****	****     1.015**
**	****Lower Limit:****	****0.909**
**	****95% CI: ****	****0.890, 1.157**

**18 Months**
**	****Ratio:****	****     0.954**
**	****Lower Limit:****	****0.831**
**	****95% CI:      0.809,1.126**

## Point Rate and RatiosKaplan-Meier Estimates (DFS)

**Months**

**0**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**100**

**Percent disease-free survival**

**90**

**80**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**Amifostine + RT****RT Alone**

**Events**

**58****59**

**Total**

**150****153**

**Log-rank - P-0.958****Hazard ratio - 0.990 (0.689-1.423)****26 month median follow-up**

**75%**

**70%**

**63%**

**63%**

**12 Months**
**	****Ratio:****	****     1.06**
**	****Lower Limit:****	****0.941**
**	****95% CI: ****	****0.920, 1.221**

**18 Months**
**	****Ratio:****	****     1.01**
**	****Lower Limit:****	****0.868**
**	****95% CI: ****	****0.844, 1.205**

## Point Rate and RatiosKaplan-Meier Estimates (OS)

**90**

**100**

**Percent survival**

**Months**

**0**

**80**

**70**

**60**

**50**

**40**

**30**

**20**

**10**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**   ****Total**

**Log-rank - P-0.184****Hazard ratio - 1.351 (0.865-2.109)**

**89%**

**82%**

**81%**

**73%**

**12 Months**
**	****Ratio:****	****     1.08**
**	****Lower Limit:****	****1.003**
**	****95% CI: ****	****0.988, 1.190**

**18 Months**
**	****Ratio:          ****	****1.12**
**	****Lower Limit:****	****1.004**
**	****95% CI: ****	****0.983, 1.270**

## Preservation of Anti-tumor EfficacyDifference in LRC Rates-Crude Data Analysis

**Local/regional control rate*****	****Amifostine + RT****	****RT Alone**
**Difference between rates**
**95% confidence interval (2-sided****)**

**12 Months**

**0.7165****0.7111**
**0.0054**
**-0.104, 0.115**

**18 Months**

**0.6111****0.6391**
**-0.0280**
**-0.146, 0.090**

**Preservation of Anti-tumor Efficacy****Difference in LRC Rates-Crude Data Analysis**

***Crude rate calculation**

## Preservation of Anti-tumor EfficacyDifference in LRC Rates - Kaplan Meier Estimates

**Local/regional control rate****	****Amifostine + RT****	****RT Alone**
**Difference between rates**
**95% confidence interval (2-sided****)**

**12 Months**

**0.7613****0.7501**
**0.0112**
**-0.088, 0.110**

**18 Months**

**0.6533****0.6846**
**-0.0313**
**-0.142, 0.079**

**Preservation of Anti-tumor Efficacy****Difference in LRC Rates - Kaplan Meier Estimates**

## Preservation of Anti-tumor EfficacyDifference in DFS Rates - Kaplan Meier Estimates

**Disease-Free survival rate****	****Amifostine + RT****	****RT Alone**
**Difference between rates**
**95% confidence interval (2-sided****)**

**12 Months**

**0.7464****0.7045**
**0.0419**
**-0.061, 0.145**

**18 Months**

**0.6332****0.6279**
**0.0053**
**-0.107, 0.118**

**Preservation of Anti-tumor Efficacy****Difference in DFS Rates - Kaplan Meier Estimates**

## Preservation of Anti-tumor EfficacyDifference in Survival Rates - Kaplan Meier Estimates

**Overall survival rate****	****Amifostine + RT****	****RT Alone**
**Difference between rates**
**95% confidence interval (2-sided****)**

**12 Months**

**0.8943****0.8249**
**0.0694**
**-0.010, 0.149**

**18 Months**

**0.8127****0.7273**
**0.0854**
**-0.012, 0.183**

**Preservation of Anti-tumor Efficacy****Difference in Survival Rates - Kaplan Meier Estimates**

## ConclusionsPreservation of Anti-tumor Efficacy

**Lower limits of one- and two-sided 95% ****	****confidence intervals are sufficiently ****	****high to assure non-inferiority of ****	****	****amifostine group**

## Supportive Studies

**Lesley Russell, MD**
**Senior Director, Clinical Research****U.S. Bioscience**

## Amifostine Efficacy (Xerostomia)in Radiation Therapy

**	**

**Study****	****	****	****       Design****	****             ****	****          Patients (N)**
**Brizel (WR-38)****	****	****Phase III, Open label, parallel group ****	****	****303**
**Antonadou****	****	****Phase II, Open label, parallel group****	****  ****	****  45**
**Bohuslavizki****	****	****Phase II, Double-blind, placebo controlled        50**
**Takahashi****	****	****Phase I, Single-arm, historical control****	****	****105**
**McDonald****	****	****Phase I/II, Single-arm, historical control             12**
**B********ntzel****	****	****Phase II, Open label****	****	****	****	****  39**
**	****	****	****TOTAL PATIENTS TREATED ****	****	****554**

## Treatment Schedule

**R**
**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**E**

**Radiation 2 Gy/day, total dose 60-74 Gy**
**Carboplatin 90 mg/m****2****/week**
**Amifostine 300 mg/m****2****/day**
**n=22**

**Radiation 2 Gy/day, total dose 60-74 Gy**
**Carboplatin 90 mg/m****2****/week**
**n=23**

**Antonadou**

## Patient Demographics

**Well-balanced pre-treatment for:**
**Age**
**Gender**
**Tumor site**
**Tumor stage**
**Nodal status**

## Xerostomia Results*

**Xerostomia Results***

**N=22**

**4**
**12**
**6**
**0**
**6**

**18%**
**55%**
**27%**
**-----**
**27%**

**N=23**

**0**
**4**
**17**
**2**
**19**

**  ****0**
**17%**
**74%**
**  ****9%**
**83%**

**Radiation Toxicity/**
**RTOG Grade**

**Late-Effect Xerostomia****	****Grade 0**
**	****Grade 1**
**	****Grade 2**
**	****Grade 3**
**	****Total ********Grade 2**

**Amifostine + RCT**

**RCT**

**%**

**%**

## Xerostomia Results*

**Xerostomia Results***

**Updated Information **

**N=24**

**2**
**2**
**4**
**2**
**0**
**2**

**  ****8.3%**
**  ****8.3%**
**16.6%**
**  ****8.3%**
**—**
**  ****8.3%**

**N=25**

**15**
**3**
**18**
**13**
**1**
**14**

**60%**
**12%**
**72%**
**52%**
**4%**
**56%**

**Radiation Toxicity/**
**RTOG Grade**

**9 Months****	****Grade 2**
**	****Grade 3**
**Total ********Grade 2**
**12 Months**
**Grade 2**
**Grade 3**
**Total ********Grade 2**

**Amifostine + RCT**

**RCT**

**%**

**%**

## Anti-tumor Efficacy Results

**Anti-tumor Efficacy Results**

## Safety

**Safety**

**Nausea/vomiting****	****	****	****1%**
**Transient hypotension****	****	****3%**

## Conclusions

**Significant reduction in ********Grade 2     ****	****	****late xerostomia**
**Preservation of anti-tumor efficacy**
**Amifostine well tolerated**

## Supportive Studies

**Preservation of Anti-tumor Activity**

## Rectal Cancer Survival

**Liu, et al (WR-9001)**

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**0.0**

**0**

**5**

**10**

**15**

**20**

**25**

**30**

**Proportion of patients alive**

**Months**

**Amifostine + RT****	****    16%****	****       15.0**
**RT Alone****	****	****    10%            12.6**

**Response Rates   Survival (months)  **

**95% CI****	****	****0.647-1.546**

## Ovarian Cancer Survival

**Kemp, et al  (WR-1)**

**80**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0**

**10**

**20**

**30**

**50**

**40**

**70**

**60**

**Time (months)**

**Survival**

## Conclusions

**Three randomized, well-controlled ****	****	****Phase III studies demonstrate that ****	****	****amifostine does not compromise anti-****	****tumor efficacy**

**Anti-tumor Efficacy**

## Benefits/Risks of Amifostinein Radiation Therapy forHead and Neck Cancer

**Walter Curran, MD**
**Professor and Chairman, Radiation Oncology**
**Kimmel Cancer Center**
**Jefferson Medical College**
**Chairman, Radiation Therapy Oncology Group****Philadelphia, Pennsylvania**

## Local-Regional ControlRTOG-Database Compared to WR-38

- *Using estimates of locoregional failure from RTOG studies and the percentages of definitive, low risk, and high risk patients in WR-38 (33%, 20%, and 47% respectively).

**71%**

**61%**

**RTOG   N=517**

**WR-38**

## Local/Regional Failure

**Year 1**

**Year 2**

**Year **_**>**_**3**

**Estimated Rates Using Matched Controls from**
**RTOG Database**

## Conclusions

**Wolfgang Oster, MD**
**U.S. Bioscience, Inc.**

## Substantial Evidence

**New indication for drug already ****	****	****approved in cancer treatment**
**Reduction of irreversible ****	****	****	****morbidity—xerostomia**
**WR-38 plus supportive studies ****	****	****confirm efficacy in xerostomia**
**All studies consistently report ****	****	****positive xerostomia results**

## WR-38

**Different, but logically linked, endpoints**
**All statistically very persuasive**
****** ****Grade 2 acute xerostomia****	****	*****p****** *****<0.0001**
****** ****Grade 2 late xerostomia  ****	****	*****p****** *****=0.0019**
**Saliva production >0.1 gm   ****	****	*****p****** *****=0.0033**
**PBQ longitudinal at month 11  ****	*****p****** *****=0.0067**
**PBQ oral dryness at month 11  ****	*****p****** *****=0.001**
**Statistically significant correlation of endpoints**
**Clinically meaningful**
**Patients experienced significant clinical benefit**

## Amifostine SNDAConclusions

**Reassuring evidence for safety**
**Demonstration that amifostine ****	****	****preserves anti-tumor efficacy**

## Amifostine SNDAConclusions

**Amifostine is safe and effective for the ****	****	****indication:**
**	*****To reduce the incidence of moderate to ******	******	******severe radiation-induced xerostomia***