# Presentation: 205711

## PHOTOFRIN® PDT for High-grade Dysplasia in Barrett’s Esophagus  

**Edvardas Kaminskas, M.D.**
**Medical Officer, CDER, ODE III, DGCDP**
**Milton Fan, Ph.D.**
**Statistical Reviewer, CDER, ODE III, DGCDP **
**CDER GI Drugs Advisory Committee**
**June 26, 2003**

## Overview

**Background**
**Clinical trials**
**Efficacy endpoints and results**
**Patient disposition**
**Other therapies**
**Safety issues**

## Background

**HGD is treated to decrease the risk of progression to cancer. **
**Incidence of adenocarcinoma of esophagus increasing; however,**
**Most cancer cases (94% - 98%) do not have a prior diagnosis of BE**
**Most BE patients do not develop cancer: annual incidence of 0.5% or less**
**Cancer risk to an older patient with GERD is very low: 6500 cases per year among 10 million (0.00065 per year) **

## Proposed New Indication

**“****the ablation of high-grade dysplasia (HGD) in Barrett’s esophagus (BE) among patients who are not considered to be candidates for esophagectomy.”**
**“****the ablation of HGD in BE among patients who refuse esophagectomy and who are in overall good health.”**

## Clinical Trials in Support of the New Indication

_**PHO BAR 01**_**. Multicenter, randomized, 2-arm trial with minimum 24-month f/u. Patients randomized 2:1 ratio**
**138 patients to PHOTOFRIN PDT + omeprazole**
**  ****70 patients to OM (omeprazole) only**
_**TCSC 93-07 and TCSC 96-01.**_** Single center, open-label trials, minimum 12-month follow-up. **_**All patients treated with PHOTOFRIN PDT + omeprazole.**_** In 93-07 patients randomized to 2 light doses; in 96-01, to  +/- post-PDT steroids to test effect on stricture incidence.**
**186 patients, 86 with HGD**

## PHOTOFRIN Photodynamic Therapy in PHO BAR 01

-     **	****	****	****	****Course 1****	****Course 2****	****Course 3**
**Patients****	****	****N = 130****	****	****N = 89****	****	****N = 42**
_**First laser light session**_
**Nodule pre-Rx            N = 35****	****	****N = 27****	****	****N = 12**
**Balloon light****	**** N = 129****	****	****N = 89****	****	****N = 41**
_**Second laser light session**_
**Treatment of skip**
**areas****	****	****N = 60****	****	****N = 49****	****	****N = 21**

## Efficacy Endpoints

**Primary endpoint: Complete ablation of HGD and replacement with **
**normal squamous cell epithelium (CR1),**
**with some metaplasia remaining (CR2), or**
**with some low-grade dysplasia or indefinite dysplasia (CR3)**
**at 24 months’ follow-up.**

## Efficacy Endpoints

**Secondary endpoints:**
**Complete Response (CR3 or better) at 6, 12, 18, and 24 months**
**Quality of Complete Response (% of patients with CR1, CR2, and CR3)**
**Duration of Response**
**Time to Progression to Cancer**
**Time to Treatment Failure (progression to cancer, or other intervening therapy than study treatment)**
**Survival time**

## Efficacy Endpoints

**Agency’s concerns at Initiation of PHO BAR 01 study:**
**The primary response variable must reflect an improvement in the long-term clinical outcome.**
**Histopathological effects might be a surrogate endpoint for measuring clinical benefit.**
**A follow-up time of 5 years or more recommended, but follow-up of at least 2 to 3 years acceptable.**

## Efficacy Results

## Efficacy Results

##  Efficacy Results

-  **Efficacy Results**

## Efficacy Results

## Efficacy Results

_**PDT group**_**: Patients who progressed to cancer were CR3 responders (6) and non-responders (12). **
_**OM Only group**_**: The one (1) responder who progressed to cancer had CR3. The rest (19) were non-responders.**

## Selection of Appropriate Patients

**Patients without HGD may be referred for PHOTOFRIN PDT. In PHO BAR 01:**
**Patients with HGD referred     485**
**Diagnosis not confirmed           237 (49%)**
**Diagnosis of HGD should be confirmed by a Reference Laboratory**

## Patient Disposition

## Other Therapies

## Safety Issues

**Acute events related to light treatment ****(chest pain, abdominal pain, fever, nausea, vomiting, dysphagia, odynophagia)**
**Skin photosensitivity **
**Sub-acute events related to healing**
**Esophageal strictures, defined as**
_**Esophageal narrowing (on endoscopy) that required dilation**_

## Safety IssuesStrictures

## Safety IssuesNumber of Dilations

## Summary

**Aggressive surveillance: **
**Not a good option for most patients in PHO BAR 01 study; 84% chose active treatment.**
**Information on risk of cancer in HGD is essential for evaluation of treatment options, but may be difficult to obtain.**
**Esophagectomy: **
**Follow-up information not available.**

## Summary

**PHOTOFRIN PDT:  **
**Relatively well tolerated. Few withdrew because of adverse events.**
**No deaths due to treatment or esophageal cancer.**
**Most SAEs were GI and dehydration.**
**Strictures were troublesome but manageable.**

## Summary

** ****2-year follow-up suggests PHOTOFRIN PDT is effective. PDT patients had:  **
**50% lower cancer rate**
**CR rates twice as high. CR associated with lower risk of cancer**
**Mainly in high quality CR1. Only patients with CR3 progress to cancer **

## Summary

**But a 2-year follow-up is too short to demonstrate effectiveness in reducing the **_**long-term risk of cancer**_**. **
**Rate of recurrence of HGD not known**
**Rate of HGD progression to cancer not known**
**PHO BAR 02 in process **

## Slide 25

## Questions for the Committee - 1

**Is the proposed **_**INDICATION**_** for PHOTOFRIN PDT appropriate?**
** “****the ablation of HGD in BE among patients who refuse esophagectomy and who are in overall good health”**
**If not, what would be an appropriate **_**INDICATION**_**?**

## Questions for the Committee - 2

**Is a 2-year follow-up period adequate for the claim of cancer risk reduction in High-grade Dysplasia patients treated with PHOTOFRIN PDT?**

## Questions for the Committee - 3

**In view of failure to confirm the diagnosis of High-grade Dysplasia in about 50% of  patients, what safeguards would the Committee recommend to insure that only HGD patients are treated with PHOTOFRIN PDT?**

## Questions for the Committee - 4

**Should treatment with proton pump inhibitors be recommended, and for what length of time, before treatment of High-grade Dysplasia patients with PHOTOFRIN PDT?**** **
**Should the diagnosis of High-grade Dysplasia be confirmed by a reference laboratory of acknowledged expertise before PHOTOFRIN PDT is undertaken?**

## Questions for the Committee - 5

**Are there ethical concerns about continuing patients in the Omeprazole Only arm of the study?**

## Questions for the Committee - 6

**Are there patients with High-grade Dysplasia who should not undergo PHOTOFRIN PDT, because of **
**safety concerns**
**uncertainties in the natural history of HGD**
**other considerations?**

## Questions for the Committee - 7

**How would the availability of PHOTOFRIN PDT on the market impact the current approach to the treatment of HGD?**