# Presentation: 708380

## Clinical Trials Endpoints

**Mario Eisenberger M.D.**
**R. Dale Hughes Professor **
**Oncology/Urology**
**Sidney Kimmel Comprehensive**
**Cancer Center at Johns Hopkins**
**The Johns Hopkins University**

## Clinical Trials in Docetaxel Failures

**Docetaxel is first-line standard in AIPC**
**Median survival on first-line Rx candidates is 18-19 months (TAX-327 , SWOG 9916)**
**Median progression- free survival with 1****st**** line Rx is **_**probably**_** +/- 6 months (SWOG 9916, TAX-327 ???)**
**Most patients remain candidates for further treatment**
**No clearly established standard 2****nd**** line treatment**

## HRPC STATEDocetaxel failures - M+ patients

**HRPC**
**Docetaxel**

**Median**
**PFS**
**6 mos.**

**2****nd**** line **
**candidates**

**Death**

**Median**
**Survival**
**12 mos.**

## Clinical Trials Design“2nd line treatment”

**Conventional phase II designs for initial screening**
**Phase III trials with the following endpoints: Survival , PFS , Palliation**

## Phase II trials

**Single arm study (conventional endpoints)**
**Randomized phase II studies**
**What constitutes a “positive” study**
**Accelerated approval ?**

## Registration Studies

**Conventional phase III study ****→ survival remains the “gold standard”**
**Control arm (s). **
**   ****Symptomatic treatment such as mitoxantrone + P, prednisone alone ,second-line hormonal Rx etc  **

## Registration Studies

** ****   ****- Combinations involving more than one experimental (targeted) agents. **
**   ****Drug A + atrasentan vs. atrasentan vs. A**
**    ****- Proof of principle trials **
**    ****Paclitaxel + imatinib vs. paclitaxel vs.imatinib   **
**   ****Radiopharmaceuticals + chemotherapy vs. chemotherapy vs. radiopharmaceuticals **
**   ****- Dose/response assessments (pain, bone markers,  **

## “Progression endpoints”

**Many endpoints used**
**What is “clinically relevant”?**
**How do we ensure that all endpoints are collected?**
**Could these lead to registration at this point?**

## Progression-free survivalTAX-327

**Significance of observations is questionable because:**
**- Frequent censoring with all endpoints**
**- Individual patient management decisions are complex and affect clinical trials outcome**
**- Observations are protocol driven ( e.g. frequency of evaluations , loopholes ****→ “...as clinically indicated” etc)**

## “Real life scenarios”

**65 yrs**
**Pain level 8**
**PSA = 80ng/ml**
**10 lesions on bone scan**

**Baseline at study**
**entry**

**Pain level 0-1**
**PSA = 50ng/ml**
**13 bone lesions**

**Pain level 1-2**
**PSA = 120 ng/ml**
**10 bone lesions**

**Pain level 9-10**
**(needs radiation)**
**PSA 25ng/ml**
**Bone scan **
**same**

**At 3 months**

**Objective **
**Progression**
**PSA/pain**
** ****censored**

**PSA **
**Progression**
**Pain/objective**
**censored**

**Pain **
**Progression**
**PSA/objective**
**censored**

## Pain PFS 

**Heavily censored (62-68%) **
**Study chemotherapy main censoring reason  **

**Time (months)**

**Proportion not progressed**

**Median    HR    p-value**
**8.3 mo    0.85   0.2110**
**9.0 mo    0.70   0.0087**
**6.4 mo      ****–****          ****–**** **

**D q3w**

**D wkly**

**MTZ**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Number of patients at risk:**

- 335

- 156

- 85

- 45

- 14

- 6

- 3

- 334

- 153

- 96

- 40

- 18

- 9

- 4

- 337

- 126

- 69

- 38

- 17

- 10

- 5

## PSA PFS

**D q3w**

-  **D wkly**

**MTZ**

**Median    HR    p-value**
**8.6 mo    0.81   0.0638**
**9.3 mo    0.63   0.0002**
**6.4 mo      ****–****          ****–**** **

**Heavily censored (56-69%) **
**Study chemotherapy main censoring reason  **

- 0

- 3

- 6

- 9

- 12

- 15

- 18

- 0.0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5

- 0.6

- 0.7

- 0.8

- 0.9

- 1.0

- 335

- 167

- 90

- 43

- 13

- 7

- 5

- 334

- 164

- 105

- 48

- 13

- 5

- 4

- 337

- 135

- 74

- 46

- 15

- 5

- 2

**Time (months)**

**Proportion not progressed**

**Number of patients at risk:**

## Objective PFS

**D q3w**

**D qw**

**MTZ**

**Median    HR    p-value**
**8.7 mo    0.72   0.0157**
**7.5 mo    0.74   0.0222**
**6.4 mo      ****–****          ****–**** **

**Heavily censored (63-69%) **
**Study chemotherapy main censoring reason  **

- 0.0

- 0.1

- 0.2

- 0.3

- 0.4

- 0.5

- 0.6

- 0.7

- 0.8

- 0.9

- 1.0

- 0

- 3

- 6

- 9

- 12

- 15

- 18

**Time (months)**

**Proportion not progressed**

- 335

- 128

- 82

- 37

- 11

- 4

- 3

- 334

- 137

- 93

- 33

- 14

- 4

- 3

- 337

- 106

- 69

- 34

- 13

- 6

- 2

_**Number of patients at risk:**_