# Presentation: 175672

## Sipuleucel-T

**BLA 125197**
**FDA Clinical Review and Findings**
**Ke Liu, MD, PhD**
**Clinical Reviewer**
**Division of Clinical Evaluation, Pharmacology and **
**	****Toxicology (DCEPT), OCTGT, CBER, FDA**
- March 29, 2007
- Cellular, Tissue and Gene Therapies Advisory Committee Meeting

## Outline of Presentation

- Efficacy findings
- Study design
- Results
- Safety findings
- Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs)
- Cerebrovascular Accidents (CVAs) --- Sponsor’s updated information

## Terminology of Presentation

- Study Names
- Study 1 = D9901
- Study 2 = D9902A
- Study agents
- Sipuleucel-T = APC8015
- Placebo = APC-Placebo
- APC8015F = Frozen and thawed PBMC as source material, then prepared similarly as Sipuleucel T

## Proposed Indication: 
	Treatment of men with asymptomatic metastatic androgen independent prostate cancer (AIPC) 

Basis of claim: 
D9901: a 4.5-month overall survival difference
D9902A: a 3.3-month overall survival difference (not significant)

**Proposed Indication: **
**	****Treatment of men with asymptomatic metastatic androgen independent prostate cancer (AIPC)**
**Basis of claim: **
**D9901: a 4.5-month overall survival difference**
**D9902A: a 3.3-month overall survival difference (not significant)**

**Basis for BLA submission:****Overall Survival**

## D9901 and D9902A 

**Similarly designed randomized, double-blind, placebo-controlled trials in men with asymptomatic metastatic androgen independent prostate cancer. **
**Primary Endpoint: Time To Disease Progression**
**D9901 enrolled 127 subjects, 82 in Sipuleucel-T arm, 45 in Placebo**
**D9902A planned 120 subjects, but terminated early; 65 in Sipuleucel-T arm, 33 in Placebo**
**Study Period:**** **
**D9901, 01/00-09/04 **
**D9902A, 05/00-09/04**

## Key Eligibility Criteria

**Histologically documented adenocarcinoma of the prostate**
**Metastatic disease as evidenced by soft tissue and/or bony metastases. **
**PSA ****≥**** 5 ng/mL. **
**Tumor or PSA progression after hormonal therapy.**
**Castrate levels of testosterone (<50 ng/dl)**
**No cancer-related pain**

## Treatment Schema

**Asymptomatic Metastatic **
**AIPC**
**(N = 127)**

**Sipuleucel-T**
**Q 2 wks x 3**
- (**N = 82**)

**Placebo**
**Q 2wks x 3**
**(N = 45**)

**P**
**R**
**O**
**G**
**R**
**E**
**S**
**S**
**I**
**O**
**N**

**(Optional use of**
**APC8015F**
**Q 2 wks x 3)**
**Follow-up *******

**Treatment Schema**

- * **Post progression chemotherapy +/- other options allowed**

**R  A  N  D  O M   I    Z   E **
**2:1**

**Follow-up*******

## Treatment Regimen

**  ****prior to the infusion date**
** ****Sipuleucel-T or Placebo: 3 doses, q 2 wks, i.v. **
** ****The cell counts in each individual dose varied  **
**  ****depending on the apheresis yield. **
** ****Minimum for each dose of Sipuleucel-T was **
**  ****approximately 3 X 10****6 ****CD54****+ ****cells.**
** ****The dose for Placebo was 1/3 of the   **
**   ****total cells harvested from the apheresis. **
** ****Bisphosphonate allowed**
** ****Continued hormonal treatment**

**Treatment Regimen**

## Primary Endpoint 

**   ****Time to disease progression, as defined by time from randomization to the first observation of disease progression**
**Radiological Progression (**Bone Scan q 8 wks, CT/MRI q 8 wks if baseline +)
**New Cancer Related Pain** (X-ray correlation required)
**Clinical Events**
- Pathological Fracture, Cord or Nerve Root Compression
- “Other Clinically-significant disease-specific events”

## Secondary Endpoints

**Overall time from randomization to the development of disease-related pain**
**Overall time from randomization to earliest evidence of clinical progression**
**Rate of objective response**
**Duration of response**
**Time to treatment failure**

## Statistical Assumptions

**Median Time to Progression:**
** ****	****Based on the sponsor’s past experience ****	****and a review of the literature**** ****	**
** ****	****Placebo: 16 weeks****	****   Sipuleucel-T: 31 weeks  (HR = 1.92)****	****	****	****   **
** ****	****Alpha = 5% two-sided; 80% power**** **
**  ****2:1 Randomization**

## D9901 

**Efficacy **
**Results**

## D9901 Patient Demographic 

**and Baseline Characteristics **

- 					                **Sipuleucel-T****	****   ****	****      Placebo**
**	****	****	****	****	****	****              ****(n = 82)                         (n = 45)**
**Median age (range)**			  73 yrs (47–85)	 71 yrs (50–86)
**Ethnicity**
- 	Caucasian					73 (89%)		  42 (93.3%)
- 	African-American                       8 (9.8%)                    1 (2.2%)
**   **Hispanic                                     1 (1.2%)                    1 (2.2%)
-    Unknown                                    0                               1 (2.2%)
**ECOG PS**
- 	   0							       62 (75.6%)		  37 (82.2%)
-       1							       20 (24.4%)		    8 (17.8%)

## D9901 Patient Demographic and Baseline Characteristics (continued)

**	****	****	****	****	****	****	****              ****(n = 82)                      (n = 45)**
**Gleason Score** ≤ 6  n (%)		22 (26.8%)		   7 (15.6%)
-                         = 7  n (%)		28 (34.1%)		  18 (40%)
- 				       ≥ 8  n (%)		32 (39%)		  20 (44.4%)
- Disease location
- 	Bone only					34 (42.0%)	              10 (23.8%)
- 	Soft tissue only				         5 (6.2%) 	                3 (7.1%)
- 	Bone and soft tissue			 42 (51.9%)	  29 (69%)
- No. of bone metastases/subject
- 	0					             	  5 (6.1%)             	    4  (8.9%)
- 	1-5					             	31 (37.8%)              17 (37.8%)
- 	6-10				             		12 (14.6%)              12 (26.7%)
- 	> 10					            	34 (41.5%)              12 (26.7%)

**D9901 Patient Demographic and Baseline Characteristics (continued)**

## D9901 Primary Endpoint ---Time to Progression

**127 subjects randomized**
**114 had progression event**
**0 deaths prior to progression event**
**Progression documented by**
**Imaging: 97  **
**Clinical event: 10 **
**Onset of disease related pain correlated with imaging: 7**

## D9901: Time to Disease Progression

- No statistical difference by Log-rank test: p = 0.085, HR = 1.39, 95% CI: 0.95, 2.03
- Median TTP
- Sipuleucel-T:  11.1 weeks (range: 2.1 to 57.4)
- Placebo: 9.1 weeks (range 3.9 to 52.1)

## Discussion --- D9901 Primary Endpoint (TTP) Result

**After unblinding, the 1****st**** analysis showed a log rank p-value for time to progression: 0.085 **
**Changed from 0.085 to 0.052**
- Unblinded audit of clinical data
- Primarily driven by two subjects

## Discussion continued ---D9901 Primary Endpoint (TTP) Result

**Difficulties in interpretation of TTP results:**
**Overestimation of TTP:**** **
- Assumption: 16 weeks for placebo and 31 weeks for Sipuleucel-T
- Actual observation: 9-11 weeks for both arms
**Median progression prior to scheduled second assessment for progression**
**Lack of scans to detect soft tissue progressions in some bone only subjects according to the study design**
**Un-interpretable progression dates in some subjects due to protocol violations**

## Conclusion --- D9901 Primary Endpoint (TTP)

**FDA considers the p-value of 0.085 by log-rank test to be the result from the primary analysis specified in the protocol and the p-value of 0.052 to be derived from an exploratory analysis.**
**The study failed to show a Sipuleucel-T treatment effect on the primary endpoint, TTP. **

## D9901 Secondary Endpoints

**No difference observed between two arms for any of the following:**
**Overall time to the development of disease-related pain**
**Overall time to earliest evidence of clinical progression**
**Rate of objective response**
**Duration of response**
**Time to treatment failure**

## D9901 Overall Survival 

## D9901 Overall Survival 

*****All subjects were followed for 36 months or until death
- # From available data

| 
Treatment
 |   
N | Deaths before 36 months* | Deaths
after 36 months# | Alive at 
36 months | Median Survival (months) |
| --- | --- | --- | --- | --- | --- |
| Sipuleucel-T | 82 | 54 | 8 | 28 (34%) | 25.9 |
| Placebo | 45 | 40 | 0 | 5 (11%) | 21.4 |
| p-value | --- | --- | --- | 0.0046 chi2
 | 0.010
Log-rank |

## Therapy After Progression D9901  

| Treatment arm | ITT population | Chemo info available | Received Taxane (%) | Received any chemo (%) |
| --- | --- | --- | --- | --- |
| Sipuleucel- T | 82 | 79 | 34 (43.6) | 43 (54.4) |
| Placebo | 45 | 43 | 22 (53.7) | 27 (62.8) |

-   Chemotherapy

-   Placebo subjects “cross-over” to
-    APC8015F:  34/45 (75.6%)

## Potential Chemotherapy Confounding Effects on Overall Survival

- Analysis of the time from randomization to 1st chemotherapy use did not suggest an earlier initiation of chemotherapy in Sipuleucel-T subjects
- The dose and cycles of chemotherapy were not collected
- Potential chemotherapy confounding effects on overall survival are unlikely, but cannot be ruled out

## D9901 Efficacy Summary

- N = 127, randomized 2:1 to Sipuleucel-T (Sipuleucel-T) : Placebo
- A small sample size
- No difference between two arms in the pre-specified efficacy endpoints
- Overall Survival:
- 4.5-month difference in median survival in Sipuleucel-T arm (p = 0.010, HR 1.7)

## CD54 Upregulation and Survival

**Above the mean**

**Below the mean**

## Interpretation of CD54 Results 

**Intrinsic property of individual patients**
**Intrinsic property of individual products **
**	****after manufacturing process. (Placebo did not undergo the same process as Sipuleucel-T)**
**Other factors?**

## Immunological Analyses --- T cell Stimulation Index

| Antigen  | Sipuleucel-T  |  | Placebo  | p-value  |
| --- | --- | --- | --- | --- |
|  | Median of the Geometric Mean  |  |  |  |
| Week 0 to Week 8  | n = 31  | n = 16  |  |  |
| PA2024  | 16.91  | 1.99  |  | 0.0004  |
| Human PAP  | 1.07  | 1.90  |  | 0.2238  |
| Week 0 to Week 16  | n = 14  | n = 8  |  |  |
| PA2024  | 13.22  | 0.91  |  | 0.0001  |
| Human PAP | 0.99  | 0.40  |  | 0.0890  |

## Interpretation of Stimulation Assays 

**Proliferation assay not a direct assay for T cell response**
**Assays performed only in a small subset of patients**
**No response to human PAP**

## D9902A 

**Efficacy **
**Results**

## Study D9902 

** ****Same design as D9901**
**  ****Planned 120 subjects**
** ****Time To Disease Progression **
**   ****as 1****0**** endpoint**

**     ****D9902A **
** ****Insufficient sample size **
** ****Not powered to see a difference **
**  ****in TTP or overall survival**

**Renamed ****D9902A ****: 98 subjects already enrolled**

**                   ****Terminated (3/2003) **
**Because of D9901 overall negative efficacy**

## D9902A Patient Demographic and 

**Baseline Characteristics **

- 						                **Sipuleucel-T****	****      Placebo**
**	****	****	****	****	****	****	****              ****(n = 65)                      (n = 33)**
**Median age (range)**			70.0 yrs (51–84)	71.0 yrs (57–87)
**Ethnicity**
- 	Caucasian					59 (90.8%)		  31(93.9%)
- 	African-American                      2 (3.1%)                    2 (6.1)
-    Hispanic                                     1 (1.5)                      0
-    Other                                   	 3  (4.6)		    0
**ECOG PS**
- 	   0							       51 (78.5%)		  23 (69.7%)
-       1							       14 (21.5%)		  10 (30.3%)

## D9902A Patient Demographic and Baseline Characteristics (continued)

**	****	****	****	****	****	****	****              ****(n = 65)                      (n = 33)**
**Gleason Score** ≤ 6  n (%)		15 (23.4%)		   9 (27.3%)
-                         = 7  n (%)		29 (45.3%)		  8 (24.2%)
- 				       ≥ 8  n (%)		20 (31.3%)		  16 (48.5%)
**Disease location**
- 	Bone only					31 (47.7%)	              10 (30.3%)
- 	Soft tissue only				         7 (10.8%) 	   7 (21.2%)
- 	Bone and soft tissue			 27 (41.5%)	  16 (48.5%)
**No. of bone **
**metastases/subject** 				 N = 61                     N = 32
- 	0					             	  5 (8.2%)             	    4  (8.9%)
- 	1-5					             	19 (31.1%)              11 (34.4%)
- 	6-10				             		6 (9.8%)              	   2  (6.3%)
- 	> 10					            	31 (50.8%)              12 (37.5%)

**D9902A Patient Demographic and Baseline Characteristics (continued)**

## D9902A Time to Disease Progression

- The estimated median TTP:
-   **10.9** weeks in the Sipuleucel-T arm (Range  3.4 to 106.6 wks)
-    **9.9** weeks in the APC placebo arm  (Range  1.7 to 130.1 wks)

## D9902A Overall Survival

**D9902A Overall Survival**

- Median survival time (MST) Estimates:
- Sipuleucel-T: **19.0** months (13.6, 31.9)
- Placebo **15.7** months (12.8, 25.4)

## D9902A Efficacy Summary

**N = 98, randomized 2:1 to Sipuleucel-T: Placebo**
**Similar trial design and execution as D9901**
**Stopped early. Insufficient sample size to detect a difference in TTP or overall survival**
**No statistical difference in time to progression, overall survival between treatment arms**

## Safety Evaluation 

**Main analyses from D9901and D9902A database: **
**146 subjects received Sipuleucel-T**
**76 subjects received Placebo **
**Cerebrovascular accidents (CVA) events from an updated database including other phase 3 trials, D9902B and P-11**
**Complete safety database update was submitted last week to include a total of 461 subjects who received Sipuleucel T and 231 subjects who received Placebo**

## Infusion Exposure (D9901 and D9902A)

| 

Infusions |  | Sipuleucel-T |  | Placebo |  |
| --- | --- | --- | --- | --- | --- |
|  |  | N = 147 |  | N = 78 |  |
|  |  | # | % | # | % |
|  | 3 | 132 | 89.8 | 70 | 89.7 |
|  | 2 | 10 | 6.8 | 5 | 6.4 |
|  | 1 | 4 | 2.7 | 1 | 1.3 |
|  | 0 | 1 | 0.7 | 2 | 2.6 |

##           Death (D9901 and D9902A) 

| Cause of Death | Sipuleucel-T
N = 107 |  | Placebo
N = 66 |  |
| --- | --- | --- | --- | --- |
|  | # | % | # | % |
| Disease Progression | 70 | 65.4 | 51 | 78.5 |
| Unknown | 21 | 19.6 | 10 | 15.4 |
| CVA | 5 | 4.6 | 1 | 1.5 |
| CHF | 2 | 1.9 | 3 | 4.5 |
| Infection | 1 | 0.9 | 0 | 0 |
| Other known cause# | 8 | 7.5 | 1 | 1.5 |

- # Included one death from each of the following in Sipuleucel-T arm: Cardiac Arrest; Dementia; Glioblastoma; Met. Esophageal Ca; Orthopedic Complication; Renal Failure; Sepsis and ARDS; UTI; one death from Small Cell Carcinoma In Placebo

## SAEs* (≥ 2%, D9901 and D9902A)

| SAE |  Sipuleucel-T 
N = 147 |  | Placebo 
N = 78 |  |
| --- | --- | --- | --- | --- |
|  | # | % | # |  % |
| Chills | 5 | 3.4 | 0 | 0 |
| Dyspnoea | 4 | 2.7 | 1 | 1.3 |
| Pyrexia | 4 | 2.7 | 0 | 0 |
| Cerebrovascular accident (CVA) | 3 | 2.0 | 0 | 0 |
| Dehydration | 3 | 2.0 | 2 | 2.6 |
| Urinary retention | 2 | 1.4 | 3 | 3.8 |
| Haematuria | 2 | 1.4 | 2 | 2.6 |

******* **Other than Death

## in D9901 and D9902A*

**in D9901 and D9902A*******

| AE #  | Sipuleucel-T
 N = 146 |  | Placebo
 N = 76@ |  |
| --- | --- | --- | --- | --- |
|  | # | % | # |  % |
| Chills | 85 | 58.2 | 6 | 7.9 |
| Pyrexia | 48 | 32.9 | 5 | 6.6 |
| Headache | 28 | 19.2 | 5 | 6.6 |
| Asthenia | 22 | 15.1 | 5 | 6.6 |
| Nausea | 22 | 15.1 | 6 | 7.9 |
| Paraesthesia | 19 | 13.0 | 7 | 9.2 |
| Vomiting | 17 | 11.6 | 2 | 2.6 |
| Dyspnoea | 16 | 11.0 | 2 | 2.6 |

*** ****>10 % in Sipuleucel T subjects**
**#**  **Adverse events that occurred more often in Sipuleucel-T subjects**
**@ Subjects who had at least one leukapheresis**

## Trials Subjects for CVA Analyses

| Trials | Sipuleucel-T | Placebo |
| --- | --- | --- |
| AIPC (proposed indication) |  |  |
|      D9901 | 82 | 45 |
|      D9902A  | 65 | 31 |
|      D9902B (Study 3) | 198 | 96 |
|      AIPC Sub-total | 345 | 172 |
| Androgen Dependent Prostate Cancer (ADPC) |  |  |
|      P-11 | 116 | 59 |
| Total | 461 | 231 |

## CVA Events

| Group | Sipuleucel-T
n / N (%) | Placebo
n / N (%) | Odds Ratio
(95% CI) | p-value  |
| --- | --- | --- | --- | --- |
| All Subjects |  |  |  |  |
| All CVA’s | 18 /461 (3.9%) | 6/231 (2.6%) | 1.52 (0.596, 3.892) | 0.510 |
| Deaths attributed to CVAs | 7 / 461 (1.5%)  | 2 / 231 (0.9%) | 1.76 (0.364, 8.566)  | 0.725  |
| AIPC (Proposed Indication) |  |  |  |  |
| All CVA’s | 17 / 345 (4.9%) | 3 / 172 (1.7%) | 2.92 (0.84, 10) | 0.092 |
| Deaths attributed to CVAs | 7 / 345 (2.0%) | 2 / 172 (1.2%) | 1.76 (0.36, 8.6) | 0.724 |
| ADPC (P-11) |  |  |  |  |
| All CVA’s | 1 / 116 (0.9%) | 3 / 59 (5.1%) | 0.16 (0.016, 1.596) | 0.112 |
| Deaths attributed to CVAs | 0 | 0 | --- | --- |

## Safety Conclusions

- Almost all Sipuleucel-T treated subjects developed Adverse Events (98.6% Sipuleucel-T versus 96.1% placebo).
- Most AEs were grade 1 to 2 and resolved within 48 hours.
- 24% Sipuleucel-T subjects developed SAEs, not different from 23% of Placebo treated subjects.
- Although the differences did not reach statistical significance, the increased CVA events observed in Sipuleucel-T subjects is a potential safety signal.

## Conclusions --- Efficacy 

**Neither study met pre-specified efficacy endpoint **
**Survival analyses**
**D9901: a 4.5-month overall survival difference. Statistically significant by log-rank test **
**D9902A: a 3.3-month overall survival difference --- Not statistically significant**

## Discussion --- Overall Survival in Cancer Clinical Trials

**The most reliable cancer endpoint**
**Usually the preferred endpoint when studies can be conducted to adequately assess it.**
**An improvement in survival is a clinical benefit.**
**The endpoint is precise and easy to measure, documented by the date of death.  Bias is not a factor in endpoint measurement.**
**Demonstration of a statistically significant improvement in overall survival has supported new drug approvals**

## Discussion --- Overall Survival Difference in D9901

**4.5 month median survival difference is Clinically meaningful**
**Limitations of survival result**
**Post hoc analyses**
**Survival not the pre-specified endpoint**
**Primary method for survival analysis not pre-specified**
**One study with a small sample size**
**Difference could be due to chance**