Division of Biostatistics
Office of Biostatistics and Epidemiology
Center for Biologics Evaluation and
Research
Food and Drug Administration
Cellular, Tissue and Gene Therapies
Advisory Committee Meeting
March 29, 2007
Statistical Briefing Document
PROVENGEฎ (Sipuleucel T)
For the treatment of men with asymptomatic metastatic androgen independent prostate cancer.
Table of Contents
OVERVIEW
.
3
STATISTICAL EVALUSTION
.
4
I.
Study D9901
4
1.0
Statistical Analysis Plan
. 5
3.0 Statistical
Findings and Comments
..22
II.
Study D9902A
29
1.0
Statistical Analysis Plan
29
2.0
Efficacy Evaluation
...30
3.0 Statistical
Findings and Comments
..39
III.
Integrated Summary and
Other findings
42
1.0 Summary of Efficacy
42
2.0 Summary
of Safety
44
3.0 Statistical
Findings and Comments
45
SUMMARY AND CONCLUSIONS
. 47
References
48
INTRODUCTION
Dendreon is seeking licensure of sipuleucel-T (Provengeฎ,
APC8015) for the treatment of men with asymptomatic, metastatic androgen
independent prostate cancer (AIPC). The proposed indication is based upon analyses
comparing overall survival between APC8015 treated and placebo groups with the
relative absence of significant toxicity in this patient population.
Sipuleucel-T is an autologous active cellular
immunotherapy product designed to stimulate an immune response against prostate
cancer. APC8015 consists of autologous peripheral blood mononuclear cells
(PBMCs), including antigen presenting cells (APCs), that have been activated in
vitro with a recombinant fusion protein. The recombinant fusion protein,
PA2024, is composed of prostatic acid phosphatase (PAP), an antigen expressed
in prostate adenocarcinoma, linked to granulocyte-macrophage colony-stimulating
factor (GM-CSF), an immune cell activator.
Sipuleucel-T falls into the class of therapies
known as active cellular immunotherapies, sometimes termed therapeutic cancer
vaccines. Such immunotherapy products are designed to elicit a specific immune
response to a target antigen. While the precise mechanism of action is unknown,
sipuleucel-T is designed to induce a cellular immune response targeted against
a recombinant fusion protein containing prostatic acid phosphatase (PAP), an
antigen expressed in prostate cancer tissue. During ex vivo culture, antigen
presenting cells (APCs) take up and process the recombinant target antigen into
small peptides that are then displayed on the APC surface. In vivo, T cells
bind to and recognize the target antigen peptides on the APC surface, eliciting
a response characterized by the proliferation and activation of T cells. These
activated T cells are the effector cells thought to be responsible for
recognition and destruction of prostate cancer cells in vivo. Sipuleucel-T has
been shown to stimulate the proliferation of PAP-specific T cell hybridomas in
vitro.
The proposed target indication for sipuleucel-T
is for the treatment of men with asymptomatic metastatic androgen independent
prostate cancer (AIPC).
All submissions are under BLA 125197. The electronic
BLA is in CTD format and organized in folders corresponding to BLA structure. Pursuant to the Fast Track Designation
agreement and the agreement to submit portions of the application (rolling
Biologics License Application), the first portion of the BLA including all
clinical and nonclinical sections, draft proposed labeling, and appropriate
administrative documents (e.g., forms, table of contents, certifications) was
submitted on August 21, 2006. The second/final portion which contains all
quality sections along with the final proposed labeling was submitted on
November 9, 2006. In addition, Dendreon intends to submit the 4 Month Safety
Update in February/March 2007.
Study overview
Clinical studies of sipuleucel-T have been performed
under BB-IND 6933 and include Phase 1, 2, and 3 studies in men with prostate
cancer.
Early Phase 1 and 2 clinical studies in men with
AIPC were conducted to test the safety and preliminary efficacy of sipuleucel-T
(Small 2000, Burch 2000, Burch 2004). The results demonstrated the following:
1) Intravenous infusions of sipuleucel-T in subjects with prostate cancer were
generally well tolerated with no dose limiting toxicities observed; 2)
Prostate-specific antigen (PSA) reductions of >50% in approximately 10% of
subjects were noted, as well as one striking objective response; 3) Three doses
of sipuleucel-T resulted in substantial PAP-specific immune responses. Results of open-label Phase 2 trials in men
with androgen dependent prostate cancer (ADPC) also demonstrated that
intravenous infusions of sipuleucel-T were generally well tolerated with no
dose limiting toxicities observed. Additionally, prolongation of PSA doubling
time was observed in these studies (Rini 2005a, Rini 2005).
The Phase 3 clinical development program for
sipuleucel-T was originally designed based on the results of Phase 1 and 2
trials in men with AIPC and guidance received from the Center for Biologics
Evaluation and Research (CBER) and practicing oncologists and urologists. The
program consisted of Protocols D9901 and D9902, two identically designed,
multicenter, randomized, double blind, placebo-controlled studies in men with
asymptomatic, metastatic AIPC. The target number of subjects to be enrolled was
120 in each study, and the primary endpoint for both studies was time to
objective disease progression (TTP). Each of the 2 studies was powered to
independently meet the primary endpoint of TTP; a pooled analysis of the
combined studies was required for sufficient power to meet the secondary
endpoint of time to onset of disease-related pain (TDRP). In 1999, no therapy
had been shown to prolong survival in men with asymptomatic metastatic AIPC,
and there were no Phase 1 or 2 survival data specifically for sipuleucel-T.
Therefore, survival was not used as the primary endpoint. However, in both
trials, subjects were to be followed until death or until a pre-specified
cut-off of 36 months from the time of randomization, whichever occurred first.
The second study (D9902) was initiated shortly
after the first study. The trial design, patient eligibility, objectives and
statistical considerations were the same as those in the study 1 with a planned
sample size of 120 subjects. After the first
study results became available showing no overall significance of TTP in 2002,
the sponsor did a subset analysis of the study 1 and found that there was a difference
of TTP favoring Provenge arm for subjects who had Gleason score ≤ 7. At this point, the study 2 had already enrolled 98 subjects. The sponsor decided to split the second study
into two parts (A and B). Part A (D9902A)
contained the initial 98 subjects with Gleason scores ≤ 7 or ≥ 8,
and part B to enroll subjects only with Gleason score ≤ 7. The BLA contains data from the two pivotal
studies: Studies D9901 and D9902A.
Since
data/results from the two pivotal trials were submitted as the main efficacy
evidence under this BLA to support the licensing application, the
focus of the statistical review is mainly on the two Phase 3 trials (Studies D9901
and D9902A).
Statistical evaluation
I. Study D9901
This was a prospective Phase 3, multicenter,
double blind, placebo-controlled, randomized trial of immunotherapy with
APC8015 for the treatment of subjects with asymptomatic metastatic AIPC. A
total of 127 subjects were randomized
at multiple investigative centers (19
clinical study centers) across the
An independent third party was employed to
generate the randomization schedule for the study. The specifics about the
method of randomization employed (block size and degree of imbalance at each
study site) were not made known to Dendreon until after the study was
unblinded. Subjects were stratified by clinical study center and use of
bisphosphonate therapy (yes or no) prior to being randomized. The allocation of subjects to treatment
utilized multiple blocks, each of size 6, to generate a separate master
randomization schedule for each stratum. A centralized, adaptive randomization
procedure was employed to maintain the overall enrollment in the study at an
approximately 2:1 randomization, while preventing the enrollment at any
clinical study center from departing from the 2:1 randomization ratio by a
large amount.
Following randomization, subjects from both
groups underwent a series of 3 standard leukapheresis procedures (in Weeks 0,
2, and 4), and each procedure was followed 2 days later by infusion of either
autologous antigen loaded APCs (APC8015; active treatment) or autologous
quiescent APCs without antigen (APC-Placebo; control). The treatment phase of
the protocol was complete following the third (Week 4) infusion. For subjects on the control arm, the remaining two-thirds of the
quiescent APCs from each leukapheresis that were not used to make APC-Placebo
were cryopreserved for possible later use in the preparation of APC8015F for
the Phase 2 salvage trial D9903.
At the time that subjects developed disease
progression, study treatment could be unblinded. Subjects in the APC8015 group
were then treated at the physicians discretion. Subjects in the APC-Placebo
group had the option to enter a Phase 2, open label, single-arm salvage trial
(Protocol D9903) with a product similar to APC8015. Subjects treated with APC8015
on D9901 were not eligible to participate in the salvage trial.
Regardless of subsequent treatment, subjects
without disease-related pain at the time of disease progression were to be
followed with weekly pain logs for 4 additional weeks. After subjects developed
disease progression, follow-up documentation included treatment-related AEs,
first anticancer treatment, and survival for 3 years from the time of
randomization or until death, whichever occurred first. Per the statistical
analysis plan (Appendix 16.1.9.8), the final analysis of survival was performed
36 months following randomization of the last subject.
1.0 Statistical Analysis Plan
1.1 Efficacy variables
The primary efficacy variable, overall time to
disease progression (TTP), was defined as the time from randomization to the
first observation of disease progression.
Disease progression was defined by any of the following:
Measurable Disease
A greater than 50% increase in the sum of the products of the perpendicular
diameters of all bidimensionally measurable lesions. The change was measured
against the smallest sum observed, or compared with baseline if there was no
response, using the same techniques as baseline.
An appearance of at least 2 new lesions or the reappearance of any lesion that
had disappeared. All lesions had to have a minimum size of at least 2 cm in 1
dimension to be considered measurable.
Evaluable Disease
Unidimensionally measurable disease: at least 50% increase in the sum of the
measurements of all unidimensionally measurable lesions over the smallest sum
observed (over baseline if no response) using the same techniques as baseline.
Nonmeasurable disease: Clear worsening of nonmeasurable, evaluable disease.
Scan only bone disease: The appearance of at least 2 new areas of abnormal
uptake on bone scan. Increased uptake of pre-existing lesions on bone scan did
not constitute progression.
Development
of Prostate Cancer-Related Events
The development of a prostate cancer-related event (e.g., spinal cord
compression, a pathologic fracture, the development of a requirement for
radiation therapy, or other clinically significant disease specific event)
constituted progression.
Failure to return for evaluation due to death or deteriorating condition
constituted progression unless the event was clearly unrelated to prostate
cancer.
Development
of Prostate Cancer-Related Pain
On the basis of the Investigators opinion, all of the following criteria had
to be met: pain that had the quality and consistency of cancer-related pain,
pain that occurred since enrollment in the trial, and pain that occurred in a
location that correlated with a site of cancer, as demonstrated by objective
radiographic means.
Secondary efficacy measures included time to development
of disease-related pain, objective response rate, and duration of response,
time to clinical progression, time to treatment failure, and incidence of Grade
3 or greater treatment-related AEs in all subjects who underwent at least 1
leukapheresis for trial purposes.
Survival as an endpoint was not defined in the
protocol and its amendments though the sponsor stated that all subjects would
be followed for survival for 36 months after their date of randomization or
until death, whichever occurred first. Regarding
survival analysis, the sponsor did state that This study is not powered to show a survival
effect. However, survival data will be summarized descriptively. The definition for a survival endpoint was
later added to the study report in the BLA submission as:
The
survival times for subjects who died during the 3-year follow-up period were
defined as the time span (in months) from the date of randomization to the date
of death. The survival times for subjects who were alive at the end of the
3-year follow-up period were censored and defined as the time span (in months)
from the date of randomization to the censor date of 3 years after the date of
randomization.
1.2 Analysis plan
The statistical analysis plan included 2 interim
analyses and a final analysis. The first analysis was conducted on data from
control subjects only for the purpose of sample size confirmation so no alpha
adjustment was made and the sample size was not adjusted based on the results.
The second interim analysis was performed on data from 79 subjects from both
treatment arms to assess the conditional probability of trial success (i.e.,
futility analysis) and was conducted at the 0.001 level. The final analysis was
conducted at the 0.049 level using an O.Brien-Fleming adjustment. Both interim
analyses were conducted by an independent third party and Dendreon personnel
remained blinded to treatment assignments.
These data were analyzed using the ITT and
Safety populations. The ITT population included all randomized subjects, and
the Safety population included all subjects who underwent at least 1
leukapheresis. Since all randomized subjects underwent at least 1 leukapheresis
in this trial, both populations are identical.
1.3 Analysis of primary efficacy data
The time to disease progression curves were
constructed with the Kaplan-Meier technique for the two treatment groups, and
the primary null hypothesis (no difference between treatment groups) was tested
using the log rank test.
The date of data cut-off for the primary
efficacy evaluation was April 30 2002.
Subjects who did not experience disease progression by the time of the efficacy
analysis were censored at the time of their last known radiographic imaging
study. Similarly, if a subject had no disease progression and was lost to
follow-up prior to the data analysis, the subject was censored at the date of
last radiographic imaging study.
The primary efficacy variable was also
summarized by the following subgroups:
PAP immunohistochemistry expression: 2 subject groupings based on the
proportion of cancer cells staining positive for PAP (25% to 74%, = 75%).
Baseline alkaline phosphatase (within normal limit [WNL] versus above ULN of
local reference range).
Baseline serum PAP levels (WNL of local reference range, > 1 ื ULN to < 3
ื ULN; = 3 ื ULN).
Prior systemic therapy (castration only, combined androgen blockade, combined
androgen blockade plus other; castration plus other was also considered if
there were sufficient numbers in the data).
Inferential tests with appropriate adjustment
for multiplicity were carried out for the above mentioned variables, but such
inferential statistics were only carried out for time to disease progression.
Treatment by subgroup interactions were tested to evaluate if any of them
represented effect modifiers. These interactions were tested before simple
effects and the latter only tested in the event of a significant interaction.
Adjustments were made for the 4 interaction tests using the Sidak-Holm method.
The tests for simple effects were not considered reportable unless the
corresponding interactions were significant (at the P ≤ 0.10 level).
Subjects were followed for survival for 3 years
following their date of randomization. Subjects who were alive at 3 years
following randomization were censored at 3 years from their date of
randomization. Survival was analyzed using the Kaplan-Meier technique. Survival
rate estimates at 3, 6, 9, 12, and every 6 months thereafter and median
survival were obtained from the Kaplan-Meier method. Corresponding confidence
intervals (CIs) were also computed.
Sample size
The most current version of the protocol
(amendment 7, dated 25 JUL 2002) indicates that approximately 120 subjects were
planned, with 80 subjects in the APC8015 group and 40 subjects in the
APC-Placebo group. A 2:1 randomization was used in order to increase the number
of subjects exposed to APC8015. Based on past experience and a review of the
literature, a median time to disease progression for subjects treated with
APC-Placebo was assumed to be 4 months. A delay in the time to disease
progression of 3.7 months (from 4 to 7.7
months) was considered clinically significant for subjects with metastatic
AIPC. This represents a hazard ratio (HR) of 1.925 assuming an exponential
distribution. It was further assumed that accrual into this study would be done
within 16 months and that each subject would be followed for up to 3 years.
With a 2-sided 5% level of significance and a 2:1 subject-allocation ratio
between the APC8015 and APC-Placebo groups, a total of 80 events was needed to
achieve 80% power to detect the specified difference of 3.7 months in median
time to disease progression; it was projected that 87 subjects would be
sufficient to attain the 80 events (Lachin 1981). To account for non-uniform
subject entry and 5% loss to follow-up (Lachin 1986) a total of 96 subjects
(64:32 subjects for APC8015:APC-placebo) was necessary.
It was assumed that the same HR would apply to
time to disease-related pain. Therefore, a total of 80 pain progression events
would also be required to power the disease-related pain endpoint at 80%.
However, it was further assumed that 60% of the pain events would be censored
when the requisite number of progression events had been recorded. This high
level of censoring would result in 32 pain progression events from Study D9901
alone. Increasing the sample size from 96 to 120 would result in a projection
of approximately 40 events from pain progression. In order to achieve 80% power
and capture 80 pain events for the disease-related pain endpoint, enrollment of
240 subjects was required. Therefore, enrollment of 120 subjects in each of the
Phase 3 trials (D9901 and D9902A) was planned with a final pooled analysis for
this endpoint.
2.0 Efficacy Evaluation
2.1 Disposition of subjects
As shown in Figure 1, 127 of the 186 subjects
screened for eligibility were randomized between 04 JAN 2000 and 08 OCT 2001.
Of these, 82 subjects were randomized to receive APC8015 and 45 subjects were
randomized to receive APC-Placebo. All 127 subjects underwent at least 1
leukapheresis procedure and received at least 1 infusion.
Of the 59 subjects who were screened for the
trial but were not randomized, the majority of subjects failed to satisfy the
inclusion criteria (52 of 59 subjects, 88%). Five subjects (8.5%) chose not to
participate in the trial following their registration visit. Two additional
subjects (3.4%) withdrew for other reasons (aortic aneurysm and participation
in a separate clinical trial).
Twelve subjects discontinued the 3-year study
before completing the trial, but survival at 36 months following randomization
was available for all 12 subjects. Four subjects treated with APC8015 and 1
subject treated with APC-Placebo withdrew consent prior to meeting the primary
endpoint of disease progression. Rising PSA was not reported as the primary
reason for any subject to discontinue the trial.
Figure 1 Schematic
of Subject Disposition
Major protocol eligibility deviations occurred
for 7.9% of subjects (8 subjects treated with APC8015 and 2 subjects treated
with APC-Placebo) and included the following: no evidence of metastatic disease
at entry, evidence of pleural effusion at study entry, not medically or
surgically castrate at study entry or medical castration therapy discontinued
during trial, PSA values demonstrating or confirming androgen independence
obtained outside the protocol-specified window, and radiation therapy received
during the active period.
2.2 Demographics and other baseline characteristics
A summary of demographics and baseline
characteristics is provided in Table 1. The demographic characteristics were
similar between the 2 treatment groups. All
subjects enrolled in this trial were male, and the majority of subjects were
Caucasian (90.6%). The median age in this population was 73.0 years; ages
ranged from 47 years to 86 years. The majority of subjects from both treatment
groups had a baseline ECOG performance status of 0 (75.6% of subjects treated
with APC8015 and 82.2% of subjects treated with APC-Placebo).
Baseline laboratory evaluations were well
matched between the treatment groups and are provided in Table 1.
The estimated median time from diagnosis to
randomization for subjects treated with APC8015 was 397.6 weeks (approximately
7.6 years) compared to 356.9 weeks (approximately 6.9 years) for subjects
treated with APC-Placebo.
Table 1
Summary of Subject Demographics and Baseline Characteristics, ITT
The protocol required subjects to have a tumor
specimen (tissue block, core biopsy, or pre-cut unstained slides) submitted to
a central pathology facility for immunohistochemistry testing of PAP.
Eligibility required a positive PAP immunohistochemistry reaction in ≥ 25%
of cells. The PAP immunohistochemistry results are summarized in Table 2. A
higher percentage of subjects in the APC8015 group than in the APC-Placebo
group had tumor specimens with at least 75% PAP-positive cells.
Table 2 Summary of PAP Immunohistochemistry, ITT
For this study, 116 of 127 subjects (91.3%) had
a Gleason score assigned by a central pathology laboratory prior to
randomization. The Gleason scores obtained by local pathology facilities were
used for those subjects not given Gleason scores by the central pathology
facility. Gleason score and tumor status at baseline is presented in Table 3.
Overall, a majority of the subjects had a Gleason score ≤ 7 (75 subjects
[59.1%] versus a Gleason score ≥ 8 (52 subjects [40.9%]). Differences
between the treatment groups were not statistically significant.
Table 3 Summary of Gleason Score and Tumor
Status at Baseline, ITT
It should be noted that p-values provided by the
sponsor in the above tables should not be considered as those from a hypothesis
test for the difference between the two arms.
They just reflect the chance of obtaining the observed difference (and
more extreme) between the two arms in these demographic and baseline
characteristics factors when in fact the two samples were randomly drawn from the
same population.
2.3 Efficacy results
The protocol prospectively designated time to
disease progression as the primary endpoint and specified that complete
survival data (up to 36 months) would be collected. Survival is the focus of
this study report. Survival is objectively ascertained, represents the standard
for establishing clinical benefit in oncology clinical trials, and best represents
the therapeutic effect of APC8015. To be consistent with the prospectively
defined protocol, time to disease progression and the secondary endpoints are
presented first in this study report, but the most extensive information and
critical analyses are focused on survival.
The
efficacy review focuses on the survival endpoint.
2.3.1 The primary endpoint
The sponsor states in this BLA that the primary
efficacy endpoint was the overall time to disease progression. The following analyses for the primary
endpoint presented in the study report by the sponsor were based on the
unblinded review data. The terminology
change for the primary endpoint and the adequacy of using unblinded review data
will be discussed later in the section Statistical Findings and Comments.
Out of 127 subjects randomized on this study,
115 subjects (90.6%) contributed a progression event. Ninety-eight subjects
(77.2%) had progression documented by imaging (as determined by independent,
blinded, radiology review). Of the 98 subjects who progressed based on imaging
studies, 48 subjects treated with APC8015 and 24 subjects treated with
APC-Placebo progressed based on bone disease, while 15 subjects treated with
APC8015 and 11 subjects treated with APC-Placebo progressed based on soft
tissue disease. Ten subjects (7.9%) had progression based on clinical events
other than radiographic events, as defined in the protocol, and 7 subjects
(5.5%) had progression based on the onset of cancer-related pain. Additionally,
6 subjects (4.7%) were censored prior to meeting the disease progression
endpoint and 6 subjects (4.7%; all in the APC8015 group) were censored without
disease progression at the primary efficacy evaluation cut-off date (30 APR
2002).
When the Kaplan-Meier curves for time to disease
progression were compared, there was a delay from randomization to disease
progression in the APC8015 group compared with the APC-Placebo group (P =
0.052, log rank; unadjusted HR = 1.45 [95% CI: 0.99, 2.11]; Figure 2). After Week 8 the Kaplan-Meier curves showed a
marked separation that persisted throughout the remainder of follow-up. The estimated median time to disease
progression was 11.7 weeks in the APC8015 group compared with 10.0 weeks in the
APC-Placebo group.
Figure 2 Primary Efficacy Endpoint, Time to Disease
Progression (Kaplan-Meier Method), ITT
The sponsor also reported time to objective
disease progression confirmed by imaging studies as follow (p74 of the Study
Reports for D9901): During the trial, available imaging studies were evaluated
for all subjects by a central, independent radiology facility. A supplementary
analysis was conducted on the time from randomization to objective disease
progression confirmed by imaging studies. Results of this analysis indicated
that statistical significance was not reached in the ITT population (P = 0.183,
log rank; unadjusted HR = 1.32 [95% CI: 0.87, 2.00]).
2.3.2 The secondary endpoints
There was no statistically significant difference
between the treatment groups with respect to time to onset of disease-related
pain progression (P = 0.210 log rank; unadjusted HR = 1.47 [95% CI: 0.80,
2.68]). The median time to onset of disease-related pain in subjects treated
with APC-Placebo was estimated to be 24.0 weeks, while the median time to onset
of disease-related pain in subjects treated with APC8015 was not estimable. The
pain-free rate estimate at 12 weeks, 71.5% of the subjects treated with APC8015
and 69.7% of the subjects treated with APC-Placebo had not experienced onset of
disease-related pain progression.
Since no subjects experienced a tumor response
based on review by the central radiology facility, there is no evaluation on tumor
response rate and duration of response.
Time to clinical progression was analyzed to
determine the difference in the primary endpoint in cases where both subjective
evidence and independently confirmable evidence of disease progression were
present. For the time to clinical progression analysis, the first evidence of
disease progression for each subject was used, whether based on subjective or
independently confirmable evidence. (For the primary endpoint of time to
disease progression, the date of independently confirmable disease progression
was used when available.) Twenty-two subjects treated with APC8015 and 18
subjects treated with APC-Placebo had a clinical progression date that differed
from their time to disease progression date. There was a trend toward a prolonged time from
randomization to clinical progression in the APC8015 group compared with the
APC-Placebo group, which approached but did not reach statistical significance
(P = 0.061, log rank; unadjusted HR = 1.44 [95% CI: 0.98, 2.10]).
Time to treatment failure was defined as the
time from randomization until any of the following occurred: disease
progression, death, or withdrawal for any reason except withdrawal of consent.
(Withdrawal of consent caused the subject to be censored at the time of the
last visit.) Initiation of other primary anticancer therapy, including
radiation therapy, in the absence of study withdrawal was considered treatment
failure for the purpose of this endpoint, as of the date the therapy was
initiated. The difference between APC8015 and APC-Placebo in time to treatment
failure was not statistically significant (P = 0.124, log rank; unadjusted HR =
1.34 [95% CI: 0.92, 1.94]).
2.3.3 Overall survival
The primary comparison between two arms in overall
survival WAS NOT pre-specified in the protocol and the statistical analysis
plan before unblinding the data.
The analysis of the 3-year survival data was
based on the ITT population of all 127 randomized subjects. Every subject was followed until death or the
pre-specified cut-off of 36 months(i.e.: the cutoff date should be in October
2004 since the last patient was enrolled in October 2001); there were no
censored events prior to the 36th month of follow-up. Although there was one subject who lost to
follow-up as shown in Figure 1, this is just specific for the time to
disease progression endpoint.
The first analysis of the survival data were
based on the Kaplan-Meier technique and the log rank test. Subjects treated
with APC8015 demonstrated an improvement in overall survival, compared to those
treated with APC-Placebo (P = 0.010, log rank; Figure 3). The unadjusted HR was
1.71 (95% CI: 1.13, 2.58), indicating a 41% reduction in the death rate for
subjects treated with APC8015 compared to APC-Placebo. The median survival time
for subjects treated with APC8015 was 4.5 months longer than that for subjects
treated with APC-Placebo (median survival times of 25.9 months and 21.4 months,
respectively). Table 4 and Table 5
present key summary statistics that characterize the differences between the 2
treatment arms.
Figure 3 Overall
Survival (Kaplan-Meier Method), ITT
Table 4
Summary Statistics, ITT
Table 5
Kaplan-Meier Survival Rate Estimates, Percent ITT
Following study closure, Dendreon attempted to
obtain death certificates and other source documents to confirm the cause of
death. Based on a review of these additional documents as well as data obtained
from the death summary CRF, all causes of death were ascertained. Given the
importance of the death date, Dendreon also compared the death date recorded by
the clinical study center (on the Death Summary CRF) to the date listed on the
Social Security Death Index (SSDI) for 93 of the 94 subjects who died during
the 36 month follow-up (An SSDI death date was not available for 1 subject). In
the majority of these cases (86 of 93 cases) the death dates from the 2 sources
were identical. Discrepancies were noted
for 4 subjects treated with APC8015 and for 3 subjects treated with
APC-Placebo. The observed differences are minor and would not substantively
change the survival difference observed between APC8015 and APC-Placebo (Detailed
results of these findings are contained in Section 12.3.3.1).
Several other sensitivity analyses were
performed to test the robustness of the survival results. Specifically, these
sensitivity analyses included the following:
Removal of influential subjects
Removal of investigational study centers
Reversing the treatment assignment of subjects
with randomization errors
Removal of subjects with protocol deviations
Assessing the influence of cell processing
centers (CPCs) on survival
Comparison of use of chemotherapy during
long-term follow-up
Assessing the influence of prognostic factors
on the observed survival effect
Six of the longest surviving subjects in the
APC8015 group had to be removed before the p-value exceeded 0.05.
The exclusion of study center 69 was the only
one that resulted in a non-significant p-value (P = 0.062, log rank). This was
the largest study center with a total of 20 subjects (15.8% of all subjects). Each of the other study center exclusions
yielded a significant survival finding.
2.3.4 Proportional model for survival analysis
The sponsor evaluated the individual effect of
the 21 potential prognostic factors as listed in Appendix 16.1.9.11 and found
that eight of these prognostic factors (age, alkaline phosphatase, hemoglobin, lactate
dehydrogenase [LDH], localization of disease, number of bone metastases, PSA,
and weight) could be independently identified as predictors of survival at the
0.05 level. The sponsor also stated that each one of these 8 variables has
previously been identified in the literature as a significant prognostic factor
of survival. Additional prognostic
factor, serum PAP, was also identified as a significant prognostic factor by
the sponsor, but the sponsor excluded it from the model since they believed
that it had substantially more missing data.
In order to build a model that was predictive of
survival, the 9 prognostic factors (including serum PAP) identified in the
univariate analyses were considered as candidates and included in a
multivariate PHR model.
The backwards stepwise selection method (P =
0.05 for entry and P = 0.10 for removal, likelihood ratio test) was then used
to identify the prognostic factors that added significantly to the fit of the
model. Serum PAP was found not to be significant following the backwards
elimination procedure. This analysis was repeated without serum PAP as a
covariate since there was a relatively large number of missing PAP values. The
results of this analysis reduced the number of prognostic factors remaining in
the model to 5. The 5 baseline prognostic factors that remained in the final
model were LDH (ln), PSA (ln), localization of disease, number of bone
metastases, and body weight (lbs). It should further be noted that the
treatment effect continued to be significant at every step of the backward
elimination procedure and was a predictor of survival in the final model.
Following identification of these 5 prognostic factors and in order to utilize
all of the data available, the PHR analyses were conducted with just these 5
variables and the treatment effect in the model because the 3 eliminated
variables had missing data. The results of these analyses are presented in
Table 6. Note that the p-value for localization was greater than 0.05 but less
than 0.10. The treatment effect was significant (P = 0.002, Wald.s test;
adjusted HR = 2.16).
Table 6
Proportional Hazards Regression Model of Survival Cox model (I)
2.3.5 Cell dose and product potency
While the design of the study was not one in
which the cell dose was specified, the analysis of cell dose and product
potency was requested as a means of examining the relationship between survival
and cell dose. To this end, survival data for subjects treated with APC8015
were assessed in the context of the key release specification parameters of the
product, notably, the TNC, CD54 cell count, and the upregulation of CD54. CD54
cell count and CD54 upregulation were chosen as biologically relevant release
specifications because of CD54s uniform expression on APCs, its role in the
immunologic synapse between APCs and T cells, and its role as a marker of APC
activation. Specifically, experiments have demonstrated that the CD54+
population of mononuclear cells possesses the ability to take up the PA2024
antigen and present epitopes of PAP to hybridoma cell lines recognizing PAP
epitopes.
In the simple Cox PHR model, subjects who had a
CD54 cell count at or above the median of 2.5 x 109 cells, or CD54
upregulation ratio at or above the median of 23.3, had an improved survival
compared to those subjects below the median (HR = 0.63 and HR = 0.79,
respectively). A significant effect on survival was observed between subjects
above and below the median TNC count of 10.8 x 109 cells (HR = 0.52;
P = 0.018; Table 7). A multivariate Cox
PHR model was used to determine whether cell counts correlated with survival
when correcting for the 5 key prognostic variables of baseline PSA, lesion
count, localization of disease, baseline LDH, and weight. A similar trend was
observed when TNC was included in the multivariate Cox PHR model (P = 0.054; HR
= 0.56). As in the simple Cox model,
there was no statistically significant correlation for total CD54 cell count (P
= 0.233; HR = 0.70) or CD54 upregulation (P = 0.274, HR = 0.72) in the
multivariate Cox PHR model.
It should be noted that there was no information on the cell dose and characteristics from the placebo group and the study was not designed to provide confirmative evidence for relationship between survival and cell dose. The significant result below may just