Post-Progression Treatment with APC8015F may have Prolonged Survival of Subjects in the Control Arm of Sipuleucel-T Phase 3 Studies

L.G. Gomella1, C. Nabhan2, J.B. Whitmore3, M.W. Frohlich3, and D.J. George4 (1Jefferson Medical College, Philadelphia PA, 2Advocate Lutheran General Hospital, Park Ridge IL, 3Dendreon Corp., Seattle WA, 4Duke Univ., Durham NC)

Introduction
Sipuleucel-T is an autologous cellular immunotherapy FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Integrated results from 3 randomized, double blind, controlled Phase 3 studies provided evidence of survival prolongation in the study population (HR=0.735 [95% CI: 0.613, 0.882]; P<0.001). Control was nonactivated, autologous peripheral blood mononuclear cells. Subjects with disease progression following participation in the control arm of these 3 studies could participate in a Phase 2, open-label study and receive APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation. Here we report an analysis of the APC8015F treatment effect across the 3 studies. Control Infusions

Results
Figure 2. Control Arm Flow Diagram
APC8015F Infusions
155 received APC8015F 61 did not receive APC8015F

Results
Figure 4. Overall Survival Following Disease Progression (Kaplan-Meier)
6 7

Results Results
Table 4. Incidence of Adverse Events with Onset 1 Day After Infusion Reported in >2% of APC8015F Subjects
Preferred Term Any Subject Reporting an AE Chills Nausea Pyrexia Fatigue Back Pain Constipation Hypertension Pain in Extremity Arthralgia Dizziness Musculoskeletal Pain Vomiting Anorexia Weight Decreased Control1 (N=244) n (%) 126 (51.6) 11 (4.5) 6 (2.5) 5 (2.0) 37 (15.2) 11 (4.5) 7 (2.9) 2 (0.8) 11 (4.5) 9 (3.7) 1 (0.4) 7 (2.9) 2 (0.8) 3 (1.2) 3 (1.2) APC8015F (N=165) n (%) 71 (43.0) 23 (13.9) 13 (7.9) 13 (7.9) 10 (6.1) 8 (4.8) 6 (3.6) 6 (3.6) 6 (3.6) 5 (3.0) 5 (3.0) 5 (3.0) 5 (3.0) 4 (2.4) 4 (2.4) Sipuleucel-T1 (N=485) n (%) 390 (80.4) 254 (52.4) 64 (13.2) 114 (23.5) 88 (18.1) 20 (4.1) 6 (1.2) 25 (5.2) 9 (1.9) 21 (4.3) 22 (4.5) 7 (1.4) 41 (8.5) 12 (2.5) 5 (1.0)
8

Randomization to control group

249 control subjects in 3 mCRPC studies

216 with confirmed disease progression*

*10 control subjects did not have confirmed disease progression and were treated with APC8015F

Methods
Figure 1. Trial Design: Studies D9901, D9902A, and IMPACT
Sipuleucel-T Q2 weeks x3 Asymptomatic or Minimally Symptomatic1, Metastatic, Castrate Resistant Prostate Cancer P R O G R E S S I O N Treated at Physicians Discretion Treated at Physicians Discretion, Including Optional Entry into a Phase 2 Open-Label Study2 S U R V I V A L

Median time from randomization to first APC8015F infusion was 5.2 months (range 1.8-33.1) Median time from disease progression to first APC8015F infusion was 2.2 months (range 0.5-14.6)

Sipuleucel-T: median survival time 20.7 months Control With APC8015F: median survival time 20.0 months Control Without APC8015F: median survival time 9.8 months

Table 1. Baseline Characteristics

Characteristic Age, median (range, years) Weight ,median (range, lbs) Race, Caucasian, n (%) ECOG Performance Status = 0, n (%) Gleason Sum, n (%) 7 8 Number of bone metastases, n (%) 0-5 6-10 > 10 56 (66.7) 28 (33.3) 33 (39.3) 10 (11.9) 40 (47.6) 117.0 12.6 196.0 62.1 115 (69.7) 49 (29.7) 79 (47.9) 29 (17.6) 57 (34.5) 97.0 12.9 184.0 40.8 351 (72.0) 136 (27.9) 206 (42.2) 67 (13.7) 211 (43.2) Control (N=84) 71 (53-89) 186 (135-300) 78 (92.9) 59 (70.2) APC8015F (N=165) 70 (40-87) 191 (132-282) 151 (91.5) 140 (84.8) Sipuleucel-T1 (N=488) 72 (47-91) 194 (116-384) 437 (89.5) 393 (80.5)

Control Q2 weeks x3

Endpoints for D9901 and D9902A Primary:Time to Disease Progression Planned Analysis: Overall Survival
1Studies

Endpoints for IMPACT Primary: Overall Survival Secondary: Time to Objective Disease Progression

APC8015F-treated control subjects had improved post-progression survival relative to untreated control subjects. Because APC8015F-treated control subjects had more favorable baseline characteristics, modeling approaches to adjust for baseline and post-progression covariates were therefore undertaken.

AEs from safety population of studies D9901, D9902A, and IMPACT 1 day after initial infusion of sipuleucel-T or control. Table ordered by APC8015F events.

Summary
APC8015F-treated control subjects had improved post-progression survival relative to untreated control subjects, which persisted after adjusting for baseline and post-progression variables Cumulative CD54 upregulation and TNC count product parameters were correlated with survival in APC8015F-treated control subjects, consistent with correlations observed between product parameters and survival for sipuleucel-T subjects APC8015F-treated control subjects generally experienced more of the most common AEs than untreated control subjects and fewer of the most common AEs than subjects treated with sipuleucel-T

D9901 and D9902A enrolled only asymptomatic subjects 2 Treatment with APC8015F under salvage protocol D9903 for subjects from studies D9901 and D9902A, and salvage Baseline Laboratory Results Alkaline phosphatase, median (U/L) protocol PB01 for subjects from the IMPACT study

Table 2. Modeling Approaches

103 .0 12.9 190.0 51.5
Unadjusted Adjusted for baseline PSA and LDH Adjusted for baseline age, PSA, LDH, and post-randomization docetaxel use HR=0.52 (95% CI: 0.37, 0.73); P=0.0001 HR=0.56 (95% CI: 0.40, 0.80); P=0.001 HR=0.55 (95% CI: 0.39, 0.78); P<0.001 Post-progression APC8015F effect in control subjects (log rank test, Cox regression)

Analysis of APC8015F Treatment Effect Across Studies D9901, D9902A, and IMPACT
APC8015F is an autologous immunotherapy made from cells cryopreserved at the time of control generation and required to meet the same potency specifications (CD54 upregulation) as sipuleucel-T Disease progression was evaluated by imaging studies (bone scan and CT) and confirmed by independent, blinded review committees Following disease progression, subjects in the control arms of D9901, D9902A, and IMPACT were offered 3 infusions of APC8015F Baseline characteristics and adverse events (AEs) were reported in the APC8015F group for any subject who received at least one infusion of APC8015F whether or not disease progression was confirmed APC8015 treatment effect analyses were performed using data from control subjects with confirmed disease progression

Hemoglobin, median (g/dL) Lactate dehydrogenase, median (U/L) Serum PSA, median (ng/mL)
1Baseline

characteristics are reported for all randomized subjects from the 3 mCRPC studies.

2 3

Figure 3. Overall Survival from Randomization (Kaplan-Meier)

Adjusted for independent predictors of overall survival and with APC8015F treatment and docetaxel as time dependent covariates1 APCF8015F treatment effect Docetaxel effect HR=0.78 (95% CI: 0.54, 1.11); P=0.17 HR=0.86 (95% CI: 0.60, 1.22); P=0.40

Independent baseline predictors were determined by backwards stepwise method, and included lower LDH, alkaline phosphatase, ECOG status, age, number of bone metastases, and higher hemoglobin

Conclusions
There is no evidence that treatment with APC8015F adversely affected outcome APC8015F demonstrated evidence of clinical activity
Associated with longer survival Demonstrated modest treatment-related AEs Cumulative CD54 upregulation correlated with prolonged survival

Sipuleucel-T: median survival time 25.4 months Control With APC8015F: median survival time 23.6 months Control Without APC8015F: median survival time 12.7 months

Docetaxel was received post-randomization in 78/155 (50.3%) of APC8015F-treated control subjects and in 28/61 (45.9%) of untreated control subjects

Statistical Analyses of Overall Survival Following Disease Progression

Unadjusted analysis based on Cox model (stratified by study D9903 or PB01) and the 4 log-rank test Stratified Cox regression model adjusted for baseline PSA and LDH Stratified Cox regression model adjusted for baseline age, PSA, LDH, and postrandomization docetaxel use (yes/no) Model-based analysis using backward selection to identify significant (P<0.10) baseline prognostic variables. Post-randomization APC8015F treatment and docetaxel use were fit as time dependent co-variates, and were retained in the model

Table 3. Cumulative Product Parameters

Correlation with Overall Survival Subsequent to First APC8015F Infusion1 (n=155) Median CD54 upregulation (fold) CD54 counts (x 109) Total nucleated cell count (x 109) 21.98 0.50 1.90 HR 0.555 0.916 0.751 95% CI 0.322, 0.958 0.732, 1.145 0.571, 0.987 P value 0.03 0.44 0.04

To eliminate the effect of variability in time to disease progression (at which point the control subjects became eligible to receive APC8015F), an analysis of survival subsequent to disease progression was undertaken (Figure 4).

HR, 95% CI, and p-value from Cox regression model with log-transformed cumulative product parameter adjusted for log-transformed baseline PSA and LDH, stratified by salvage protocol D9903 or PB01.

APC8015F may have prolonged survival of the control arm in the three Phase 3 studies of sipuleucel-T, potentially diminishing the observed survival benefit
Contact: Daniel J. George, MD (daniel.george@duke.edu) PP-1940.00 02JUN11