Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormone Therapy
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Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormone Therapy By Payam Javanmardi and Syeda Jamal Academy of Applied Pharmaceutical Sciences Canada, Toronto, December 2014 1
Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormone Therapy
1. Sipuleucel_T Immunotherapy forMetastatic Prostate Cancer
after FailingHormone TherapyBy Payam Javanmardi and Syeda
JamalAcademy of Applied Pharmaceutical SciencesCanada, Toronto,
December 20141
2. Prostate cancer is the most common noncutaneouscancer among
men in the United States and is thesecond leading cause of death
from cancer in men.Localized prostate cancer may be cured with
surgeryor radiation therapy, but the disease recurs inapproximately
20 to 30% of patients.2
3. Androgen-deprivation therapy, the most commontreatment after
recurrence, is effective, but the diseaseeventually progresses in
most patients who receivesuch treatment.On April 29, 2010 FDA
approved Sipuleucel_T(Provenge) to treat asymptomatic or
minimallysymptomatic metastatic HRPC.3
4. Sipuleucel-T is an active cellular Immunotherapy, a typeof
therapeutic cancer vaccine, consisting of
autologousperipheral-blood mononuclear cells (PBMCs),
includingantigen-presenting cells (APCs), that have beenactivated
ex vivo with a recombinant fusion protein(PA2024).PA2024 consists
of a prostate antigen, prostatic acidphosphatase, that is fused to
granulocyte-macrophagecolony-stimulating factor, an immune cell
activator.4
5. 5
6. In a randomized, placebo-controlled trial involving
127patients with metastatic castration resistant prostatecancer,
men in the sipuleucel-T group had a relativereduction in the risk
of death of 41%, as compared withthose in the placebo group.A
second randomized, placebo-controlled study showeda trend toward
increased survival with sipuleucel-T,although it was not
statistically significant.6
7. These studies did not show a significant effect on thetime
to progression, the primary end point of both trials.To confirm
these survival findings, the Immunotherapyfor Prostate
Adenocarcinoma Treatment (IMPACT)clinical study was conducted to
support FDA approval.7
8. Immunotherapy for Prostate
AdenocarinomaTreatmentClinicalTrials.gov Identifier:
NCT00065442Study Type: InterventionalStudy Design: Randomized,
Double blind, Placebo-controlled inParallel Assignment across 75
clinical trial sites in USA andCanadaEnrollment: 512Start Date:
July 2003Study Completion Date: January 2009Study Phase: Phase
3Sponsor: Dendreon CorporationPurpose: Provenge is an
investigational product designed toactivate a mans own antigen
presenting cells, so that they candetect prostate cancer cells and
initiate an immune responseagainst them 8
9. Primary Outcome Measure: Overall Survival within a Time
Frame fromrandomization until death due to any cause bymeans of a
stratified Cox regression modeladjusted for baseline levels of
serum prostate-specificantigen (PSA) and
LactatedehydrogenaseSecondary Outcome Measure:Time to Objective
Disease Progression wasmonitored by means of computed
tomography(CT) at weeks 6, 14, 26, and 34 and every 12weeks
thereafter) 9
10. Intervention: Biological: Sipuleucel-TEach dose of
sipuleucel-T contains a minimum of 50 millionautologous CD54+ cells
activated with a PAP-GM-CSF. A courseof therapy consists of 3
complete doses at approximately 2-week intervals. Biological:
APC-PlaceboEach dose of APC-Placebo contains approximately
one-third ofthe quiescent APCs prepared from a single
leukapheresisprocedure. A course of therapy consists of 3 complete
dosesgiven at approximately 2-week intervals.10
11. Eligibility Criteria: Histologically documented
adenocarcinoma of the prostate Cancer that has progressed while on
adequate hormonetherapy This state of the disease is androgen
independentprostate cancer (AIPC) Cancer that has spread outside
the prostate to lymph nodesor bone The absence of or minimal
current cancer-related pain Additionally Amended Criteria Male, 18
Years and older11
12. Methods: 512 patients randomly assigned in a 2:1 ratio to
receive eithersipuleucel-T(341 patients) or placebo(171 patients)
every 2 weeks,for a total of three infusions Patients were
scheduled for three leukapheresis procedures (atweeks 0, 2, and 4),
each followed approximately 3 days later byinfusion of sipuleucel-T
or placebo Infusions of sipuleucel-T were prepared from PBMCs
collected bymeans of a single standard leukapheresis and then APCs
werecultured for 36 to 44 hours at 37C with medial containing
PA2024 Placebo was prepared by culturing APCs from one third of
theleukapheresis collection in medium for 36 to 44 hours at 2 to 8
C,without PA202412
14. 14Results: Baseline
MeasuresAPC-PlaceboSipuleucel-TTotalParticipants 171 341 512AgeMean
SD70.1 9.0 71.1 8.9 70.8 8.9AgeMedian (FullRange)70(40 to 89)72(49
to 91)71(40 to 91)GenderFemale 0 0 0Male 171 341 512
15. 15Results: Primary Outcome MeasureAPC-Placebo
Sipuleucel-TParticipants 171 341Overall Survival(Months)95%
Confidence Interval21.717.7 to 23.825.822.8 to 27.7Statistical
Analysis 1 All groupsMethod Regression, CoxP Value 0.032Hazard
Ratio95% Confidence Interval0.7750.614 to 0.979
16. 16Results: Primary Outcome MeasureStatistical Analysis 2
All groupsMethod Log RankP Value 0.023Hazard Ratio95% Confidence
Interval0.7660.608 to 0.965
17. 17Results: Secondary Outcome MeasureAPC-Placebo
Sipuleucel-TParticipants 171 341Time to ObjectiveDisease
Progression(Weeks)14.4 14.6Statistical Analysis All groupsMethod
Log RankP Value 0.628Hazard Ratio95% Confidence Interval0.9510.773
to 1.169
18. AEs were reported for 496 of 506 (98%) and were mild to
moderate for330 patients (65.2%)AEs that were reported more
frequently in the sipuleucel-T group thanin the placebo group
included chills, fever, headache, influenza-likeillness, myalgia,
hypertension, hyperhidrosis, and groin painAEs that were reported
more frequently in the placebo group includedanorexia, anxiety,
depression, flank pain, and contusion as well
ashydronephrosisCerebrovascular events were reported as 2.4% and
1.8% in thesipuleucel-T group and the placebo group,
respectively18Results: Serious Adverse Events
19. More men in the sipuleucel-T group were alive 3 years after
thestart of the study than men not treated with
sipuleucel-TSipuleucel-T reduced the risk of death by 22.5% for
patientswho received the vaccineOnly 1.5% of men discontinued
treatment with sipuleucel-T dueto side effectsProvenge is the only
personalized treatment that is clinicallyproven to help extend life
in certain men with advancedprostate cancer19Conclusion