1. 1. Sipuleucel_T Immunotherapy forMetastatic Prostate Cancer after FailingHormone TherapyBy Payam Javanmardi and Syeda JamalAcademy of Applied Pharmaceutical SciencesCanada, Toronto, December 20141
2. 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. 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. 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. 5
6. 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. 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. 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. 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. 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. 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. 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
13. 13. 13Results: Participant Flow in Overall StudyAPC-PlaceboSipuleucel-TStarted 171 341Completed 46 121Not Completed 125 220Lost to Follow-up 1 1Death 121 (70.8%) 210 (61.6%)Withdrawal bySubject3 9
14. 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. 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. 16. 16Results: Primary Outcome MeasureStatistical Analysis 2 All groupsMethod Log RankP Value 0.023Hazard Ratio95% Confidence Interval0.7660.608 to 0.965
17. 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. 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. 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
20. 20. Referenceswww.fda.govwww.Clinicaltrials.govwww.nejm.org20