18 september 2017: ESMO 2017

Aanvullend op onderstaande informatie van oktober 2012 lees dit review studierapport uit 2015 over drie gerandomiseerde studies bij prostaatkankerpatiënten en waarvan de resultaten werden bevestigd als correct op ESMO 2017: Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy waaruit blijkt dat immuuntherapie met Provenge - Sipuleucel-T gevolgd door dendritische celtherapie (APC8015F = een autologe cellulaire immunotherapie) een optie kan zijn voor patiënten met uitgezaaide prostaatkanker.

De overall overleving na de start van de immuuntherapie was echt beduidend langer, 20,7 maanden versus 9,8 maanden, en geeft volgens de onderzoekers een 47% vermindering in kans op overlijden aan prostaatkanker met een APC8015F behandeling (P < 0.001;) , dus wanneer een behandeling met Provenge werd gevolgd door dendritische celtherapie met autologe cellen.

Echter er is geen vergelijking gemaakt met abiraterone en enzalutamine dus of deze resultaten ook echt waardevol zijn en een verandering van behandelingsprotocol kunnen betekenen is niet bewezen. Wel lijkt het interessant om deze aanpak uit te voeren in een eerder stadium van prostaatkanker.

De reviewstudie gaat over deze drie studies, klik op studienummer om te zien welke patienten daarvoor in aanmerking kweamen en welke behandelingen ze hebben gehad. :

D9901 (January 2000–September 2004; clinicaltrials.gov NCT00005947),
D9902A (May 2000–May 2005; NCT01133704),
IMPACT (August 2003–April 2009; primary analysis data cutoff: January 2009; NCT00065442;

Deze onderstaande resultaten zijn nog eens een keer bevestigd:

Provenge reviewstudie resultaten

Onderstaand de grafiek van overall overleving, maar neem daarbij in aanmrkring dat deelnmende patienten veel andere behandelingen hebben gehad en allemaal uitgezaaide hormoonresistente prostaatkanker hadden.

Geschatte overlevingswinst voor sipuleucel-T, na correctie voor een APC8015F behandeling

Uit de gegevens van de drie fase III-studies, werd mediaan een verschil gevonden van 3,9 maanden overall overleving tussen sipuleucel-T en controlegroepen in het voordeel van Provenge - sipuleucel-T. 66,3% van de patiënten uit de controlegroep (n = 165/249) kregen echter ook alsnog APC8015F. Met behulp van IPE-modellering werd de OS-curve van de groep herberekend alsof een APC8015F-behandeling niet had plaatsgevonden; Het verwachte sipuleucel-T behandelingseffect op het mediaan OS was tussen 3,9 maanden (als APC8015F geen effect had) en 8,1 maanden als APC8015F en sipuleucel-T even effectief waren, Figuur 3). Alleen voor de IMPACT-studie, kreeg 63,7% van de patiënten uit de controlegroep APC8015F, en het geschatte sipuleucel-T behandelingseffect op media-OS was tussen 4,1 en 7,8 maanden.

Zie onderstaande grafiek

Figure 3.

Estimates of OS for all patients on the sipuleucel-T phase III trials (N = 737), with adjustment for APC8015F treatment (IPE model). Dotted red line assumes 100% effectiveness of APC8015F, compared with sipuleucel-T, and solid red line assumes 0% effectiveness.

Survival estimates

Kaplan–Meier estimates of median OS from randomization were 25.4 months for sipuleucel-T–treated patients (n = 488), 23.6 months for APC8015F-treated control patients (n = 165), and 12.7 months for control patients not receiving APC8015F (n = 84). Patients were not eligible to receive APC8015F before disease progression. To reduce variability associated with time from randomization to disease progression, analyses of survival from protocol-defined disease progression were also performed; median survival estimates were 20.7 months for sipuleucel-T–treated patients (n = 419), 20.0 months for APC8015F-treated control patients (n = 155), and 9.8 months for control patients not receiving APC8015F (n = 61). Comparing control patients who did/did not receive APC8015F, the unadjusted HR for death was 0.53 (95% CI, 0.38–0.74), representing a 47% reduction in risk of death associated with APC8015F treatment (P < 0.001;

1 oktober 2012: Bron Trial register, met dank aan Henk-Jan

Op de ESMO, het congres in Wenen maakte Dendreon de producent van Provenge - Sipuleucel-T bekend dat zij een open label studie opzetten waaraan prostaatkankerpatiënten uit in principe alle landen uit Europa aan deel kunnen nemen.

Als u hier klikt ziet u de voorwaarden waaronder een adres waar u informatie kunt verkrijgen hoe in te schrijven voor deze studie. Echter de plaatsen zijn wel beperkt - 24 voor nederland - en de voorwaarden zijn wel zwaar. Maar wanneer u denkt hiervoor in aanmerking te komen dan kunt u het natuurlijk altijd proberen.

Hier de aankondiging zoals gedaan op de ESMO:

First Patient In Dendreon EU Open-Label Study Begins Sipuleucel-T Infusion Treatment
Sipuleucel-T Data To Be Presented At The ESMO 2012 Congress (European Society for Medical Oncology)

SEATTLE--(BUSINESS WIRE)-- September 27, 2012--Dendreon Corporation (NASDAQ:DNDN) today announced the first patient enrollment and initiation of treatment for the sipuleucel-T European Union (EU) open-label study. The open-label study is being conducted in European men with metastatic castrate-resistant prostate cancer (mCRPC) to describe product release parameters and report on safety in a European population. The study may enroll up to 45 patients in four sites across the EU. Dendreon has submitted a marketing authorization application (MAA) for sipuleucel-T which is currently under review by the European Medicines Agency (EMA). Sipuleucel-T is not approved for use outside the U.S. Sipuleucel-T is approved by the Food and Drug Administration (FDA) in the U.S. for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. It is marketed under the name PROVENGE®.

"We are extremely pleased with the progress of this new study and that the first patient has begun his treatment," said Thomas Powles MD, MRCP, Barts Cancer Institute, St. Bartholomew's Hospital, London. "We are also excited about the potential study outcomes and look forward to a successful program with the support of our committed clinical team and dedicated patients."

In addition to the current EU open-label study, the following data presentations are taking place at the ESMO 2012 Congress in Vienna, Austria, 28 September —2 October:

· Saturday, September 29, 13:00-14:00 CEST — Abstract #939P: "Neoadjuvant Sipuleucel-T in Localized Prostate Cancer: Effects on Immune Cells within the Prostate Tumor Microenvironment." Poster presentation.

· Saturday, September 29, 13:00-14:00 CEST — Abstract #940P: "Overall Survival Benefit with Sipuleucel-T by Baseline PSA: An Exploratory Analysis from Three Phase 3 Trials." Poster presentation.

· Saturday, September 29, 13:00-14:00 CEST — Abstract #941P: "Impact of Salvage Therapy with AC8015F on the Overall Survival Benefit Achieved with Sipuleucel-T in Three Phase III Studies of Metastatic Castrate-Resistant Prostate Cancer. Poster presentation.

· Saturday, September 29, 13:00-14:00 CEST — Abstract #943P: "OpenACT: Phase II, Open-Label Study of Sipuleucel-T in Metastatic Castrate-Resistant Prostate Cancer (mCRPC)." Poster presentation.

· Saturday, September 29, 13:00-14:00 CEST — Abstract #942P: "Antigen Presenting Cell (APC) Activation in Sipuleucel-T: Is Activation Increased in Earlier Prostate Cancer Disease States?" Poster presentation.

Indication and Important Safety Information

Approved for use in the U.S. only.

PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

The safety evaluation of PROVENGE was based on 601 prostate cancer patients in four randomized clinical trials who underwent at least one leukapheresis. The most common adverse events (incidence greater-than or equal to 15%) are chills, fatigue, fever, back pain, nausea, joint ache, and headache. Serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

To fulfill a post marketing requirement and as a part of the company's ongoing commitment to patients, Dendreon will conduct a registry of approximately 1500 patients to further evaluate a small potential safety signal of cerebrovascular events. In four randomized clinical trials of PROVENGE in prostate cancer patients, cerebrovascular events were observed in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

Exploratory analyses indicate that APC8015F treatment may have extended patient survival, suggesting the sipuleucel-T OS advantage in CRPC may be more robust than previously estimated.

Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy

Daniel J. George, , Todd DeVries, James B. Whitmore and

DOI: 10.1158/2326-6066.CIR-15-0006 Published September 2015

Abstract

Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). After disease progression, control-arm patients on three double-blind, randomized phase III sipuleucel-T trials were offered, in nonrandomized open-label protocols, APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control manufacture. These exploratory analyses evaluated potential effects on survival outcomes associated with such treatment. Of 249 control-treated patients, 165 (66.3%) received APC8015F. We explored the effects of APC8015F on the overall survival (OS; Cox regression) of control-arm patients and treatment effects of sipuleucel-T versus control adjusted for APC8015F treatment [iterative parameter estimation model (IPE)]. The median time to first APC8015F infusion was 5.2 months (range, 1.8–33.1) after randomization and 2.2 months (0.5–14.6) after progression. After disease progression, median survival was longer for APC8015F-treated versus control-only treated patients [20.0 vs. 9.8 months; HR, 0.53; 95% confidence interval (CI), 0.38–0.74; P < 0.001]; however, baseline characteristics were more favorable for APC8015F-treated patients. Multivariate regression analyses identified lactate dehydrogenase, alkaline phosphatase, hemoglobin, ECOG status, age, and number of bone metastases as potential (P < 0.1) independent predictors of postprogression survival. After adjusting for these predictors, APC8015F (HR, 0.78; 95% CI, 0.54–1.11; P = 0.17) treatment trended toward improved survival. Estimated median OS benefit for sipuleucel-T versus control adjusted for APC8015F treatment was 3.9 months if APC8015F had no effect and was 8.1 months if APC8015F was equally as effective as sipuleucel-T. Exploratory analyses indicate that APC8015F treatment may have extended patient survival, suggesting the sipuleucel-T OS advantage in CRPC may be more robust than previously estimated. Cancer Immunol Res; 3(9); 1063–9. ©2015 AACR.

References

1.↵

PROVENGE (sipuleucel-T) suspension for intravenous infusion prescribing information. 2011. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf.
2.↵
1. Small EJ,
2. Schellhammer PF,
3. Higano CS,
4. Redfern CH,
5. Nemunaitis JJ,
6. Valone FH,
7. et al.
Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006;24:3089–94.
Abstract/FREE Full Text Google Scholar
3.↵
1. Kantoff PW,
2. Higano CS,
3. Shore ND,
4. Berger ER,
5. Small EJ,
6. Penson DF,
7. et al.
Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411–22.
CrossRef PubMed Google Scholar
4.↵
1. Higano CS,
2. Schellhammer PF,
3. Small EJ,
4. Burch PA,
5. Nemunaitis J,
6. Yuh L,
7. et al.
Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009;115:3670–9.
CrossRef PubMed Google Scholar
5.↵
1. Sheikh NA,
2. Jones LA
. CD54 is a surrogate marker of antigen presenting cell activation. Cancer Immunol Immunother 2008;57:1381–90.
CrossRef PubMed Google Scholar
6.↵
1. Branson M,
2. Whitehead J
. Estimating a treatment effect in survival studies in which patients switch treatment. Stat Med 2002;21:2449–63.
CrossRef PubMed Google Scholar
7.↵
1. Robins JM,
2. Tsiatis AA
. Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Commun Stat Theory Methods 1991;20:2609–31.
CrossRef Google Scholar
8.↵
1. Schellhammer PF,
2. Chodak G,
3. Whitmore JB,
4. Sims R,
5. Frohlich MF,
6. Kantoff PW
. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology 2013;81:1297–302.
CrossRef PubMed Google Scholar
9.↵
1. Hall SJ,
2. Klotz L,
3. Pantuck AJ,
4. George DJ,
5. Whitmore JB,
6. Frohlich MW,
7. et al.
Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol 2011;186:877–81.
CrossRef PubMed Google Scholar
10.↵
1. Sheikh NA,
2. Petrylak D,
3. Kantoff PW,
4. Dela Rosa C,
5. Stewart FP,
6. Kuan LY,
7. et al.
Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer. Cancer Immunol Immunother 2013;62:137–47.
CrossRef PubMed Google Scholar
11.↵
1. Morden JP,
2. Lambert PC,
3. Latimer N,
4. Abrams KR,
5. Wailoo AJ
. Assessing methods for dealing with treatment switching in randomised controlled trials: a simulation study. BMC Med Res Methodol 2011;11:4.
CrossRef PubMed Google Scholar
12.↵
1. Armstrong AJ,
2. Garrett-Mayer ES,
3. Yang YC,
4. de Wit R,
5. Tannock IF,
6. Eisenberger M
. A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin Cancer Res 2007;13:6396–403.
Abstract/FREE Full Text Google Scholar
13.↵
1. Tannock IF,
2. de Wit R,
3. Berry WR,
4. Horti J,
5. Pluzanska A,
6. Chi KN,
7. et al.
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12.
CrossRef PubMed Google Scholar
14.↵
1. Petrylak DP,
2. Tangen CM,
3. Hussain MH,
4. Lara PN Jr.,
5. Jones JA,
6. Taplin ME,
7. et al.
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20.
CrossRef PubMed Google Scholar
15.↵
1. de Bono JS,
2. Oudard S,
3. Ozguroglu M,
4. Hansen S,
5. Machiels JP,
6. Kocak I,
7. et al.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147–54.
CrossRef PubMed Google Scholar
16.↵
1. de Bono JS,
2. Logothetis CJ,
3. Molina A,
4. Fizazi K,
5. North S,
6. Chu L,
7. et al.
Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005.
CrossRef PubMed Google Scholar
17.↵
1. Scher HI,
2. Fizazi K,
3. Saad F,
4. Taplin M-E,
5. Sternberg CN,
6. Miller K,
7. et al.
Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: results from the phase III AFFIRM study. ASCO Meeting Abstracts 2012;30(5_suppl):LBA1.
Google Scholar
18.↵
1. Parker C,
2. Heinrich D,
3. O'Sullivan JM,
4. Fossa SD,
5. Chodacki A,
6. Demkow T,
7. et al.
Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. ASCO Meeting Abstracts 2012;30(5_suppl):8.
Google Scholar
19.↵
1. Sternberg CN,
2. Petrylak DP,
3. Sartor O,
4. Witjes JA,
5. Demkow T,
6. Ferrero JM,
7. et al.
Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol 2009;27:5431–8.
Abstract/FREE Full Text Google Scholar
20.↵
1. Kantoff PW,
2. Schuetz TJ,
3. Blumenstein BA,
4. Glode LM,
5. Bilhartz DL,
6. Wyand M,
7. et al.
Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010;28:1099–105.
Abstract/FREE Full Text Google Scholar
21.↵
1. Ibrahim A,
2. Johnson J
. FDA clinical briefing document for the oncologic drug advisory committee. Washington, DC: DHSS, PHS, FDA, Center for Drug Evaluation and Research. 2005.
Google Scholar
22.↵

FDA guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. 2007. Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER).
23.↵
1. Hernan MA,
2. Brumback B,
3. Robins JM
. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology 2000;11:561–70.
CrossRef PubMed Google Scholar
24.↵
1. Robins JM,
2. Hernan MA,
3. Brumback B
. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550–60.
CrossRef PubMed Google Scholar
25.↵
1. Hernan MA,
2. Brumback B,
3. Robins JM
. Marginal structural models to estimate the joint causal effect of nonrandomized treatments. J Am Stat Assoc 2001;96:9.
Google Scholar
26.↵
1. Robins JM,
2. Finkelstein DM
. Correcting for noncompliance and dependent censoring in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics 2000;56:779–88.
CrossRef PubMed Google Scholar