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Sipuleucel-T (APC8015, Provenge),Cite error: The opening <ref> tag is malformed or has a bad name (see the help page). manufactured by Dendreon Corporation, is a patient specific therapeutic cancer vaccine for prostate cancer (CaP). A therapeutic vaccine is designed to treat the active disease. A preventive vaccine is to cure the condition (usually a virus) causing the cancer. As of 2011 there are two approved prophylactic cancer prevention vaccines. These are for the cancer causing viruses HPV and HBV.

Cancer Immunotherapeutic history

Sipuleucel-T is the first therapeutic cancer vaccine to demonstrate effectiveness in Phase III clinical trials by prolonging the life of patients who have advanced to the late stage of the disease, metastatic, asymptomatic, hormone-refractory prostate cancer (HRPC). Other names for this stage are metastatic Castrate-Resistant (mCRPC) and Androgen Independent (AI) or (AIPC). This stage leads to mCRPC with lymph node involement and distal (distant) tumors, this is the lethal stage of CaP. The Prostate cancer staging designation is T4,N1,M1c. Its approach to elicit an immune response against cancer cells results in a novel and uniquely effective treatment that "could extend the life of prostate cancer patients with far fewer of the harsh side effects of traditional treatments such as surgery, radiation and chemotherapy."

First FDA approved cancer vaccine

Sipuleucel-T was approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010 to treat asymptomatic or minimally symptomatic metastatic HRPC.

Shortly afterward, Sipuleucel-T was added to the Compendium of cancer treatments published by the National Comprehensive Cancer Network (NCCN) as a "category 1" (highest recommendation) treatment for HRPC. The NCCN Compendium is a source sanctioned by Medicare and used by major healthcare insurance providers to decide whether and when a treatment should be covered when a physician recommends it for established indications.

Treatment method

A course of Sipuleucel-T treatment consists of three basic steps:

1. A patient's own white blood cells, primarily antigen-presenting cells (APCs), also called Dendritic cells, are extracted in a leukapheresis procedure.
2. The blood product is sent to the factory and incubated with a fusion protein (PA2024) consisting of two parts,
   1. the antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells, and
   2. an immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.
3. The activated blood product (APC8015) is returned from the factory to the infusion center and re-infused into the patient to cause an immune response against cancer cells carrying the PAP antigen.

A complete Sipuleucel-T treatment repeats three courses over the span of a month, with two weeks between successive courses.

Survival benefit

Sipuleucel-T showed "overall survival (OS)" benefit to patients in three double-blind randomized phase III clinical trials, D9901, D9902a, and IMPACT.

The D9901 trial enrolled 127 patients with asymptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for patients treated with Sipuleucel-T was 25.9 months comparing to 21.4 months for placebo-treated patients. Overall survival was statistically significant with P-value 0.01, i.e., the chance of the result being a false positive was less than one percent.

The D9902a trial was designed like the D9901 trial but it enrolled only 98 patients. The median survival time for patients treated with Sipuleucel-T was 19.0 months comparing to 15.3 months for placebo-treated patients. Overall survival did not achieve statistical significance but did show a trend in improving survival as seen in the difference between treated and placebo median survival times.

The IMPACT trial served as the basis for licensing approval of Sipuleucel-T by the FDA. This trial enrolled 512 patients with asymptomatic or minimally symptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for Sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-treated patients. Overall survival was statistically significant with P-value 0.032.

Placebo patients in all three trials were allowed to cross over after disease progression to take a version of Sipuleucel-T made from their frozen blood saved on trial entry (APC8015F). The publication of the IMPACT study observed that the cross-over patients had an estimated median survival time of 23.8 months comparing to 11.6 months for those patients who never received Sipuleucel-T in any form. However, this observation was retrospective so a prospective test would be required before the implied benefit of frozen Sipuleucel-T could be confirmed.

Side effects

The side effects of Sipuleucel-T were mostly limited to chills, fever, fatigue, nausea and headache which usually occurred within the first few days of treatment. In addition, more serious cardiovascular events were observed at a rate of 2.4% in patients treated with Sipuleucel-T vs 1.8% in placebo-treated patients.

A question on tumor progression

Although the three phase III trials, D9901, D9902a and IMPACT, confirmed the survival benefit of Sipuleucel-T, they did not demonstrate that Sipuleucel-T delayed tumor progression. Only D9901 indicated such a possibility with P value 0.052 for the time-to-progression endpoint (like progression-free survival but not counting death as progression), slightly higher than the traditionally accepted level of statistical significance at 0.05. This has led to a question as stated in a review from the New England Journal of Medicine (NEJM) on how survival prolongation was possible without "some apparent measurable change in the tumor".

However, the possibility of such an anomalous result was well-known in cancer vaccine research. For example, an article in the Journal of the National Cancer Institute (JNCI) observed that the "classic criteria for measuring the efficacy of a therapeutic may not apply to vaccines" and multiple cancer vaccine trials had shown that patients lived longer even though very little shrinkage of tumors was seen.

The FDA Draft Guidance for Industry on designing trials for therapeutic cancer vaccines stated that a delayed effect could be expected in subjects receiving a vaccine because "cancer vaccines need time to elicit an immune response that could manifest as biological activity". Such a delayed effect could mean that "the endpoint curves of the trial results may show no effect for the initial portion of the study." In particular, an endpoint such as progression-free survival or time-to-progression would be difficult to achieve in a clinical trial of a cancer vaccine as tumor progression often happens while the immune system is being activated.

As the JNCI article further discussed, progression events are not always critical. Thus, once activated by an effective vaccine such as Sipuleucel-T, the immune system could still help to keep tumor growth in check and prolong survival.

Additional clinical trials

• PROTECT PRO Treatment and Early Cancer Treatment a phase IIIB clinical trial started October, 2008 and is currently underway. Its purpose is to test efficacy for patients whose CaP is still controlled by either, surgical castration or medical castration. Such patients have usually failed primary treatment of either surgical removal of the prostate, (EBRT), internal radiation, BNCT or (HIFU) for curative intent. Such failure is called biochemical failure and refers to a PSA reading of 2.0 ng/mL above nadir (the lowest reading taken post primary treatment).

• NEOACT (NEOadjuvant Active Cellular ImmunoTherapy) a phase II initially a single-site trial in men with localized CaP scheduled for prostatectomy. The sites are UCSF in San Francisco, ca, USC/Norris Comprehensive Cancer Center, Los Angeles, ca., Oregon, Health and Science University, Portland, Oregon, Kaiser Permenante, Portland, Oregon, University of Utah, School of Medicine, Salt Lake City, Utah and Virgina Mason Medical Center, Seattle, Washington.

• ProACT (PROstate cancer Active Cellular ImmunoTherapy) a phase II multicenter metastatic androgen independent CaP. Testing three different strengths of the PA2024 antigen used to fuse the PAP and GM-CSF.

Cost of treatment

The total cost for three courses of treatment with Sipuleucel-T is $93,000. The NEJM review has contrasted that cost against an average cost figure of $1,800 per patient per month. However, as a large number of patients surveyed in the study chose not to be treated with any treatment to avoid side effects, the cost estimate was not suitable to compare with a treatment with survival benefit such as Sipuleucel-T. An in-depth analysis of cost per additional month of median survival advantage showed that the cost of Sipuleucel-T was similar to that of taxotere, the standard of care for HRPC before Sipuleucel-T was approved for marketing.

References

1. Plosker GL (2011). "Sipuleucel-T: in metastatic castration-resistant prostate cancer". Drugs. 71 (1): 101–8. doi:10.2165/11206840-000000000-00000. PMID 21175243. {{cite journal}}: Unknown parameter |month= ignored (help)
2. ^ Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF (2010). "Sipuleucel-T immunotherapy for castration-resistant prostate cancer". N. Engl. J. Med. 363 (5): 411–22. doi:10.1056/NEJMoa1001294. PMID 20818862. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
3. ^ Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006). "Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer". J. Clin. Oncol. 24 (19): 3089–94. doi:10.1200/JCO.2005.04.5252. PMID 16809734. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
4. ^ Longo DL (2010). "New therapies for castration-resistant prostate cancer". N. Engl. J. Med. 363 (5): 479–81. doi:10.1056/NEJMe1006300. PMID 20818868. {{cite journal}}: Unknown parameter |month= ignored (help)
5. Clarke S, Childs D (2010-04-26). "Provenge Uses Body's Immune System to Fight Prostate Cancer". ABC News.
6. Perrone M (April 29, 2010). "FDA approves breakthrough cancer therapy Provenge". AP News.
7. "Survival Benefit of Sipuleucel-T in Prostate Cancer Appears Durable". Elsevier Global Medical News. 2010-03-11.
8. Richwine L (2010-04-29). "U.S. FDA OKs Dendreon's prostate cancer vaccine". Reuters. Retrieved 2010-04-30.
9. "Approval Letter - Provenge". Food and Drug Administration. 2010-04-29.
10. "NCCN Guidelines™ and NCCN Compendium™ Updated". Retrieved 2011-01-08. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
11. "NCCN Drugs & Biologics Compendium™". {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
12. "Sipuleucel-T: APC 8015, APC-8015, prostate cancer vaccine--Dendreon". Drugs R D. 7 (3): 197–201. 2006. PMID 16752945.
13. ^ Higano C, Burch P, Small E, Schellhammer P, Lemon R, Verjee S, Hershberg R (2005). Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial. 13th European Cancer Conference. Paris. {{cite conference}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
14. Mason K (2005-11-02). "New treatment options for patients with prostate cancer". ECCO-the European CanCer Organisation.
15. ^ Benowitz S (2008). "Rethinking cancer vaccine trials: would new measures of success make a difference?". J. Natl. Cancer Inst. 100 (4): 237–8. doi:10.1093/jnci/djn030. PMID 18270332. {{cite journal}}: Unknown parameter |month= ignored (help)
16. "Draft Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines". U.S. Food and Drug Administration. 2009-09-17. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
17. "NCT00779402: Provenge for the Treatment of Hormone Sensitive Prostate Cancer". ClinicalTrials.gov. US National Institutes of Health. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
18. Roach M, Hanks G, Thames H, Schellhammer P, Shipley WU, Sokol GH, Sandler H (2006). "Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference". Int. J. Radiat. Oncol. Biol. Phys. 65 (4): 965–74. doi:10.1016/j.ijrobp.2006.04.029. PMID 16798415. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
19. "NCT00715104: Sipuleucel-T as Neoadjuvant Treatment in Prostate Cancer". ClinicalTrials.gov. US National Institutes of Health. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
20. "NCT00715078: To Evaluate Sipuleucel-T Manufactured With Different Concentrations of PA2024 Antigen". ClinicalTrials.gov. US National Institutes of Health. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
21. Alemayehu B, Buysman E, Parry D, Becker L, Nathan F (2010). "Economic burden and healthcare utilization associated with castration-resistant prostate cancer in a commercial and Medicare Advantage US patient population". J Med Econ. 13 (2): 351–61. doi:10.3111/13696998.2010.491435. PMID 20491610. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
22. ^ Miller D (July 29, 2010). "Dendreon's Provenge Costs the Same as Chemotherapy". Retrieved 2010-08-27.

External links

• "Provenge (sipuleucel T) | Advanced Prostate Cancer |". Provenge.com. Dendreon Corporation. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
• "Dendreon". Dendreon.com. Dendreon Corporation. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)

 This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.

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