Hormone Refractory Prostate Cancer

Understanding    Treating    Maintaining Quality of Life

VACCINES FOR PROSTATE CANCER

Introduction

The leading contenders for prostate cancer vaccines are GVAX (was in phase III), Provenge (approved by FDA 4/29/2010), and Prostvac-VF

GVAX

May 3, 2010. Originally developed by Cell Genesys, it was bought out by BioSante last October.  BioSante plans new prostate cancer drug testing (or re-start testing almost two years after research was stopped -- it was put on hold in August 2008 because of a high number of deaths among patients taking the drug..) This is expected by YE2010, subject to regulatory approval. BioSante said it has started manufacturing new GVAX Prostate and is working to get the Food and Drug Administration to allow it to resume testing. It hopes to begin treating patients in a midstage clinical study in the beginning of the fourth quarter. This Vaccine was in phase III development.

Provenge (sipuleucel-T)

On April 29, 2010, the U.S. Food and Drug Administration approved sipuleucel-T (PROVENGE®, Dendreon Corporation), an autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

Sipuleucel-T is a cellular immunotherapy consisting of autologous peripheral blood mononuclear cells (PBMC's), obtained by leukapheresis and cultured (activated) with a recombinant human protein (PAP-GM-CSF) consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor.

Full availability is expected by mid-2011 with early availability for around 2000 patients before then.

First person accounts of their experience with Provenge clinical trials is on two pages with the information from Jack Beaven (see clintrialsJB1 and clintrialsJB2) and another page from SB at clintrialsSB.

Read the following as an introduction to Provenge:

Information about Provenge can be found at: www.dendreon.com which explains the theory behind using dendritic cells to train the T-cells to seek out and destroy PC cells. The immune system normally ignores them because it identifies them as part of the body.

Unlike vaccines we are familiar with (smallpox, polio, measles, etc.) which protect against diseases you are exposed to, Provenge is designed to initiate the immune response to intracellular abnormalities caused by viruses, some bacteria, and cancers.

The treated dendritic cells activate T-Cells to attack and kill the cancer cells.  These activated T-Cells survive and continue to recognize their target antigen. This vaccine approach is expected to have a long lasting therapeutic effect.  (This is logical, since recent reports say that it is expected that even those of us vaccinated against smallpox 40 years ago or so should still have at least some protection today.)

According to Dr. Valone’s presentation at the year 2000 PCRI Conference, of the 100 patients they had treated to that time, better than 80% had no side effects at all.  The most severe were similar to the reaction one gets from a flu shot, and lasted only a day or two.

2 November 2009. Dendreon released the following news item. "Dendreon Completes Submission of Biologics License Application for PROVENGE

SEATTLE (November 2, 2009) - Dendreon Corporation (Nasdaq: DNDN) today announced that it has completed the submission of the amended Biologics License Application (BLA) for PROVENGE® (sipuleucel-T), the Company's lead investigational product, to the U.S. Food and Drug Administration (FDA). Dendreon is seeking licensure for PROVENGE for men with metastatic castrate-resistant prostate cancer (CRPC). If approved by the FDA, PROVENGE would represent the first product in the new therapeutic class known as active cellular immunotherapies.

The amended BLA includes data from the IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial, which was conducted under a Special Protocol Assessment agreement with the FDA. The IMPACT study met its pre-specified primary endpoint demonstrating a statistically significant improvement in overall survival in men with metastatic CRPC.

PROVENGE is available through several ongoing clinical trials, including OpenACT, an open label trial enrolling men with metastatic CRPC, ProACT (PROstate cancer Active Cellular immunoTherapy), and NeoACT (NEOadjuvant Active Cellular immunotherapy). For more information regarding these studies, visit www.clinicaltrials.gov." The one trial that is currently recruiting (as listed on clinical trials.gov) is NCT00901342 . The description is "Subjects will receive the investigational product, sipuleucel-T, at approximately 2-week intervals, for a total of 3 infusions. The study will evaluate the safety of and magnitude of the immune responses to treatment with sipuleucel-T. All subjects will be followed for 30 days following the last infusion of sipuleucel-T. The study is also available to placebo subjects who participated in the D9902B study."

A phase III trial of Provenge for asymptomatic HRPC patients was recently presented at ASCO 2005(1). The reference below includes a link to the abstract. it was a fairly small trial with only 127 patients split between the vaccine(82) and the placebo(45). See the abstract for the results. The reference for the phase III trial as a full paper in the JCO is given below also (2).

A paper published in Cancer in 2009 by Higano et al(3) has more information. Sipuleucel-T is an investigational active cellular immunotherapy product designed to stimulate an immune response against prostate cancer. The safety and efficacy of sipuleucel-T was evaluated in 2 identically designed, randomized, double-blind, placebo-controlled trials (D9901 and D9902A) conducted in men with advanced prostate cancer.

• 225 patients randomized in D9901 or D9902A to sipuleucel-T (n = 147) or placebo (n = 78), given as 3 intravenous infusions approximately 2 weeks apart. Patients were followed for survival until death or a prespecified cutoff of 36 months after randomization.

• In the integrated analysis of D9901 and D9902A, patients randomized to sipuleucel-T demonstrated a 33% reduction in the risk of death (hazard ratio, 1.50; 95% confidence interval, 1.10-2.05; P = .011; log-rank).

• The treatment effect remained strong after performing adjustments for imbalances in baseline prognostic factors, poststudy treatment chemotherapy use, and non-prostate cancer-related deaths.

• Additional support for the activity of sipuleucel-T is provided by the correlation between a measure of the product's potency, CD54 up-regulation, and overall survival.

• The most common adverse events associated with treatment were chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. These events were primarily grade 1 and 2, with durations of 1 to 2 days.

• The conclusion was that there was a survival benefit for Provenge compared to a placebo and that the toxicity profile was modest suggesting a favorable risk-benefit ratio for Provenge in patients with advanced prostate cancer.

Manufacturing and Commercialization Preparation for Provenge

The existing capacity at Dendreon's New Jersey manufacturing facility represents 25 percent of the total future capacity at this facility. After FDA approval, the Company expects to launch PROVENGE from this existing portion of the New Jersey facility in mid-2010 and to continue to make the product available in a gradual stepwise fashion as the Company ramps up to full capacity at this facility. The Company expects to have 48 workstations in production at the New Jersey facility by the first half of 2011.

Dendreon recently signed leases for additional manufacturing facilities in Los Angeles and Atlanta.  Both are expected to have 36 workstations, and additional capacity from these facilities will be available in the second half of 2011. Dendreon will leverage established third parties for patient/physician scheduling, apheresis and product transportation.

Dendreon's primary provider for apheresis services will be the American Red Cross, which has a nationwide network of apheresis centers.  This resource will be augmented with other regional apheresis centers.  There are more than 600 apheresis centers in the U.S., and Dendreon expects to contract with 150 to 200 of them at peak demand.

The Company has developed and will implement IntellivengeT, a first-of-its-kind advanced logistical and patient treatment management and planning system, which coordinates the patient and physician scheduling as well as the operational and logistic activities should PROVENGE be approved by the FDA.  With Intellivenge, physicians and patients can log-in and track where their product is throughout the manufacturing process.

Dendreon's headcount is currently 290 and is expected to more than double by the anticipated time of product launch.

References for Provenge

PROSTVAC-VF

The most recent clinical trial results for this vaccine is a phase II trial whose purpose was to evaluate PROSTVAC-VF for safety and for prolongation of progression-free survival (PFS) and overall survival (OS). The trial was a randomized, controlled, and blinded phase II study. Details follow.
 

No. of patients: 125 randomly assigned. Patients had minimally symptomatic HRPC (mCRPC). Eighty-two patients received PROSTVAC-VF and 40 received control vectors (essentially a placebo). Patients were limited to those believed to have favorable risk features. Patients with visceral metastases or pain requiring opioid analgesics were excluded and they were required to have ECOG performance status of 0 or 1 as well as a Gleason score of ≤ 7 (2).

The vaccine: "PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections." Note that the viruses are the same cowpox virus that forms the basis of the smallpox vaccine and a bird virus called fowlpox. They are genetically engineered to carry prostate specific antigen or PSA, which is made only by prostate cells.

Progression Free Survival (PFS) - The primary end point.

• similar in the two groups.

Overall Survival (OS) (evaluated 3 years post study),

• PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls). 

Conclusion: PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. A larger phase III trial is needed.

Note: PROSTVAC-VF is being developed by BN ImmunoTherapeutics, a division of Danish biotech firm Bavarian Nordic (BAVA.CO).

References - Prostvac-VF

1. Philip W. Kantoff, Thomas J. Schuetz, Brent A. Blumenstein, L. Michael Glode, David L. Bilhartz, Michael Wyand, Kelledy Manson, Dennis L. Panicali, Reiner Laus, Jeffrey Schlom, William L. Dahut, Philip M. Arlen, James L. Gulley, Wayne R. Godfrey, Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer, J. Clinical Oncology Jan 25 2010: doi:10.1200/JCO.2009.25.0597. 

2. EJ Small et al, Developing Immunotherapy As Legitimate Therapy for Patients with Prostate Cancer, J. Clin Oncology, vol 28, 2010, editorial.

 Author: Howard Hansen, last update May 4, 2010.

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