PROVENGE (sipuleucel-T) - A new treatment option
for men with HRPC disease
Author: Howard Hansen 8/12/2010
body. No donor involved. In the case of Provenge, it makes for a
very patient specific or personalized vaccine.
or just phersis) - the drawing of a patient's blood via a small tube
(catheter) from one arm, which is then separated by a machine where
the blood is separated into various components - the immune cells
are removed and the rest of the cells and plasma are returned to the
patient via another catheter -- picture in one arm, through the
machine, back in the other arm.
PAP - prostatic acid phosphatase - an
enzyme made by the cells of the prostate.
GM-CSF - granulocyte-macrophage colony-stimulating factor.
Leukine or sargramostrim are other names
Active cellular immunotherapy - agent
stimulates a host antitumor response. (e.g., Provenge)
Passive immunotherapy - agent has direct
Nonspecific - agent elicits a general
increase in immune activation.
Specific - immune response based on tumor
recognition. Provenge - active & specific.
PBMC - peripheral-blood mononuclear cells
from the patient.
PA2024 - A recombinant fusion protein
consisting of a prostate antigen(PAP) that is fused to GM-CSF (an
immune cell activator). This is written as PAP-GM-CSF.
CD54 is a surrogate marker of antigen
presenting cell activation.
Hazard Ratio - A measure of how often
a particular event happens in one group compared to how often it
happens in another group, over time. In cancer research, hazard
ratios are often used in clinical trials to measure survival at
any point in time in a group of patients who have been given a
specific treatment compared to a control group given another
treatment or a placebo. A hazard ratio of one means that there
is no difference in survival between the two groups. A hazard
ratio of greater than one or less than one means that survival
was better in one of the groups.
p-value - A term in statistics. It
helps show whether a difference found between groups that are
being compared is due to chance. A small p-value usually means
that the difference between groups is not due to chance alone,
but is due to some other factor, such as a treatment one of the
groups received. A large p-value usually means that the
difference between groups is probably due to chance alone.
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.
PROVENGE is made from
each patient's immune cells. The cells are
approximately 3 days before each scheduled infusion of PROVENGE. You go to a cell collection center for this. Dendreon is mostly using the American red Cross. The collection
is called leukapheresis (pronounced loo-kuh-fuh-REE-sis). For this procedure,
a small tube (catheter) is placed into veins in each arm or in a vein in
the upper chest or neck. They may or may not be able to use a chemo
port. Once the procedure begins, blood will flow from
your vein into a machine where the blood is separated into various components.
The immune cells (along with some of the platelets and a small amount of
red blood cells) are removed. The rest of the cells and the plasma are returned
to your body using the 2nd catheter. A leukapheresis procedure
can last from 3 to 4 hours. This has to be done 3x over the
course of getting Provenge. These are separated by about 2 weeks.
Information about Provenge can be found at:
www.provenge.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
prescribing information is available at the above websites or directly at:
You are probably familiar with vaccines such as the
ones for 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. It is a one time treatment as opposed to chemotherapy which can
involve multiple treatments over months.
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. (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.)
Provenge Fact Sheet
provides a brief summary of Provenge. References (9) and (10) also
provide information on Provenge (PCRI's Insights Newsletter).
Phase III Clinical Trials
There have been several phase III trial of
Provenge vs placebo. A phase III trial of Provenge for asymptomatic HRPC patients was 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 J. Clinical Oncology is given below (2).
D9901 and D9902A. A paper published in Cancer in 2009 by Higano et al(3) has more information. The safety and
efficacy of Provenge (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, post study 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.
IMPACT - Immunotherapy for Prostate
Adenocarcinoma Treatment (4). This was a double-blind,
placebo-controlled, multicenter trial with overall survival as the
primary end point.
512 patients, randomized to Provenge (341 patients) and a
placebo (171 patients)
Median age was 71 years (range 40-91 years)
The median time from the first infusion to the third infusion
was 28 days (range 21 to 119 days).
All patients had received previous androgen-deprivation therapy
(presumably, just an LHRH agonist such as Lupron); 82% had had
combined androgen blockade; 53.9% had radiotherapy of the
prostate or prostate bed; 35.2% had previously received a
radical prostatectomy and 18.2% chemotherapy.
Median follow-up time was 34.1 months.
treatment effect consistently favored the
sipuleucel-T group in the assessment of more than 20
baseline characteristics of the patients as effect
modifiers. Therapy with sipuleucel-T was
also associated with a positive overall survival
effect in an analysis that included 18 additional
deaths observed between the data-cutoff and
study-completion dates, with a median of 36.5
months of follow-up (hazard ratio, 0.76; 95% CI,
0.61 to 0.95; P = 0.02).
The estimated probability of survival 36 months after
randomization was 31.7% in the sipuleucel-T group and
23.0% in the placebo group.
Provenge vs placebo: adjusted hazard ratio for death was
0.78 (95% CI, 0.61 to 0.98), representing a relative
reduction in the risk of death of 22% (P = 0.03).
The reduction in the risk of death from prostate cancer
in the sipuleucel-T group
(hazard ratio, 0.77; 95% CI, 0.61 to 0.98; P = 0.04) was
similar to the reduction in the risk of death from
Median time to
median time to objective disease progression was
14.6 weeks (3.7 months) in the sipuleucel-T
group and 14.4 weeks (3.6 months) in the
placebo group (hazard ratio, 0.95; 95% CI, 0.77 to
1.17; P = 0.63).
Similar results were observed for the
time to clinical disease progression (hazard
ratio, 0.92; 95% CI, 0.75 to 1.12; P = 0.40). One patient in
the sipuleucel-T group had a partial objective
of at least 50% on two visits at
least 4 weeks apart)
|8 of 311 patients (2.6%)
||2 of 153 patients (1.3%)
- Among patients with PSA assessments after baseline.
There were 3 abstracts presented at ASCO 2010 on Provenge - see
references 5, 6 and 7. The July 2010 ASCO Post had an abbreviated
versions of the actual abstract which is quoted in its entirety for
Abstract 4550. 3 Provenge trials, 737 patients revealed consistent
results across trials and within subgroups and there was a
significant treatment effect with independent baseline predictors of
overall survival including ECOG status, number of bone mets, nodal
disease, age, weight, PSA, LDH, Hgb and time from diagnosis to
Abstract 4551. "In another assessment based on the three-study
integrated analysis described in abstract 4550, a Provenge treatment
effect was observed whether or not patients received subsequent
docetaxel. Later use of the taxane improved overall survival
compared with no later docetaxel use. However, when this factor was
considered as a time-dependent covariate, it was not a significant
predictor of survival (HR=.941, P=.54) and the Provenge effect
remained significant (HR=..736, P,.001)." This says, I think, that
taxotere didn't change the survival effect of Provenge.
Abstract 4552 (7) concludes Provenge provides broad engagement of
the immune system thus contributing to Provenge survival findings.
Adverse Events (4, 8)
Events were reported for 496 of 506 patients (98.0%) in the safety
population. The events were mild to moderate (grade 1 or 2) for 330
that were reported more
frequently in the sipuleucel-T group than in the placebo group
included chills, fever (pyrexia), headache,
influenza-like illness, myalgia, hypertension,
hyperhidrosis, and groin pain. Except for groin pain, most of these
events occurred within 1
day after infusion and resolved within 1 to 2 days.
that were reported more frequently in
the placebo group included anorexia, anxiety, depression, flank
pain, and contusion, as well as hydronephrosis (in 7.1% of patients
in the placebo group vs. 3.8% in the sipuleucel-T group).
most common adverse events in the sipuleucel-T
group within 1 day after infusion were
chills (in 51.2%), fever (22.5%), fatigue (16.0%),
nausea (14.2%), and headache (10.7%).
events of grade 3 or more within 1 day after infusion were
reported in 23 of 338 patients (6.8%) in
the sipuleucel-T group and 3 of 168 patients
(1.8%) in the placebo group. Among patients in the
sipuleucel-T group, grade 3 events that were
reported for at least 1 patient within 1 day after
infusion were chills (in 4 patients), fatigue (3 patients), and
back pain, hypertension, hypokalemia, and muscular weakness (in 2
grade 4 event was reported (intravenous catheter–associated bacteremia).
Overall, only 3 of 338 patients
(0.9%) in the sipuleucel-T group were unable to
receive all three infusions because of
infusion-related adverse events.
Dendreon is now required
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.
Cerebrovascular events were reported for 8 of 338 patients (2.4%) in
the sipuleucel-T group and 3 of
168 patients (1.8%) in the placebo group (P = 1.00 by Fisher’s exact
The incidence rate was
1.33 cerebrovascular events per 100 person years (95% CI, 0.58 to
2.62) in the sipuleucel-T
group and 1.11 per 100 person-years (95% CI, 0.23 to 3.24) in the
interval between the most recent infusion and the event was 210 days
in the sipuleucel-T group and 196
days in the placebo group.
Post marketing requirement:
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.
Manufacturing and Commercialization
Preparation for Proveng>
Availability is limited until mid-2011 when Dendreon is planning on
having all their manufacturing up and running. Early availability is
limited to approximately 2000 patients treated at the 50 centers
that participated in phase III trials.
The existing capacity at
Dendreon's New Jersey manufacturing facility represents 25 percent
of the total future capacity at this facility. Dendreon 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 is 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 for PROVENGE. With Intellivenge, physicians and patients can log-in and track where
their product is throughout the manufacturing process.
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.
References for Provenge
(1) EJ Small et al, Results of a
placebo-controlled phase III trial of immunotherapy with APC8015
for patients with hormone refractory prostate cancer (HRPC), J.
Clin Oncol (Meeting Abstracts) 2005 23: 4500,
(2) Small EJ 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 Jul
1;24(19):3089-94. PMID: 16809734
(3) Higano CS, Schellhammer PF, Small EJ, Burch PA,
Nemunaitis J, Yuh L, Provost N, Frohlich MW., 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 Aug
(4) PW Kantoff et al, Sipuleucel-T Immunotherapy for
Castration-Resistance Prostate Cancer, The New England J. of
Medicine, Volume 363, No. 5, July 29, 2010. See also the editorial
"New Therapies for Castration-Resistant Prostate Cancer by Dan L.
Longo, M.D. - here is one brief sentence, taken out of context, but
interesting, "...the prolongation of survival without a measurable
antitumor effect is surprising. It is hard to understand how the
natural history of a cancer can be affected without some apparent
measurable change in the tumor, either evidence of tumor shrinkage
or at least disease stabilization reflected in a delay in tumor
progression." You are encouraged to read the entire editorial in the
NEJM plus there is more than just Provenge covered.
(5) C. S. Higano, E. J. Small, P. F. Schellhammer,
P. Kantoff, C. H. Redfern, J. J. Nemunaitis, C. Nabhan, Y. Xu, J. B.
Whitmore, M. W. Frohlich; Predictors of outcome and subgroup results
from the integrated analysis of sipuleucel-T trials in metastatic
castration-resistant prostate cancer; J Clin Oncol 28:15s, 2010 (suppl;
(6) D. P.
Petrylak, N. A. Dawson, T. Gardner, L. Klotz, B. D. Curti, R. C.
Flanigan, M. N. Fishman, Y. Xu, J. B. Whitmore, M. W. Frohlich, Persistence
of immunotherapy survival effects of sipuleucel-T and relationship
to post randomization docetaxel use in phase III studies, J Clin Oncol
28:15s, 2010 (suppl; abstr 4551).
F. P. Stewart, C. P. dela Rosa, N. A. Sheikh,
D. G. McNeel, M. W. Frohlich, D. L. Urdal, N. M. Provost;
Correlation between product parameters and
overall survival in three trials of sipuleucel-T, an autologous
active cellular immunotherapy for the treatment of prostate
J Clin Oncol 28:15s, 2010 (suppl; abstr 4552).
(8) More Information about Provenge can be found at:
www.provenge.com which explains the theory behind using dendritic
cells to train the T-cells to seek out and destroy PC cells. Full
prescribing information is available at the above websites or directly at:
(9) Jan Manarite, PROVENGE Approved in the
U.S.A for Metastataic, Castrate Resistant Prostate Cancer, PCRI
Insights Newsletter, May 2010, Volume 13: No.2.
(10) W. Cavanagh, Immunotherapy and Advanced
Prostate Cancer, PCRI Insights Newsletter, February 2008, volume 11,
This appendix is being added to sweep up some
miscellaneous information about Provenge -- namely the Phase III
(IMPACT) patient requirements to enter the clinical trial and what
the FDA may have approved it for. Note that there seem to be several
requirements depending on where you live. See also the paper
published in the NEJM (4).
Per Kantoff et al, NEJM (reference 4)
"Patients Eligible men had metastatic
castration-resistant prostate cancer and an expected survival of at least 6 months. A previous randomized trial of
sipuleucel-T suggested a positive effect on disease progression in men with increased tumor
differentiation at diagnosis, as indicated by a Gleason score of 7 or less (on a scale of 2 to 10, with
higher scores indicating more aggressive disease).
On the basis of these results, we (Kantoff et al) initially
enrolled only men with a Gleason score of 7 or less. In addition,
only patients with asymptomatic disease were enrolled. After the
overall survival analysis in the aforementioned trial, which
indicated a positive treatment effect that was independent of the
Gleason score, we amended the eligibility criteria to include men
with any Gleason score, as well as those whose disease was minimally
Additional eligibility criteria were a serum
prostate-specific antigen (PSA) level of 5 ng per
milliliter or more, a serum testosterone level
of less than 50 ng per deciliter (17 nmol per liter),
and progressive disease on the basis of imaging
studies or PSA measurements.
Exclusion criteria were an Eastern Cooperative
Oncology Group (ECOG) performance status of 2 or more (on a scale
from 0 to 5, with higher scores indicating greater disability),16
visceral metastases, pathologic long-bone fractures, spinal cord
compression, and treatment within the previous 28 days with systemic
glucocorticoids, external-beam radiation, surgery, or systemic
therapy for prostate cancer (except medical or surgical castration).
Patients were also excluded if they had initiated or discontinued bisphosphonate therapy within the previous 28
days, if they had undergone previous treatment with more than two
chemotherapy regimens, or if they had undergone chemotherapy within
the previous 3 months. Continuation of medical castration or
bisphosphonate therapy was required at least until the time of
FDA Approval; Pivotal Clinical Trial Data
PROVENGE was granted licensure by the U.S. Food and Drug
Administration (FDA) on April 29, 2010. The pivotal clinical trial on which the
FDA approval of PROVENGE was based was D9902B, also known as IMPACT (Immunotherapy for Prostate
The IMPACT Trial:
Phase 3, randomized, double-blind,
placebo-controlled trial, which enrolled 512 men with
asymptomatic or minimally symptomatic metastatic castrate
resistant (hormone refractory) prostate cancer (CRPC)
The primary endpoint was overall survival
The trial met its primary endpoint of
significantly improving overall survival in the PROVENGE group
compared with the control group.
Prescribing Information on
INDICATIONS AND USAGE
PROVENGE is an autologous cellular
immunotherapy indicated for the treatment of asymptomatic or
minimally symptomatic metastatic castrate resistant (hormone
refractory) prostate cancer.
"April 29, 2010 FDA Approval
Letter - Provenge
Our STN: BL
Attention: Elizabeth C. Smith
Vice President of Regulatory Affairs
3005 First Avenue
Seattle, WA 98121
Dear Ms. Smith:
We are issuing Department of
Health and Human Services U.S. License No. 1749
to Dendreon Corporation, Seattle, Washington,
under the provisions of section 351(a) of the
Public Health Service Act controlling the
manufacture and sale of biological products.
The license authorizes you to introduce or
deliver for introduction into interstate
commerce, those products for which your company
has demonstrated compliance with establishment
and product standards.
Under this license, you are
authorized to manufacture the product sipuleucel-T.
Sipuleucel-T is indicated for the treatment of
asymptomatic or minimally symptomatic metastatic
castrate resistant (hormone refractory) prostate
Under this authorization, you
are approved to manufacture sipuleucel-T at your
facility in Morris Plains, New Jersey. You may
label your product with the proprietary name
PROVENGE and will market it in 250 mL infusion
bags." There is more, but this is the main
portion as far as HRPCa is concerned.
How can I get PROVENGE?
Dendreon ON Call is available to answer
questions about PROVENGE treatment, coverage and reimbursement, and
patient support. For more information, healthcare providers and
patients may contact Dendreon ON Call at 1.877.336.3736, Monday
through Friday from 8 a.m. to 11 p.m. ET.
Author: Howard Hansen,
12 August 2010