Pancreatic cancer drugs:

Pancreatic carcinoma is cancer of the
pancreas.
A tumor or cancer in the pancreas may
often grow without any symptoms at
first. This may mean pancreatic cancer
is more advanced when it is first found.




DRUG COMBO IS PROMISING
In February 2012 an investigational
drug that targets areas of oxygen
starvation within a tumor had promising
results against advanced pancreatic
cancer in a phase IIb clinical trial.

When combined with gemcitabine
(Gemzar), the drug -- dubbed TH-302
-- reduced the risk of disease
progression by 39% compared with
gemcitabine alone, according to
Threshold Pharmaceuticals, of South
San Francisco, Calif.

"We are again very encouraged that
TH-302 is conferring benefit to patients
with aggressive and difficult-to-treat
cancers," Threshold CEO Barry Selick,
PhD, said in a statement.

Most cancer drugs target the rapidly
dividing cells near the tumor's blood
vessels, but TH-302 is intended to
attack cells in regions of low oxygen
concentration caused by the
disordered vasculature of the tumor.

The compound is a prodrug of dibromo
isophoramide mustard, a potent DNA
alkylating agent, and is activated by
hypoxic conditions within tumors. It is
being tested, in combination with other
drugs, in a range of solid cancers,
including a phase III trial in first-line
advanced soft tissue sarcoma.

The pancreatic cancer trial included
214 patients randomly assigned to
gemcitabine alone or to the drug
combined with one of two doses of TH-
302 -- 240 or 340 mg/m2.




FDA APPROVES AFINITOR
In May 2011 Novartis has received
Food and Drug Administration
approval on Afinitor for treating a rare
type of pancreatic tumor.

Afinitor is the first new drug in 30 years
approved to treat patients with
advanced pancreatic neuroendocrine
tumors. These tumors grow more
slowly than other pancreatic cancers,
but they also have few treatment
options.

The drug is already approved for
treating kidney cancer. Thomson
Reuters projects Afinitor sales could
reach sales of $1.3 billion in 2015.
Novartis also has applications pending
in Europe for use of the drug to treat
pancreatic cancer.

AFINITOR INCREASED SURVIVAL IN
PANCREATIC CANCER
A Phase III study showed that Afinitor
everolimus tablets plus best supportive
care (BSC) more than doubled
progression-free survival, or time
without tumor growth, versus placebo
plus BSC in patients with advanced
pancreatic neuroendocrine tumors.

These results  have led to calls for a
new standard of care for this disease.

Pancreatic neuroendocrine tumors
affect the hormone-producing tissues
within the pancreas, and are relatively
rare, affecting annually only 2 to 4
people per million worldwide. However,
the incidence is rising, and has
quadrupled in the past 30 years,
according to data from the National
Cancer Institute. The most common
treatment is surgery, which can be
curative, but patients who are not
suitable candidates have been treated
with chemotherapy. Targeted agents
now stand to offer a new treatment
option, with lower toxicity and the
convenience of oral dosing.

Both Dr. Lebwohl and Dr. Raymond
predicted that the new data will lead to
a change in the way that patients with
pancreatic neuroendocrine tumors are
treated. In the past, patients who were
unsuitable for surgery had been
treated with chemotherapy, including
streptozocin, anthracyclines, and
fluoropyrimidines, but the data for this
come from old studies and do not show
a definitive benefit, unlike the new data
with the targeted agents. In addition,
the targeted agents are less toxic and
have the convenience of oral dosing.




BIOMARKER IDENTIFIED
In May 2011 North Carolina cancer
researchers have found a key
pancreatic cancer biomarker that could
open doors to new therapies to treat
the disease.

A team of scientists at North Carolina
Central University in Durham  found
that mutations in the known cancer
gene called K-Ras resulted in higher
levels of a protein called Pim-1.

Researchers studied laboratory
models of human pancreatic ductal
adenocarcinoma, a form of cancer of
the pancreatic duct. Researchers
found that suppression of Pim-1
resulted in decreased cancer growth,
an indication Pim-1 is required for
growth of these cancer cells.


NEWLINK OF IOWA DEVELOPS
ADJUVANT TREATMENT
NewLink Genetics Corporation  of
Iowa, US, has a  lead product
candidate, HyperAcute Pancreas
cancer immunotherapy. It  is being
studied in a Phase 3 clinical trial in
surgically resected pancreatic cancer
patients.




TELOVAC  VACCINE TRIAL IN PHASE
3 WITH HIGH PROMISES FOR
PANCREATIC CANCER
The drug being tested in the TeloVac
trial, GV1001, works fundamentally
differently from conventional
chemotherapy. Rather than killing
rapidly growing cells, it's designed to
switch on the body's immune system
and encourage it to kill the tumor – so-
called 'immunotherapy'. This is a
concept that has been showing huge
promise in recent years.

There are many different ways
immunotherapy can work – in the case
of GV1001, it works a little like a
vaccine. The drug is made of
fragments of a protein, called
telomerase, which is known to be
present in higher concentrations on
the surface of certain types of cancer
cell. The theory is that, when patients
are injected with the drug, it
'vaccinates' them against their own
cancer, and their immune system
works in tandem with traditional
chemotherapy drugs to attack the
disease.

In the largest trial of its kind in the UK,
more than 1,000 men and women in
the late stages of pancreatic cancer
are either being given the vaccine
alongside their normal drugs or treated
as usual.

The results from the 53 hospitals
taking part will not be available until
2012 but, anecdotally, some patients
credit their participation in the trial with
giving them an extra year or two of life.

In earlier, smaller trials, the vaccine
gave those in the late stages of the
disease an average of an extra three
months.

Pancreatic cancer cells are normally
invisible to the immune system but the
vaccine 'spots' the telomerase spilling
out from them and kick-starts the fight
back.
Professor Neoptolemos, of Liverpool
University, said: 'It is like the immune
system has a blindfold on and the
vaccine takes the blindfold off.'

Healthy cells escape the attack
because their levels of telomerase are
too low to bother the immune system.
This cuts the risk of side-effects such
as nausea and hair loss normally seen
with cancer drugs.
If the latest study, which is funded by
Cancer Research UK, proves the jab's
worth, it could be available to treat
advanced pancreatic cancer by the
end of 2013.
In time, it could be used earlier in the
disease – and even to prevent it.

Dr Jay Sangjae Kim, the founder of
GemVax, the Korean company
developing the TeloVac vaccine, said:
'We strongly believe this has the
potential to overcome the limits of
other current cancer vaccines and
become part of the standard of care
not only for pancreatic cancer but for
various other types of cancers.
'In other words, a truly "universal"
vaccine will be available in the near
future.'



FOLFIRINOX COMBINATION TESTED
FOR PANCREATIC CANCER
Gemcitabine has been a cornerstone
of pancreatic cancer treatment for 15
years now, used alone or more
recently in combination with erlotinib
(Tarceva), but the new results suggest
that it should be replaced with the
FOLFIRINOX combination
(5-fluorouracil, leucovorin, irinotecan,
and oxaliplatin).
“This is the first time in a randomized
phase III study we have achieved an
11-month median survival for
metastatic pancreatic cancer,” said Dr.
Thierry Conroy, who presented the
findings at the annual meeting of the
American Society of Clinical Oncology.

These results were reported from the
Centre Alexis Vautrin, Vandoeurve les
Nancy, France. The trial (known as
PRODIGE 4/ACCORD 11) was
conducted at 48 centers across
France.
The 10-month overall survival seen
with the combination is the longest that
has ever been reported in a phase 3
trial in this setting, and concluded that
FOLFIRINOX should become the new
international standard of care for
patients with metastatic pancreatic
cancer. Some doctors warn that
enthusiasm must be tempered by the
treatment's attendant side effects.

“So we recommend Folfirinox as the
new international standard of care for
patients with metastatic pancreatic
cancer, but only in patients with quite
normal levels of bilirubin and
performance status 0 or 1. This
combination will be tested in the
adjuvant setting,” Dr Conroy said.
Bilirubin is excreted in bile and urine,
and elevated levels may indicate
certain diseases. It is responsible for
the yellow color of bruises, urine, and
the yellow discoloration in jaundice.


OVERVIEW

PANCREATIC CANCER TREATMENT
ADVANCES

Pancreatic cancer is a quiet,
deadly disease.
According to the National Cancer
Institute, in 2010, in the US about
43,000 people was diagnosed and
just under 6,000 will survive.
Often, symptoms are not present
until very late, when it has spread
to other areas and surgical
removal is impossible.
Those who are  diagnosed early
have about a 22.5 percent five-
year survival rate compared to
those with late-stage disease at
the time of diagnosis who have a
less than 2 percent five-year
survival.
Visibility for the disease is already
on the rise due to recent celebrity
victims, including Apple's Steve
Jobs and Hollywood actor Patrick
Swayze.
Patrick Swayze was diagnosed with
stage IV pancreatic cancer that
had already spread to the liver in
March  2008 and lost his battle with
the disease in September 2009 at
the age of 57.
Steve Jobs, co-founder and chief
executive of Apple Inc.,  was
diagnosed with this rare, slow-
growing pancreatic tumor in 2004.
He reportedly underwent
'Whipple's procedure' (technically,
called a pancreatico-
duodenectomy) – meaning removal
of the pancreas and part of the
duodenum in July 2004 after
initially rejecting conventional
medical intervention.
The area surrounding pancreatic
cancers is very dense, fibrotic,
and hostile. This is one of the main
reasons standard therapies for
this disease often work so poorly.

To date, there are no screening
tests available to  the general
population.
Pancreatic cancer is dangerous to
screen for. The pancreas is
extremely sensitive--biopsies can
lead to potentially fatal
complications--but with few
symptoms, the cancer is usually
detected too late.


ACTIVATING THE IMMUNE SYSTEM:  
NOVEL TREATMENT AT PENN STATE
Researchers at the University of
Pennsylvania's Abramson Cancer
Center have discovered a novel
way of treating pancreatic cancer
by activating the immune system to
destroy the cancer's scaffolding.
The strategy was tested in a small
cohort of patients with advanced
pancreatic cancer, several of
whose tumors shrank substantially.
The results, published in the
March 25 2011  issue of Science.
"Until this research, we thought
the immune system needed to
attack the cancer directly in order
to be effective," said senior author
Robert H. Vonderheide, MD. "Now
we know that isn't necessarily so."
"Attacking the dense tissues
surrounding the cancer is another
approach, similar to attacking a
brick wall by dissolving the mortar
in the wall. Ultimately, the immune
system was able to eat away at this
tissue surrounding the cancer,
and the tumors fell apart as a
result of that assault. These
results provide fresh insight to
build new immune therapies for
cancer."
In the clinical trial led at Penn
pancreatic cancer patients
received standard gemcitabine
chemotherapy with an
experimental antibody
manufactured by Pfizer
Corporation. The antibody binds
and stimulates a cell surface
receptor called CD40, which is a
key regulator of T-cell activation.
The team initially hypothesized that
the CD40 antibodies would turn on
the T cells and allow them to attack
the tumor.
The treatment appeared to work,
with some patients' tumors
shrinking substantially and the
vast majority of tumors losing
metabolic activity after therapy,
although all of the responding
patients eventually relapsed.
When the researchers looked at
post-treatment tumor samples,
obtained via biopsy or surgical
removal, there were no T cells to
be seen. Instead, they saw an
abundance of another white blood
cell known as macrophages.
To understand what was
happening in the tissues of these
patients, Vonderheide and Beatty
and colleagues turned to a mouse
model of pancreatic cancer
developed several years ago at
Penn. Unlike older mouse models
that were simplistic models of
human disease, new genetically
engineered mice develop
spontaneous cancers that are very
close reproductions of human
tumors. "We can perform
preclinical trials in these mice with
the same principles we use in our
patients," Vonderheide says,
noting that the team even used a
randomization protocol to assign
individual mice to different arms of
the study.
When the investigators treated
mice that developed pancreatic
cancer with gemcitabine in
combination with CD40 antibodies,
the results looked like those of the
human trial. Some mouse tumors
shrank and were found to be
loaded with macrophages but
contained few or no T cells. Closer
inspection showed that the
macrophages were attacking what
is known as the tumor stroma, the
supporting tissue around the
tumor. Pancreatic tumors secrete
chemical signals that draw
macrophages to the tumor site, but
if left to their own devices, these
macrophages would protect the
tumor. However, treating the mice
(or patients) with CD40 antibodies
seemed to flip that system on its
head. "It is something of a Trojan
horse approach," Vonderheide
says. "The tumor is still calling in
macrophages, but now we've used
the CD40 receptor to re-educate
those macrophages to attack – not
promote – the tumor."
This clinical trial has been
completed (NCT00711191)


The current finding comes on the
heels of another, separate report
issued earlier this year by a
French-American team of
researchers (led by Dr. James Yao
of the University of Texas M.D.
Anderson Cancer Center), which
indicated that two growth-factor
inhibiting drugs (everolimus and
sunitinib) more than doubled
survival among patients
diagnosed with pancreatic
neuroendocrine tumors.



NEW DRUGS IN DEVELOPMENT
In advanced clinical development  
are the following products:
In Phase 3:
Abraxine, a  chemo from Celgene
and Abraxame. Abraxane is chemo,
paclitaxel protein-bound particles
for injectable suspension.  
It increased survival as a   the first-
line treatment of patients with
advanced pancreatic cancer in
Phase  1 and 2 trials. In 44 patients
treated at the recommended dose
of 125 mg/m2 Abraxane plus
gemcitabine [1000 mg/m2], the
median overall survival time was
12.2 months, an impressive
doubling of survival compared to
historical control of gemcitabine
administered alone

Afinitor, a signal transduction
inhibitor from Novartis.

Apple cofounder and CEO Steve
Jobs was on Novartis' Afinitor
treatment. Afinitor is used to treat
patients with advanced pancreatic
NET—neuroedocrine tumors that
cannot be removed through
surgery or has metastasized. In its
advanced stage, where
approximately 60 percent are
diagnosed, a five-year survival is
27 percent. With Afinitor, the first
new treatment in nearly 30 years,
tumor growth and progression are
significantly delayed.

In June 2010 Novartis reported
that its RADIANT-3 Phase 3 study of
Afinitor  (everolimus), plus best
supportive care met its primary
endpoint, showing that the drug
more than doubled median
progression-free survival,  or time
without tumor growth, from 4.6 to
11.0 months when compared with
placebo in patients with advanced
tumor.

And these are in Phase 2:
AMG 479, a monoclonal antibody
from Amgen. Amgen is developing
AMG 479,  a human monoclonal
antibody.
It   targets type 1 insulin-like
growth factor receptor [IGF-1R],
which plays an important role in
the regulation of cell growth and
survival.
From a Phase 2 study Amgen
reported  that the addition of AMG
479 to gemcitabine resulted in an
overall survival rate at six months
of 57% versus 50% with
gemcitabine alone and 39% versus
23% at 12 months.

TH-302, a chemo from Threshold
pharma. Threshold's   hypoxia-
activated prodrug, TH-302, in
combination with gemcitabine in
thirty-four patients with advanced
pancreatic cancer had one patient
with a complete response and 8
patients had a partial response.

Reolysin, a reovirus from
Oncolytics

GI-4000, a targeted molecular
immunotherapy from Celgene

PCI-27483, a signal tansduction
inhibitor from Pharmacyclics

GVAX Pancreas vaccine from
Biosate Pharma


.