Immunotherapy Study in Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer
A Phase III Study of Chemotherapy With or Without Algenpantucel-L (HyperAcute®-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer
Unfortunately, despite the best clinical efforts and breakthroughs in biotechnology, most
patients diagnosed with pancreatic cancer continue to die from the rapid progression of
their disease. One primary reason for this is that the disease is typically without symptoms
until significant local and/or distant spread has occurred and is often beyond the chance
for cure at the time of the diagnosis. The lack of any treatment to substantially increase
long term survival rates is reflected by the poor outcomes associated with this disease,
specifically time to disease progression and overall survival.
However, another important part of the body is now being looked at as a target for therapy
against this disease - the immune system. Scientists have clearly shown that pancreatic
tumor cells produce a number of defective proteins, or express normal proteins in highly
uncharacteristic ways, as part of this cancer. In some cancers, these abnormalities can
cause an immune response to the cancer cells much in the way one responds to infected
tissue. In progressive cancers however, the immune system fails to effectively identify or
respond to these abnormalities and the cancer cells are not attacked or destroyed for
reasons not yet fully understood. This clinical trial proposes a new way to stimulate the
immune system to recognize pancreatic cancer cells and to stimulate an immune response that
destroys or blocks the growth of the cancer.
This new method of treatment helps the immune system of pancreatic cancer patients to
"identify" the cancerous tissue so that it can be eliminated from the body. As an example,
most people are aware that patients with certain diseases may require an organ transplant to
replace a damaged kidney or heart. After receiving their transplant, these patients receive
special drugs because they are at great danger of having an immune response that destroys or
"rejects" the transplanted organ. This "rejection" occurs when their immune system responds
to differences between the cells of the transplanted organ and their own immune system by
attacking the foreign tissue in the same way as it would attack infected tissue. When the
differences between foreign tissues and the patient's body are even larger, as with the
differences between organs from different species, the rejection is very rapid, highly
destructive, and the immunity it generates is longlasting. This is called hyperacute
rejection and the medicine used to immunize patients in this protocol tries to harness this
response to teach a patient's immune system to fight their pancreatic cancer just as the
body would learn to reject a transplanted organ from an animal.
To do this, Algenpantucel-L immunotherapy contains human pancreatic cancer cells that
contain a mouse gene that marks the cancer cells as foreign to patient's immune systems. The
immune system therefore attacks these cancer cells just as they would attack any truly
foreign tissue, destroying as much as it can. Additionally, the immune system is stimulated
to identify differences (aside from the mouse gene) between these cancer cells and normal
human tissue as foreign. This "education" of the immune system helps treat the patient
because pancreatic cancer cells already present in a treated patient are believed to show
some of the same differences from normal tissue as the modified pancreatic cancer cells in
the product. Due to these similarities, the immune system, once "educated" by the
Algenpantucel-L immunotherapy, identifies the patient's cancer as foreign and attacks.
The chemotherapy combination to be used in this study has been shown to improve survival in
advanced pancreatic cancer and is being combined with an experimental pancreatic cancer
immunotherapy that stimulates the immune system to recognize and attack the cancer. One goal
of this study is to determine whether chemotherapy and immunotherapies can work
cooperatively to increase anti-tumor effects to levels beyond what would be seen with either
In this experimental study, all patients are given a strong combination of anti-tumor
chemotherapies while some patients are also given injections of an immunotherapy drug
consisting of two types of pancreatic cancer cells that we have modified to make them more
easily recognized and attacked by the immune system. We propose to test this new treatment
protocol in patients with locally advanced pancreatic cancer to demonstrate that treatment
with the immunotherapy increases the time until the tumor progresses or increases overall
survival when given in combination with the current standard of care therapy for this
This protocol attempts to treat pancreatic cancer therapy using a naturally occurring
barrier to xenotransplantation in humans to increase the efficacy of immunizing patients
against their pancreatic cancer. In this protocol, the transfer of the murine α(1,3)
galactosyltransferase [α(1,3)GT] gene to immunotherapy component cells results in the cell
surface expression of α(1,3)galactosyl-epitopes (αgal) epitopes on membrane glycoproteins
and glycolipids. These epitopes are the major target of the hyperacute rejection response.
This response occurs when organs are transplanted from lower animal donor species into
primates and results in rapid destruction of transplanted tissue and an augmented response
against transplant antigens, including antigens not related to the αgal epitopes. Human
hosts have pre-existing anti-α-gal antibodies that are thought to result from chronic
immunological stimulation due to exposure to α-gal epitopes that are naturally expressed on
normal gut flora and these antibodies may comprise up to 1% of serum immunoglobulin G (IgG).
Opsonization and lysis of the immunotherapy component cells mediated by this antibody is
believed to increase the efficiency of antigen processing by targeting vaccine components to
antigen presenting cells via the Fcγ receptor.
- A histological diagnosis of adenocarcinoma of the pancreas confirmed by pathology.
- Patients must have borderline resectable or locally advanced unresectable pancreatic
cancer with no metastatic spread as determined by a baseline diagnostic CT scan with
intravenous contrast (or MRI). CT should be performed according to a defined pancreas
protocol such as triphasic cross-sectional imaging with thin slices. Optimal
multi-phase technique including a non-contrast phase plus arterial, pancreatic
parenchymal and portal venous phase of contrast enhancement with thin cuts (3mm)
throughout the abdomen is preferred. Studies must be evaluated by a radiologist
and/or surgeon and deemed borderline resectable or locally advanced unresectable as
defined per the NCCN Practice Guidelines in Oncology V2.2012, as:
- Borderline resectable- Tumors considered borderline resectable are defined as
1. No distant metastases
2. Venous involvement of the SMV/portal vein demonstrating tumor abutment with
impingement and narrowing of the lumen, encasement of the SMV/portal vein but
without encasement of the nearby arteries, or short-segment venous occlusion
resulting from either tumor thrombus or encasement but with suitable vessel
proximal and distal to the area of vessel involvement, allowing for safe
resection and reconstruction
3. Gastroduodenal artery encasement up to the hepatic artery with either short
segment encasement or direct abutment of the hepatic artery without extension to
the celiac axis.
4. Tumor abutment of the SMA not to exceed greater than 180 degrees of the
circumference of the vessel wall.
- Tumors considered to be unresectable due to local advancement include an absence of
distant metastases as well as:
1. Head: Greater than 180 degrees SMA encasement or any celiac abutment or
unreconstructible SMV/portal occlusion or aortic invasion or encasement.
2. Body: Greater than 180 degrees SMA or celiac encasement or unreconstructible
SMV/portal occlusion or aortic invasion.
3. Tail: SMA or celiac encasement greater than 180 degrees.
4. Nodal status: Involvement of lymph nodes beyond the field of resection should be
considered unresectable due to distant spread and therefore not eligible for
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
- Serum albumin ≥ 2.0 gm/dL.
- Expected survival ≥ 6 months.
- Adequate organ function including:
1. Marrow: WBC ≥3000/mm^3 and platelets ≥100,000/mm^3.
2. Hepatic: serum total bilirubin ≤ 1.5 mg/dL, ALT (SGPT) and AST (SGOT) ≤3 x upper
limit of normal (ULN) at time of enrollment. If a patient has elevated liver
function tests at the time of initial presentation or develops them during
work-up and they are the result of a mechanical obstruction of biliary drainage
by tumor compression or invasion, a biliary drain may be placed as described in
NCCN Practice Guidelines in Oncology V2.2012. If drainage allows for the liver
function tests to come within inclusion criteria, the patient may be enrolled.
3. Renal: serum creatinine (sCr) ≤2.0 x ULN, or creatinine clearance (Ccr) ≥30
- Patients must have the ability to understand the study, its inherent risks, side
effects and potential benefits and be able to give written informed consent to
participate. Patients may not be consented by a durable power of attorney (DPA).
- All subjects of child producing potential must agree to use contraception or
avoidance of pregnancy measures while enrolled on study and receiving the
experimental product, and for one month after the last immunization.
- Age <18-years-old.
- Active metastases.
- Other malignancy within five years, unless the probability of recurrence of the prior
malignancy is <5% as determined by the Principal Investigator based on available
information. Patient's curatively treated for squamous and basal cell carcinoma of
the skin or patients with a history of malignant tumor in the past that have been
disease free for at least five years are also eligible for this study.
- History of organ transplant.
- Current, active immunosuppressive therapy such as cyclosporine, tacrolimus, etc.
- Subjects taking chronic systemic corticosteroid therapy for any reason are not
eligible. Subjects may receive steroids as prophylactic anti-emetics per the
FOLFIRINOX or gemcitabine/nab-paclitaxel regimen. Subjects receiving inhaled or
topical corticosteroids are eligible. Subjects who require chronic systemic
corticosteroids after beginning treatment, will be removed from study.
- Significant or uncontrolled congestive heart failure (CHF), myocardial infarction or
significant ventricular arrhythmias within the last six months.
- Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring
- Autoimmune disease (e.g., systemic lupus erythematosis (SLE), rheumatoid arthritis
(RA), etc.). Patients with a remote history of asthma or mild active asthma are
- Other serious medical conditions that may be expected to limit life expectancy to
less than 2 years (e.g., active liver cirrhosis) or a serious illness in medical
opinion of the clinical investigator.
- Any condition, psychiatric or otherwise, that would preclude informed consent,
consistent follow-up or compliance with any aspect of the study (e.g., untreated
schizophrenia or other significant cognitive impairment, etc.).
- A known history of allergy or hypersensitivity to any of the study drugs or any of
- Pregnant or nursing women due to the unknown effects of immunization on the
developing fetus or newborn infant. (For patients with child bearing potential, a
βHCG must be completed within 14 days of first treatment).
- Known HIV positive.
- Prior treatment with chemotherapy or radiation for pancreatic cancer or prior
treatment with radiation for other diagnoses to expected pancreatic cancer treatment
- Current grade II or higher peripheral neuropathy.