Immunotherapy Study in Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer

Pancreatic Cancer Clinical Trial

— PILLAR  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01836432
• Other study ID #: NLG0505
• Secondary ID: 1210-1195
• Status: Terminated
• Phase: Phase 3
• Start date: May 2013
• Est. completion date: March 24, 2017

Study information

• Verified date: May 2020
• Source: Lumos Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 treatment alone.

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 disease.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 302
• Est. completion date: March 24, 2017
• Est. primary completion date: July 29, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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 follows:

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 this protocol.

• 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 mL/min.

• 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.

Exclusion Criteria:

• 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 systemic therapy.

• Autoimmune disease (e.g., systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), etc.). Patients with a remote history of asthma or mild active asthma are eligible.

• 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 their excipients.

• 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 ßHCG 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 fields.

• Current grade II or higher peripheral neuropathy.

Related Conditions & MeSH terms

• Locally Advanced Malignant Neoplasm
• Neoplasms
• Pancreatic Cancer
• Pancreatic Carcinoma Non-resectable
• Pancreatic Neoplasms

Intervention

Drug:
• FOLFIRINOX
FOLFIRINOX consisting of Oxaliplatin 85 mg/m^2 IV over 2 hours; Irinotecan 180 mg/m^2 IV over 90 minutes; Leucovorin 400 mg/m^2 IV over 2 hours; Fluorouracil 2.4 g/m^2 IV over 46 hours

Biological:
• Algenpantucel-L Immunotherapy
Algenpantucel-L Immunotherapy (HAPa) consisting of 300 Million HAPa cells given by intradermal injection

Radiation:
• 5-FU Chemoradiation
5-FU Chemoradiation consisting of 5-FU continuous IV infusion of 200-250 mg/m^2/day given 5-7 days each week over 5.5 weeks concurrently with external beam radiation

Drug:
• Gemcitabine
Gemcitabine 1000 mg/m^2 given intravenously over 30 minutes for 3 weeks (days 1, 8 and 15) with 1 week rest.
• Capecitabine
Capecitabine consisting of 825 mg/m^2 PO BID M-F concurrently with external beam radiation
• Nab-Paclitaxel
Nab-Paclitaxel 125 mg/m^2 given intravenously over 30-40 minutes

Locations

Country	Name	City	State
United States	Illinois Cancer Specialists	Arlington Heights	Illinois
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	University of Virginia	Charlottesville	Virginia
United States	The Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Indiana University Health Goshen Center for Cancer Care	Goshen	Indiana
United States	Vince Lombardi Cancer Center	Green Bay	Wisconsin
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	University of Miami	Miami	Florida
United States	Virginia Piper Cancer Institute	Minneapolis	Minnesota
United States	Jersey Shore University Medical Center	Neptune	New Jersey
United States	Mount Sinai Medical Center	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Renown Regional Medical Center	Reno	Nevada
United States	Beaumont CCOP	Royal Oak	Michigan
United States	Sutter Institute for Medical Research	Sacramento	California
United States	California Pacific Medical Center	San Francisco	California
United States	University of Washington - Seattle Cancer Center Alliance	Seattle	Washington
United States	Stamford Hospital	Stamford	Connecticut
United States	H. Lee Moffitt Cancer Center	Tampa	Florida
United States	USF Tampa General	Tampa	Florida
United States	Arizona Cancer Center	Tucson	Arizona
United States	University of Kansas Cancer Center	Westwood	Kansas
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
NewLink Genetics Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	The primary objective of this study is to assess overall survival (OS) in pancreatic cancer patients with borderline resectable or locally advanced unresectable pancreatic cancer who will receive a regimen of FOLFIRINOX or gemcitabine/nab-paclitaxel with or without algenpantucel-L Immunotherapy.	13.5 months (assuming enrollment period of 1-2 years)
Secondary	Progression Free Survival	A secondary objective of this study is to assess progression free survival after treatment with a regimen of FOLFIRINOX or gemcitabine/nab-paclitaxel with or without algenpantucel-L immunotherapy in subjects who have borderline resectable or locally advanced pancreatic cancer.	13.5 months (assuming enrollment period of 1-2 years)
Secondary	Frequency and grade of adverse events of FOLFIRINOX or gemcitabine/nab-paclitaxel in combination with algenpantucel-L Immunotherapy versus FOLFIRINOX or gemcitabine/nab-paclitaxel alone	A secondary objective of this study is to assess the safety (frequency and grade of adverse events) of administration of algenpantucel-L Immunotherapy given in combination with a standard of care regimen of chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel, to be referred to as standard of care, or SOC).	13.5 months (assuming enrollment period of 1-2 years)
Secondary	Immune Response	A secondary objective of this study is to assess the immunologic responses of subjects with pancreatic cancer undergoing antitumor immunization with algenpantucel-L Immunotherapy as measured by correlative laboratory studies.	13.5 months (assuming enrollment period of 1-2 years)

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