A Pilot Study, Evaluating the Efficacy of Regulatory T-cell Suppression by Ontak in Metastatic Pancreatic Cancer

• Sponsor: Loyola University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00726037
• Collaborator: Riveria Country Club Organization (Other), Eisai Inc. (Industry)
• Enrollment: 7
• Location: 1
• Arm: 1
• Duration (Months): 39
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is designed to determine the duration of T reg suppression in patients with metastatic pancreatic cancer receiving Ontak. The goal is to define the optimal time for future dendritic cell vaccine administration.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Pancreatic Cancer	Drug: Ontak	Phase 2

Detailed Description

Despite improved insight into the epidemiology and biology, pancreatic cancer remains a significant health problem as evidenced by the disappointing survival rates associated with advanced disease. Because of its aggressive growth and early metastatic dissemination, only 20% of patients can be treated by surgery at the time of diagnosis. Furthermore, the overall 5-year survival rate of stage IV disease is < 5% [1-3] despite chemotherapy. With such a dismal outlook, it is obvious that novel treatment strategies are required.

There is limited experience in the literature with the use of Ontak in the treatment of metastatic pancreatic cancer. Viehl, et al, demonstrated in a murine model of pancreatic cancer, that ontak combined with whole tumor vaccine led to a significantly increased T cell-dependent antitumor immune response, as well as an improved survival compared to controls. Our group has an active trial at Loyola evaluating the role of dendritic cell vaccine in patients with unresectable, not metastatic, pancreatic cancer. Preliminary data suggests a correlation with time to progression and restoration of Tregs following an initial decrease after the DC injection. The goal of the current proposal is to determine the time point at which the Tregs reach the nadir within four weeks of ontak injection. When this is determined, we will eventually propose administering ontak followed by DC vaccine at the nadir Treg time point for patients with unresectable pancreatic cancer

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Evaluating the Efficacy of Regulatory T-cell (T-reg) Suppression by Denileukin Diftitox (Ontak) in Metastatic Pancreatic Cancer
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Three doses of Ontak 9 mcg/Kg IV over 30 minutes every other day for 1 week	Drug: Ontak; One dose of Ontak 9 mcg/Kg IV over 30 minutes times 3 doses. 1 dose every other day; Other Names: Denileukin diftitox

Outcome Measures

Primary Outcome Measures

1. T-reg Suppression From a Fractionated Dose of Ontak in Patients With Metastatic Pancreatic Cancer [days 8, 12 ,19,26 and 33 post administration]

   The duration of T reg suppression from a fractionated dose of Ontak in patients will be measured in patients with metastatic pancreatic cancer.

Secondary Outcome Measures

1. Optimal Time for Future Dendritic Cell Vaccine Administration [33 Days]

   The goal is to define the optimal time with 95% sensitivity and 95% specificity for future dendritic cell vaccine administration

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male patients and nonpregnant, nonlactating female patient > 18 years old

• Histologic diagnosis of pancreatic cancer with distant disease seen on CT or MRI with no prior chemotherapy or radiotherapy for a least 4 weeks

• Karnofsky performance status equal to or greater than 70%

• Life expectancy of at least 3 months.

• No uncontrolled pain

• No symptoms of bowel obstruction

• Women with child bearing potential must agree to use adequate contraceptives. If she should become pregnant she needs to inform the treating physician

• Ability to give informed consent

Exclusion Criteria:

• Positive serologic testing for HIV, AIDS, human T-cell lymphotrophic virus type 1, hepatitis B, or hepatitis C.

• Hemoglobin <9g/dL; hematocrit <27%; platelets <100,000/ U/L without transfusion support

• Creatinine > 1.8 mg/dL

• Serum albumin < 2.0 mg/dL

• AST > 3X ULN; ALT > 3X ULN

• Bilirubin > 1.8

• Uncontrolled angina, arrhythmias, bronchospasm, hypertension, or hypercalcemia.

• Corticosteroid use within 28 days

• Chemotherapy or radiation within 28 days

• Bacteremia or other signs of active systemic infection

• History of autoimmune disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loyola Univeristy Medical Center, Cardinal Bernardin Cancer Center	Maywood	Illinois	United States	60153

Sponsors and Collaborators

• Loyola University
• Riveria Country Club Organization
• Eisai Inc.

Investigators

• Principal Investigator: Margo Shoup, MD, Loyola University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg. 1996 Mar;223(3):273-9.
• Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004 Sep;10(9):942-9. Epub 2004 Aug 22.
• Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest. 2005 Dec;115(12):3623-33. Epub 2005 Nov 23.
• Dietl J, Engel JB, Wischhusen J. The role of regulatory T cells in ovarian cancer. Int J Gynecol Cancer. 2007 Jul-Aug;17(4):764-70. Epub 2007 Feb 16. Review.
• Figgitt DP, Lamb HM, Goa KL. Denileukin diftitox. Am J Clin Dermatol. 2000 Jan-Feb;1(1):67-72; discussion 73. Review.
• Griffiths RW, Elkord E, Gilham DE, Ramani V, Clarke N, Stern PL, Hawkins RE. Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother. 2007 Nov;56(11):1743-53. Epub 2007 May 9.
• Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006 Sep 15;12(18):5423-34.
• Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M, Maekawa Y, Yasutomo K, Shimada M. Clinical roles of increased populations of Foxp3+CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas. 2006 Nov;33(4):386-90.
• Knutson KL, Disis ML, Salazar LG. CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother. 2007 Mar;56(3):271-85. Epub 2006 Jul 4. Review.
• Linehan DC, Goedegebuure PS. CD25+ CD4+ regulatory T-cells in cancer. Immunol Res. 2005;32(1-3):155-68. Review.
• Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Survival after resection for ductal adenocarcinoma of the pancreas. Br J Surg. 1996 May;83(5):625-31.
• Viehl CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP, Eberlein TJ, Goedegebuure PS, Linehan DC. Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol. 2006 Sep;13(9):1252-8. Epub 2006 Sep 3.
• Warshaw AL, Fernández-del Castillo C. Pancreatic carcinoma. N Engl J Med. 1992 Feb 13;326(7):455-65. Review.
• Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR, June CH. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002 May 1;168(9):4272-6.
• Zwar TD, van Driel IR, Gleeson PA. Guarding the immune system: suppression of autoimmunity by CD4+CD25+ immunoregulatory T cells. Immunol Cell Biol. 2006 Dec;84(6):487-501. Epub 2006 Sep 5. Review.

• Responsible Party: Loyola University
• ClinicalTrials.gov Identifier: NCT00726037
• Other Study ID Numbers: 200732
• First Posted: Jul 31, 2008
• Last Update Posted: Sep 29, 2016
• Last Verified: Aug 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Loyola University: Denileukin diftitox; Metastatic Pancreatic Cancer; Ontak; Regulatory T-cell
• Additional relevant MeSH terms: Pancreatic Neoplasms; Denileukin diftitox

Study Results

Participant Flow

Recruitment Details	Recruitment for this study began on 06/18/2008 and ended on 01/09/2012

Arm/Group Title	Ontak
Arm/Group Description	Three doses of Ontak 9 mcg/Kg IV over 30 minutes every other day for 1 week
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ontak
Arm/Group Description	Three doses of Ontak 9 mcg/Kg IV over 30 minutes every other day for 1 week
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	3 42.9%
Male	4 57.1%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

Title	T-reg Suppression From a Fractionated Dose of Ontak in Patients With Metastatic Pancreatic Cancer
Description	The duration of T reg suppression from a fractionated dose of Ontak in patients will be measured in patients with metastatic pancreatic cancer.
Time Frame	days 8, 12 ,19,26 and 33 post administration

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed, because the manufacturer withdrew support for the study due to a drug supply interruption

Arm/Group Title	Ontak
Arm/Group Description	Three doses of Ontak 9 mcg/Kg IV over 30 minutes every other day for 1 week
Measure Participants	0

2. Secondary Outcome

Title	Optimal Time for Future Dendritic Cell Vaccine Administration
Description	The goal is to define the optimal time with 95% sensitivity and 95% specificity for future dendritic cell vaccine administration
Time Frame	33 Days

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed, because the manufacturer withdrew support for the study due to a drug supply interruption

Arm/Group Title	Ontak
Arm/Group Description	Three doses of Ontak 9 mcg/Kg IV over 30 minutes every other day for 1 week
Measure Participants	0

Adverse Events

Time Frame	For each participant, adverse events were assessed from baseline through end of study (i.e., 33 days)
Arm/Group Title	Ontak
Arm/Group Description	Three doses of Ontak 9 mcg/Kg IV over 30 minutes every other day for 1 week
All Cause Mortality
	Ontak
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ontak
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Ontak
	Affected / at Risk (%)	# Events
Total	0/7 (0%)

Limitations/Caveats

This study was prematurely terminated, because the study drug Ontak is no longer supplied by the manufacturer for this study. Data is not analyzed for any outcome measures.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.