Lag-3 And Gemcitabine For Treatment Of Advanced Pancreas Cancer

Study Overview

Lag-3 and Gemcitabine for Treatment of Advanced Pancreas Cancer

The overall purpose of this research is to evaluate the safety and toxicity of an investigational medication, IMP321, in patients being treated with gemcitabine. IMP321 is a synthetic protein (made in the laboratory to simulate a protein that your body makes on its own) and was designed to stimulate the immune system with the overall objective of improving the body's capacity to react to your pancreas cancer.

This is a phase I, single center, open label, non-randomized, dose-escalation phase I study performed in the ambulatory setting in patients receiving first line chemotherapy for unresectable pancreas cancer with gemcitabine weekly and the investigational agent IMP321. IMP321 will be given at D2 and D16 of a 4-week cycle, for a period of 6 months. The hypothesis of this study is that IMP321 is safe for human administration. Additionally we hypothesize that IMP321 elicits an immunomodulatory effect that is therapeutic in the treatment of pancreas cancer. Primary Objectives * To evaluate the safety and tolerability of repeated IMP321 subcutaneous injections in patients being treated with gemcitabine for advanced pancreas cancer. * To determine any dose limiting toxicities of IMP321 in patients being treated with gemcitabine for advanced pancreas cancer. Secondary Objectives * To describe the pharmacokinetics of the last IMP321 subcutaneous injection compared to the first one, in a limited number of patients. * To determine the pharmacodynamics of IMP321 therapy by: * Quantify peripheral blood Treg (CD4+CD25+FoxP3+ T cells) in pancreatic cancer patients before and during treatment with IMP321 by flow cytometry. * Evaluate the B- and T-cell responses to the pancreatic cancer-expressed antigen, mesothelin, by testing for antibodies and T-cell response by ELISpot. * To evaluate the clinical response and time to disease progression with computed tomography examinations at two month intervals (current standard of care in gemcitabine-treated patients).

Pancreatic Neoplasms

DRUG: Gemcitabine
BIOLOGICAL: LAG-3

07-0265

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2008-08-06	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2013-06-11
First Submitted that Met QC Criteria 2008-08-08	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ESTIMATED) 2013-06-12
First Posted (ESTIMATED) 2008-08-11	Results First Posted N/A	Last Verified 2013-06

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Dose Level 0 Gemcitabine (1 mg/m2 over 30 min) will be given on days 1, 8, and 15 of a 28 day cycle.	DRUG: Gemcitabine
EXPERIMENTAL: Dose Level 1 Gemcitabine (1 mg/m2 over 30 min) will be given on days 1, 8, and 15 of a 28 day cycle. IMP321 3 mg SQ anterior surface of either the right or left thigh on Day 2. The subsequent doses will be given by subcutaneous injection on the contralateral thigh.	DRUG: Gemcitabine BIOLOGICAL: LAG-3
EXPERIMENTAL: Dose Level 2 Gemcitabine (1 mg/m2 over 30 min) will be given on days 1, 8, and 15 of a 28 day cycle. IMP321 6.5 mg SQ anterior surface of either the right or left thigh on Day 2. The subsequent doses will be given by subcutaneous injection on the contralateral thigh	DRUG: Gemcitabine BIOLOGICAL: LAG-3
EXPERIMENTAL: Dose Level 3 Gemcitabine (1 mg/m2 over 30 min) will be given on days 1, 8, and 15 of a 28 day cycle. IMP321 13 mg SQ anterior surface of either the right or left thigh on Day 2. The subsequent doses will be given by subcutaneous injection on the contralateral thigh.	DRUG: Gemcitabine BIOLOGICAL: LAG-3
EXPERIMENTAL: Dose Level 4 Gemcitabine (1 mg/m2 over 30 min) will be given on days 1, 8, and 15 of a 28 day cycle. IMP321 26 mg SQ anterior surface of either the right or left thigh on Day 2. The subsequent doses will be given by subcutaneous injection on the contralateral thigh.	DRUG: Gemcitabine BIOLOGICAL: LAG-3

Primary Outcome Measures	Measure Description	Time Frame
To evaluate the safety and tolerability of repeated IMP321 subcutaneous injections in patients being treated with gemcitabine for advanced pancreas cancer.		6 months
To determine the dose limiting toxicities of IMP321 in patients being treated with gemcitabine for advanced pancreas cancer.		6 months

Secondary Outcome Measures	Measure Description	Time Frame
To describe the pharmacokinetics of the last IMP321 subcutaneous injection compared to the first one, in a limited number of patients.	Performed only in patients enrolled in dose level 3 and 4.	Pre-dose, 2 hours, 4 hours, 8 hours, 24 hours, 72 hours, and 96 hours after IMP321 administration
To determine the pharmacodynamics of IMP321 therapy	1. Quantify peripheral blood Treg (CD4+ CD25+ Fox P3+ Tcells) in pancreatic cancer patients before and during treatment with IMP321 by flow cytometry. 2. Evaluate the B- and T-cell responses to the pancreatic cancer-expressed antigen, mesothelin, by testing for antibodies and T-cell response by ELISpot	6 months
To evaluate the clinical response and time to disease progression with computed tomography examinations at two month intervals (current standard of care in gemcitabine-treated patients).		survival

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Patient must have a newly diagnosed, histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma (primary tumor or metastasis). The histological slides or blocks must be available for review.
Patient must have advanced disease (characterized by metastasis or locally advanced disease), or unable to undergo surgical treatment due to extent of disease or pre-existing health conditions precluding surgical treatment.
Measurable or evaluable disease: RECIST Criteria will be used to assess and survey extent of disease
Patients must be ≥ 18 years old.
Performance Status: Karnofsky Performance Status (KPS) ≥ 70
Life Expectancy > 12 weeks.
No previous history of chemotherapy for pancreas cancer in the metastatic setting prior to the start of protocol treatment.
Patients must have recovered from uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia.
Patients must have adequate bone marrow function defined as an absolute neutrophil count >1,500/mm3, platelet count >100,000/mm3 and hemoglobin >10 g/dl.
Patients must have adequate renal function defined as serum creatinine ≤ 2.0 mg/dl or creatinine clearance ≥ 60 ml/min/1.73m2 for patients with creatinine levels above 2.0 mg/dl.
Patients must have adequate hepatic function with total bilirubin ≤ 1.5 times the institutional normal value and AST ≤ 2 times the institutional normal value.
Patient must have no prior or current active autoimmune disease requiring management with immunosuppression. This includes inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, sarcoidosis or other rheumatologic disease. Asthma and chronic obstructive pulmonary disease that does not require daily systemic corticosteroids is acceptable.
The patient with previous history of malignancy is eligible for this study only if the patient meets the following criteria for cancer survivor:

(i) patient has undergone potentially curative therapy for all prior malignancies;
(ii) patient has been considered disease free for at least 5 years.
For all sexually active patients, the use of adequate barrier contraception (hormonal or barrier method of birth control) will be required during therapy, prior to study entry and for the duration of study participation. Patients must agree to refrain from becoming pregnant 2 years after beginning treatment with IMP321. Non-pregnant status will be determined in all women of childbearing potential.
After being informed of the treatment involved, patients must give written consent. The patient should not have any serious medical or psychiatric illness that would prevent either the giving of informed consent or the receipt of treatment.

Patient is currently receiving other investigational agents.
Pregnant and nursing women patients are not eligible.
Patients known to be HIV (patient self-report) positive are ineligible because of the potential inability to modulate immune responses.
Patients with a QTc of >460 msec.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: William G. Hawkins, M.D., Washington Univerisity

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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Macon-Lemaitre L, Triebel F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology. 2005 Jun;115(2):170-8. doi: 10.1111/j.1365-2567.2005.02145.x.
Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA. Role of LAG-3 in regulatory T cells. Immunity. 2004 Oct;21(4):503-13. doi: 10.1016/j.immuni.2004.08.010.
Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol. 2005 Jan 15;174(2):688-95. doi: 10.4049/jimmunol.174.2.688.
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Lienhardt C, Azzurri A, Amedei A, Fielding K, Sillah J, Sow OY, Bah B, Benagiano M, Diallo A, Manetti R, Manneh K, Gustafson P, Bennett S, D'Elios MM, McAdam K, Del Prete G. Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo. Eur J Immunol. 2002 Jun;32(6):1605-13. doi: 10.1002/1521-4141(200206)32:63.0.CO;2-6.
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Tseng JF, Willett CG, Fernandez-del Castillo C, Ryan DP, Clark JW, Zhu AX, Rattner DW, Winkelmann JL, Warshaw AL. Patients undergoing treatment for pancreatic adenocarcinoma can mount an effective immune response to vaccinations. Pancreatology. 2005;5(1):67-74. doi: 10.1159/000084492. Epub 2005 Mar 15.
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Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6. doi: 10.1200/JCO.2006.07.9525. Epub 2007 Apr 23.

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