Lag-3 and Gemcitabine for Treatment of Advanced Pancreas Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Phase I Study of Soluble LAG-3 (IMP321) and Gemcitabine in Patients With Advanced Pancreas Cancer

Conditions
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Pancreatic Neoplasms

Intervention / Treatment
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* Drug: Gemcitabine
* Biological: LAG-3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dose Level 0<br>Gemcitabine (1 mg/m2 over 30 min) will be given on days 1, 8, and 15 of a 28 day cycle. | Drug: Gemcitabine<br> <br> * Other names: Gemzar;|
| Experimental: Dose Level 1<br>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. Each single injection will be separated by a 13-day administration free period. | Drug: Gemcitabine<br> <br> * Other names: Gemzar;Biological: LAG-3<br> <br> |
| Experimental: Dose Level 2<br>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. Each single injection will be separated by a 13-day administration free perio | Drug: Gemcitabine<br> <br> * Other names: Gemzar;Biological: LAG-3<br> <br> |
| Experimental: Dose Level 3<br>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. Each single injection will be separated by a 13-day administration free perio | Drug: Gemcitabine<br> <br> * Other names: Gemzar;Biological: LAG-3<br> <br> |
| Experimental: Dose Level 4<br>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. Each single injection will be separated by a 13-day administration free perio | Drug: Gemcitabine<br> <br> * Other names: Gemzar;Biological: LAG-3<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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

| Outcome Measure | 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 | Quantify peripheral blood Treg (CD4+ CD25+ Fox P3+ Tcells) 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LAG-3 and gemcitabine treatment for advanced pancreas cancer