BATS With in Combination With Low Dose IL-1 and GM-CSF for Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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This phase Ib/II trial studies the side effects and best dose of bispecific antibody armed activated T-cells when given together with aldesleukin and sargramostim and to see how well they work in treating patients with pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Bispecific antibody armed activated T-cells are the patient's own T cells that are coated with a bispecific antibody comprising 2 antibodies chemically joined together. These antibodies have specific targets and binding properties that may give the T cells a greater ability to seek out, attach to, and kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Confirm in a single dose phase I (3 to 6 patients [pts]) that 8 infusions of 10^10 epidermal growth factor receptor (EGFR) bispecific antibody armed activated T cells (BATs) given twice per week in combination with interleukin (IL)-2 (aldesleukin) (300,000 IU/m^2/day) and granulocyte-macrophage colony stimulating factor (GM-CSF) (sargramostim) (250 ug/m^2/twice weekly) beginning 3 days before the 1st infusion and ending on the day of the last infusion is safe. II. Perform a phase II clinical trial to estimate the clinical efficacy of 8 infusions of 10^10 EGFR BATs in combination with IL-2 and GM-CSF in 39 evaluable pts (including the 3-6 pts in the single dose phase I). SECONDARY OBJECTIVES: I. Determine if infusions of EGFR BATs significantly increase cellular or humoral anti-pancreatic cancer (PC) responses by peripheral blood mononuclear cells (PBMC) at different time points after last EGFR BATs infusion and if those responses persist beyond 2 months (mos). II. Obtain original tumor paraffin blocks prior to treatment and evaluate blocks for cluster of differentiation (CD)3, CD4, CD8, programmed cell death (PD)1/programmed cell death ligand (PDL)1, monocytes subpopulations, myeloid-derived suppressor cells (MDSC), and cytoplasmic interferon (IFN)-gamma and IL-10 by immunohistochemical staining to quantitate type and number of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment to estimate whether the type and number correlate with clinical responses. III. To determine the time to progression (TTP). OUTLINE: This is a phase Ib, dose-escalation study of anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells followed by a phase II study. Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride intravenously (IV) over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin subcutaneously (SC) and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion. After completion of study treatment, patients are followed up for 18 months.

Official Title
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Phase Ib/II Treatment of Advanced Pancreatic Cancer With Anti-CD3 x Anti-EGFR-Bispecific Antibody Armed Activated T-Cells (BATs) in Combination With Low Dose IL-2 and GM-CSF

Conditions
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Recurrent Pancreatic Carcinoma, Metastatic Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: Antibody Therapy
* Drug: Fluorouracil
* Drug: Gemcitabine Hydrochloride
* Drug: Irinotecan Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Leucovorin Calcium
* Drug: Oxaliplatin
* Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation
* Biological: Sargramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of pancreatic adenocarcinoma; must have locally advanced or metastatic pancreatic cancer who have received at least first line chemotherapy and may have responding, stable or progressive disease Expected survival >= 3 months Karnofsky performance scale (KPS) >= 70% or Southwestern Oncology Group (SWOG) performance status 0 or 1 Absolute neutrophil count (ANC) >= 1,000/mm^3 Lymphocyte count >= 400/mm^3 Platelet count >= 75,000/mm^3 Hemoglobin >= 8 g/dL Serum creatinine < 2.0 mg/dl, creatinine clearance >= 50 ml/mm (can be calculated or measured) Total bilirubin =< 2 mg/dl (biliary stent is allowed) Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) < 5.0 times normal Left ventricular ejection fraction (LVEF) >= 45% at rest (multigated acquisition scan [MUGA] or echocardiogram [Echo]) Females of childbearing potential, and males, must be willing to use an effective method of contraception Females of childbearing potential must have a negative pregnancy test within 7 days of being registered for protocol therapy Exclusion Criteria: Any chemotherapy related toxicities from prior treatment (> grade 2 per Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0) Known hypersensitivity to cetuximab or other EGFR antibody Treatment with any investigational agent within 14 days prior to being registered for protocol therapy Symptomatic brain metastasis Chronic treatment with systemic steroids or another immuno-suppressive agent Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to being registered for protocol therapy Active liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis Known human immunodeficiency virus (HIV) infection Active bleeding or a pathological condition that is associated with a high risk of bleeding (therapeutic anticoagulation is allowed) Has an active infection requiring systemic therapy A serious uncontrolled medical disorder that in the opinion of the investigator may be jeopardized by the treatment with protocol therapy Females must not be breastfeeding Patient (Pt) may be excluded if, in the opinion of the principal investigator (PI) and investigator team, the pt is not capable of being compliant

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (anti-CD3 x anti-EGFR BATs)<br>Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride IV over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin SC and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Biological: Antibody Therapy<br>* Given anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV<br>* Other names: passive antibody therapy;Drug: Fluorouracil<br>* Given IV<br>* Other names: Timazin;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY-188011;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation<br>* Given IV<br>* Other names: protein-bound paclitaxel;Biological: Sargramostim<br>* Given SC<br>* Other names: Sargramostatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Overall Survival (OS) | Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for OS. The median OS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method. | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker Analysis (Including CD3, CD4, CD8, PD1, PDL1, Monocytes, MDSC, IFN-gamma, IL-10, and TILs) Assessed Using Immunohistochemistry | Each biomarker and computed biomarker will be evaluated for normality and transformed (including non-parametric) if necessary to achieve normality. Summary statistics (including means, medians, and standard deviations) will be produced for each variable and subsequently associate each variable with OS using Cox regression. In addition, a threshold for each variable associating with OS will be defined using classification and regression trees. The tumor will be stained for inflammatory biomarkers. Specifically, T cells with undergo cytoplasmic staining for IFN and IL-10 and the level and ratio of these markers will be evaluated. | Up to 18 months | 
| Incidence of Toxicity (CTCAE Version 4.0) | Toxicity rates will be estimated using all treated patients. | Up to 18 months | 
| Progression Free Survival (PFS) | Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for PFS. The median PFS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method. | Up to 18 months | 
| Quantitative Immune Response | For the quantitative immune response variables, summary statistics (including means, medians, and standard deviations) will be produced pre- and post-BATs treatment. Subsequent analyses will compare the immune response variables (after a suitable transformation, if necessary) pre- and post-treatment using a paired t-test (or Wilcoxon sign ranked test if the data are not approximately normally distributed). To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyze | Up to 18 months | 
| TTP | To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyzed using logistic regression for binary endpoints and Cox regression for time to event endpoints. | Up to 18 months |