Anti-CD3 x Anti-Erbitux® Armed Activated T Cells (Phase Ib) for Gastrointestinal (GI Cancer)

Study Overview
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Brief Summary
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The purpose of this research study is for the participant to give their own T cells (a type of blood cell in the body that can fight infections and possibly cancer) to them after they have been removed, grown in a lab, and then coated with an experimental drug. This study will determine the highest dose of EGFR2Bi coated T cells that can be given without causing severe side effects. Initially a group of 3 participants will receive the same dose of study drug. If no serious side effects occur, the next group of participants will receive a slightly higher dose of study agent. The following groups of participants will receive higher doses of the study drug until a dose is reached where there are unacceptable side effects and maximum tolerated dose is found, or the planned highest dose level is reached with no side effects.

Detailed Description
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The purpose of this study is to determine in a dose-escalation phase Ib trial the safety of 3 infusions of EGFR2Bi armed activated T cells (aATC), after chemotherapy, for patients with advanced colorectal and pancreatic cancer

Official Title
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Treatment of Advanced Colorectal or Pancreatic Cancer With Anti-CD3 x Anti-EGFR-Armed Activated T-Cells (Phase Ib)

Conditions
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Colorectal Cancer, Cancer of Pancreas, Pancreatic Neoplasm, Malignant Neoplasm of Large Intestine, Malignant Tumor of Colon, Colon Carcinoma, Cancer of Colon, Pancreatic Cancer

Intervention / Treatment
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* Drug: FOLFOX6
* Biological: EGFRBi armed ATC Infusions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of colorectal or pancreatic adenocarcinoma Must have metastatic colorectal cancer or pancreatic cancer with stable disease after first line chemotherapy or patients with colorectal or pancreatic cancer who have progressed with standard chemotherapy options* Standard chemotherapy for metastatic colorectal cancer include 5-FU/capecitabine with either oxaliplatin or irinotecan based regimen with or without bevacizumab or cetuximab. Standard chemotherapy for metastatic pancreatic cancer include gemzar based regimen or FOLFIRINOX (5-FU, oxaliplatin, and irinotecan) Prior cetuximab, panitumumab, or other monoclonal antibody therapy allowed if given 28 days prior to the 1st infusion of armed T cells Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 Lymphocyte count ≥ 400/mm3 Platelet Count ≥ 50,000/mm3 Hemoglobin ≥ 8 g/dL Serum Creatinine < 2.0 mg/dl, Creatinine Clearance ≥50 ml/mm (can be calculated) Total Bilirubin ≤ 2 mg/dl (biliary stent is allowed) SGPT and SGOT < 5.0 times normal LVEF ≥ 45% at rest (MUGA or Echo) Pulse Oximetry of >88% Age ≥ 18 years at the time of consent Written informed consent and HIPAA authorization for release of personal health information 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 KPS ≥ 70% or SWOG Performance Status 0 or 1 Exclusion Criteria: Any chemotherapy related toxicities from prior treatment.(> grade I per CTCAE v4.0 Known hypersensitivity to cetuximab or other EGFR antibody Treatment with any investigational agent within 14 days prior to being registered for protocol therapy Protocol version: 07/13/2011 8 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 HIV infection Positive HbsAg Positive Hepatitis C Active bleeding or a pathological condition that is associated with a high risk of bleeding Uncontrolled systemic disease like active infections Nonmalignant medical illnesses that are uncontrolled or a controlled illness that may be jeopardized by the treatment with protocol therapy Females must not be breastfeeding Patient may be excluded if, in the opinion of the PI and investigator team, the patient is not capable of being compliant Minor changes from these guidelines will be allowed at the discretion of the attending team under special circumstances. The reasons for exceptions will be documented.

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: FOLFOX6 & EGFRBi armed ATC Infusions<br>FOLFOX6: IV administration of 85 mb/m(2) oxaliplatin and 400 mg/m(2) leucovorin over 120 mins, followed by 400 mg/m(2) 5-fluorouracil (FU) bolus then 2400 mg/m(2) 5-FU as a 46 hr infusion. All patients must have central intravenous acess (e.g. mediport, PICC line) for continuous infusion of 5-FU. Adv. colorectal and pancreatic pts. w/no other standard chemo available, & in pts who cannot receive FOLFOX chemo, immunotherapy may be given w/o antecedent chemo. EGFRBi armed ATC Infusions: Armed ATC will be infused intravenously (IV) with the rate of infusion based on the endotoxin content of the product. All patients will be observed for at least 4 hours after an infusion. Armed ATC infusions will begin 3 weeks after chemotherapy and subsequent doses will be administered once weekly, for 3 weeks, then 12 weeks post aATC#1. Dose escalation level(per infusion): Level 0-5 billion; Level 1-10 billion; Level 2-20 billion; Level 3-40 billion | Drug: FOLFOX6<br>* IV administration of 85 mb/m(2) oxaliplatin and 400 mg/m(2) leucovorin over 120 mins, followed by 400 mg/m(2) 5-fluorouracil (FU) bolus then 2400 mg/m(2) 5-FU as a 46 hr infusion. All patients must have central intravenous acess (e.g. mediport, PICC line) for continuous infusion of 5-FU. Adv. colorectal and pancreatic pts. w/no other standard chemo available, & in pts who cannot receive FOLFOX chemo, immunotherapy may be given w/o antecedent chemo.<br>* Other names: OXaliplatin;Biological: EGFRBi armed ATC Infusions<br>* Armed ATC will be infused intravenously (IV) with the rate of infusion based on the endotoxin content of the product. All patients will be observed for at least 4 hours after an infusion. Armed ATC infusions will begin 3 weeks after chemotherapy and subsequent doses will be administered once weekly, for 3 weeks, then 12 weeks post aATC#1. Dose escalation level(per infusion): Level 0-5 billion; Level 1-10 billion; Level 2-20 billion; Level 3-40 billion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determining in a dose-escalation phase Ib trial the safety of 3 infusions of EGFR2Bi aATC, and a booster infusion after 3 months, for patients with advanced colorectal or pancreatic cancer. | Participants will be assessed for changes in lab values (CBC, Sodium, potassium, calcium, magnesium, chloride, bicarbonate, glucose,BUN, creatinine, total Protein, albumin, total bilirubin, ALP, AST,ALT, CEA or CA 19-9. | 4 wks after chemo, prior to ATC infusion #2; 1 wk later prior to ATC infusion #3; Wks 2, 4 & 9 post ATC infusion #3; Wk 8 post ATC #4 (booster) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determining whether IMT enhances anti-tumor immunity;Cytokine resp., phenotypic markers, anti-tumor cytotoxicity, in vivo and in vitro specific anti-tumor antibody prod. & molecular signaling markers of T-cell activation assessed before chemo & after IMT | Immune studies: Serum cytokine responses will be quantified focus on the levels of those factors known to be important regulators of T cell responses. Phenotype analysis will measure the percent of T, B, NKT and NK cells in peripheral blood mononuclear cell (PBMC) and tumor-infiltrating lymphocyte (TIL) samples. T cell proportions would be further analyzed by subset (CD4, CD8, CD25+). Cytotoxicity is measured in percentage in PBMC. | 3 weeks after chemo prior to ATC infusion #1; At wks 4(ATC #2) & 5 (ATC #3) post chemo; wks 2 , 4 & 9 post ATC #3 infusion; Day of ATC #4 (booster infusion), then wks 2, 4 & 8; & mon 6 and 1yr post ATC #4 (booster infusion) | 
| Determining the tumor response rate | CT or PET Scan | Approximately every 8 weeks to until 1 year | 
| Overall Survival | CT or PET Scan | Approximately every 8 weeks to until 1 year |