Trial of 2nd Generation Anti-CEA Designer T Cells in Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to collect data on the safety and effectiveness of 2nd generation designer T cells in patients with breast cancer. Designer T cells are prepared by collecting white blood cells from the participant, and then modifying these cells in the laboratory so that they recognize the tumor antigen (CEA). These modified cells are then given back to the participant so that they can attack and kill tumor cells.

Detailed Description
-----------------
T cells can penetrate virtually every biologic space and have the power to dispose of normal or malignant cells as seen in viral and autoimmune diseases and in the rare spontaneous remissions of cancer. However, T cells are easily tolerized to self or tumor antigens and immune surveillance has manifestly failed in every cancer that is clinically apparent. It is the goal of this study to supply the specificities and affinities to patient T cells without regard for their endogenous T cell receptor repertoire, directed by antibody-defined recognition to kill malignant cells based on their expression of antigen. We will achieve this by preparing chimeric IgCD28TCR genes in mammalian expression vectors to yield designer T cells from normal patient cells. Prior studies in model systems demonstrated that recombinant IgCD28TCR could direct modified T cells to respond to antigen targets with IL2 secretion, cellular proliferation, and cytotoxicity, the hallmarks of an effective, self-sustaining immune response. It therefore becomes of paramount interest to extend these studies to a human system of widespread clinical relevance to explore the clinical potential of this new technology. The target antigen for these studies is carcinoembryonic antigen (CEA), which is prominently expressed on tumors of the stomach, colon and rectum, breast, pancreas and other sites. For the Phase Ia component, patients receive a single dose of gene-modified autologous T cells on this dose-escalation trial. Doses are 10^9 and 10^10 modified T cells. Patients are monitored for safety and response. Patients are on-study for one month after dosing. For the Phase Ib component, patients receive a fixed dose of gene-modified T cells (10^11 cells), randomized to receive T cell growth factor interleukin 2 (+IL2) [Experimental] or not (-IL2) [Control]. The IL2 is administered outpatient by continuous infusion for a two-week period. On Day +2 and Day +10, the patient's tumor is biopsied to assess the designer T cell presence in the tumor as a means of judging the benefit of added IL2. Patients will also be followed for tumor response.

Official Title
-----------------
Phase Ia/Ib Trial of 2nd Generation Anti-CEA Designer T Cells in Metastatic Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Biological: Gene Modified T Cells
* Biological: Gene Modified T Cells and Interleukin 2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have cancer of the breast Must have metastatic or unresectable locally advanced disease Tumor must express CEA by tumor staining or by elevated serum CEA (>10 ng/ml) Must have measurable disease radiologically or by physical exam Must have failed potentially curative standard therapy Must be 18 years of age or older Good performance status (PS 0-1) Exclusion Criteria: Requiring systemic steroids Serious medical conditions Concurrent malignancies

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ia<br> | Biological: Gene Modified T Cells<br>* Gene Modified T Cells Phase Ia: One time infusion Modified TCells given through a vein in the arm or a catheter over a 30-60 minute period<br>* Other names: CEA;|
| Experimental: Phase Ib: Control<br> | Biological: Gene Modified T Cells and Interleukin 2<br>* One time infusion Modified T Cells without or with (randomized) continuous infusion outpatient interleukin 2 (IL2) for two weeks<br>* Other names: CEA;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ia:Determine the safety of using modified T-cells by documenting the type and severity of any side effects and establishing the maximum tolerated dose (MTD). |  | 1 Month | 
| Phase Ib: Determine optimal biologic dose (OBD) in terms of value of added interleukin 2. |  | 1 Month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response |  | 1 Month | 
| Pharmacokinetic |  | 1 month | 
| Pharmacodynamic |  | 1 Month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, T cells, Gene Transfer