Dose Optimization Trial of CD19 Redirected Autologous T Cells

Study Overview
=================
Brief Summary
-----------------
This is a randomized, open-label, parallel group study to determine the optimal dose of CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR Zeta and 4-1 BB co-stimulatory domains) of the two dose levels being assessed (1-5x10e8 vs. 1-5x10e7 CART-19 cells). This trial will be conducted in two stages.

Detailed Description
-----------------
This study is being conducted to determine the optimal dose of autologous CART-19 T cells engineered to express anti-CD19 chimeric antigen receptors in patients with relapsed or refractory CD19 positive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The two dose levels being assessed are 1-5x10e8 versus 1-5x10e7. The trial will be conducted in two stages. In stage I subjects will be randomized into one of the two dose cohort with a1:1 ratio for a total of 12 subjects per dose cohort. Stage II will be to enroll an additional 8 subjects to the selected dose cohort once safety, tolerability and clinical responses have been evaluated to determine the optimal dose cohort.

Official Title
-----------------
Dose Optimization Trial of Autologous T Cells Engineered to Express Anti-CD19 Chimeric Antigen Receptor (CART-19) in Patients With Relapsed or Refractory CD19+ Chronic Lymphocytic Leukemia (CLL)

Conditions
-----------------
Adult Patients Who Have Relapsed or Refractory CLL (3rd Line) or SLL

Intervention / Treatment
-----------------
* Biological: CART-19


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Documented CD19+ CLL or SLL Successful test expansion of T-cells At least 2 prior chemotherapy regimens, not including single agent monoclonal antibody (rituxan) therapy. Single agent ofatumumab will be counted as a regimen. -Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior regimen. Patients who progress within 2 years after the second or higher line of therapy will be eligible. For instance, patients who had progression < 2 years after second or greater line therapy, but who have responded to their most recent treatment (3rd line or higher) will be eligible. Subject is not appropriate candidate for a potentially curative allogeneic SCT due to the state of disease, co-morbid illness, lack of an available donor, or patient declines Performance status (ECOG) 0 or 1 Age >/= 18 years Adequate organ system function including: Creatinine < 1.6 mg/dl ALT/AST < 3x upper limit of normal Total Bilirubin <2.0 mg/dl Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy Patients with relapsed disease after prior allogeneic SCT (myeloablative or nonmyeloablative) will be eligible if they meet all other inclusion criteria and: Have no active GVHD and require no immunosuppression Are more than 6 months from transplant No contraindications for leukapheresis Left Ventricular Ejection fraction >40% Gives voluntary informed consent Retreatment Inclusion Criteria Performance Status 0-1 Adequate organ system function including: Creatinine < 1.6 mg/dl ALT/AST < 3x upper limit of normal Total Bilirubin < 2.0 mg/dl Subject is not an appropriate candidate for a potentially curative allogeneic SCT due to the state of disease, co-morbid illness, lack of an available donor, or patient declines. Left Ventricular Ejection Fraction > 40% No contraindications for leukapheresis (if required for retreatment) Gives voluntary informed consent for retreatment Exclusion Criteria Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion. Uncontrolled active infection Active hepatitis B or hepatitis C infection Concurrent use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary. For additional details regarding use of steroid and immunosuppressant medications. Any uncontrolled active medical disorder that would preclude participation as outlined HIV infection Patients with active CNS involvement with malignancy. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was >4 weeks before enrollment. Class III/IV cardiovascular disability according to the New York Heart Association Classification Retreatment Exclusion Criteria Pregnant or lactating women. Female study participants must have a negative serum or urine pregnancy test performed within 48 hours before infusion. Uncontrolled active infection Active hepatitis or hepatitis infection Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary. Any uncontrolled active medical disorder that would preclude participation as outlined. HIV infection Patients with active CNS involvement with malignancy. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was >4 weeks before enrollment on the retreatment cohort. Class III/IV cardiovascular disability according to the New York Heart Association Classification

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Target dose of 1-5x10e8<br>Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) | Biological: CART-19<br>* CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)<br>|
| Experimental: Target dose of 1-5x10e7<br>Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) | Biological: CART-19<br>* CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Complete Response Within 3 Months | Complete response (including complete response with incomplete marrow recovery) within 3 months (in evaluable patients). The eveluable set comprise of patients who have received CART19 at intended dose level and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death. | 3 months |