A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

Study Overview
=================
Brief Summary
-----------------
Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.

Detailed Description
-----------------
Upon meeting the eligibility requirements and enrolling on study, subjects will undergo apheresis to obtain the T cells for the generation of the CD19 CAR+ T cells. In patients with a prior history of allogeneic HCT, the T cells obtained are of donor origin. The T cells are isolated from the apheresis product, the CD4 and CD8 T cells are then selected and grown separately, transduced with a lentivirus to express the CD19 CAR as well as a truncated EGFR that has no signaling capacity (noted EGFRt) and expanded in culture over a three week period. During the process of cell generation, subjects will continue to be cared for by their primary oncologist and may undergo additional treatment directed at the leukemia during this time. After the CAR+ T cells have been generated, the subject undergoes a disease assessment and determination if lymphodepletion is necessary. A variety of lymphodepletion strategies are acceptable and determined on a case by case basis. At least 48 hours after the completion of lymphodepletion, the subject will receive and infusion of CAR+ T cells at an approximate 1:1 ratio of CD4 to CD8 CAR+ T cells. Following treatment with the CAR+ T cells, subjects will be followed intensely for 2 months with serial blood testing and re-evaluation of disease status with bone marrow aspirates. After 2 months, the subjects clinical care will be resumed by their primary oncologist, and it is possible that they would receive additional chemotherapy or HCT. Some subjects will receive cetuximab for ablation of the genetically modified T cells. Criteria to receive cetuximab include acute toxicities that are life threatening, as well as an ongoing remission with continued B cell aplasia. Upon completion of the study, subjects will be followed bi-annually for 5 years, and then annually for 10 additional years with either a medical history, physical exam and blood tests or a phone call/questionnaire. This follow up will help to determine if the subject develops any long-term health problems related to the CAR+ T cells including a new cancer.

Official Title
-----------------
Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02: A Phase 1/2 Feasibility and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia

Conditions
-----------------
CD19+ Acute Leukemia

Intervention / Treatment
-----------------
* Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must be ≥12 months of age and <27 years of age at the time of study enrollment. Must be ≥10kg Confirmed CD19+ leukemia recurrence defined as ≥0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT. [N.B. Study closed to enrollment of leukemia subjects] OR No prior history of allogeneic HCT (one of the following) 2nd or greater relapse, with or without extramedullary disease (isolated extramedullary disease is eligible) 1st marrow relapse at end of 1st month of re-induction with marrow having ≥0.01% blast disease, with or without extramedullary disease Primary Refractory as defined as having M2 or M3 marrow after induction Subject has indication for HCT but has been deemed ineligible OR CD19+ Non-Hodgkin Lymphoma (NHL) refractory or relapsed with no known curative therapies available [N.B. Study remains open to enrollment of lymphoma subjects] Patients with CNS involvement are eligible provided that they are asymptomatic and in the opinion of the study PI have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion. Patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization. Patients must have a Lansky performance status score of ≥50 or a Karnofsky score of ≥ 50 for patients ≥16 years of age. Life Expectancy of >8 weeks Patients must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks prior to enrollment. Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy It must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy or maintenance chemotherapy) No systemic corticosteroids (unless physiologic replacement dosing) within 7 days of enrollment. No prior genetically modified cell therapy that is still detectable or virotherapy allowed. Normal serum creatinine based on age/gender Total bilirubin </3x ULN OR conjugated bilirubin </2mg/dl ALT </5X ULN SF of >28% by ECHO or EF >50% by MUGA ALC of >/= 100 cells/ul Pulse ox >/= 90% on room air Patient must have documented negative HIV antigen and antibody, Hepatitis B surface antigen, and Hepatitis C antibody within 3 months prior to enrollment. For patient with positive Hepatitis C Ab, negative PCR testing must be documented in order to be eligible. Patients must NOT have active clinically significant CNS dysfunction (including but not limited to such as uncontrolled seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) Must agree to highly effective contraception during and for 12 months after T cell infusion. Patients must be able to tolerate apheresis procedure, including placement of temporary apheresis line if required. Patients must NOT have an active malignancy other than CD19+ leukemia. Patients must NOT have an active severe infection defined as: A positive blood culture within 48 hours of study enrollment A fever above 38.2 C AND clinical signs of infection within 48 hours of study enrollment Patients must NOT have any concurrent medical condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy. Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial. Research participant or parent/legal guardian must agree to participate in long-term follow-up for up to 15 years, if they are enrolled in the study and receive T-cell infusion.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 26 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Cohort 1A<br>This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^5 CAR T cells/kg | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|
| Experimental: Phase 1 - Cohort 1B<br>This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^6 CAR T cells/kg | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|
| Experimental: Phase 1 - Cohort 1C<br>This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^6 CAR T cells/kg | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|
| Experimental: Phase 1 - Cohort 1D<br>This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^7 CAR T cells/kg | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|
| Experimental: Phase 1 - Cohort 1F1<br>This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10^5 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|
| Experimental: Phase 1 - Cohort 1F2<br>This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10^6 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|
| Experimental: Phase 2<br>The phase 2 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1 x 10^6 CAR T cells/kg following lymphodepletion if indicated. | Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt<br>* Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced an Adverse Event Meeting the Dose-Limiting Toxicity Definition | The safety of the T cell infusion at the maximum tolerated dose determined in Phase 1, and further characterized in Phase 2, will be described | Initial CAR T cell infusion through 30 days post infusion | 
| Number of Participants With an MRD Negative Complete Remission After Initial CAR T Cell Infusion | The efficacy of the T cell infusion will be estimated based on the number of participants who have an MRD negative bone marrow aspirate following the initial T cell infusion | Initial CAR T cell infusion through Day 63 post infusion assessment (+/- 14 days) | 
| Number of Participants Who Have a Releasable Cell Product Generated | The feasibility of manufacturing and releasing T cell products from pediatric and young adult patients with CD19+ relapsed or refractory leukemia | Up to 28 days per manufacturing attempt | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistence of Functional CD19 CAR+ T Cells | Participants will be followed for 63 days to determine if the transferred T cells remain detectable in the blood and bone marrow | Initial CAR T Infusion through Day 63 post infusion assessment (+/- 14 days) | 
| Number of Participants With Recrudescence or Development of Acute GVHD (Graft Versus Host Disease) Symptoms Post CAR T Infusion |  | Initial CAR T Infusion through Day 63 post infusion assessment (+/- 14 days) | 
| Number of Participants That Received Cetuximab Who Have T Cells Successfully Ablated | The efficacy of cetuximab to ablate the T cells will be measured by loss of detection of T cells and any associated toxicities as well as facilitating B cell recovery. | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pediatric, T cell, young adult, acute lymphoblastic leukemia, CD19, leukemia, Chimeric Antigen Receptor