CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

Study Overview
=================
Brief Summary
-----------------
Background: B-cell leukemias and lymphomas are cancers that are often difficult to treat. The primary objective of this study is to determine the ability to take a patient's own cells (T lymphocytes) and grow them in the laboratory with the CD19/CD22-CAR receptor gene through a process called 'lentiviral transduction (also considered gene therapy) and growing them to large numbers to use as a treatment for hematologic cancers in children and young adults.. Researchers want to see if giving modified CD19/CD22-CAR T cells to people with these cancers can attack cancer cells. In addition, the safety of giving these gene modified cells to humans will be tested at different cell doses. Additional objectives are to determine if this therapy can cause regression of B cell cancers and to measure if the gene modified cells survive in patients blood. Objective: To study the safety and effects of giving CD19/CD22-CAR T cells to children and young adults with B-cell cancer. Eligibility: People ages 3-39 with certain cancers that have not been cured by standard therapy. Their cancer tissue must express the CD19 protein. Design: A sample of participants blood or bone marrow will be sent to NIH and tested for leukemia. Participants will be screened with: Medical history Physical exam Urine and blood tests (including for HIV) Heart and eye tests Neurologic assessment and symptom checklist. Scans, bone marrow biopsy, and/or spinal tap Some participants will have lung tests. Participants will repeat these tests throughout the study and follow-up. Participants will have leukapheresis. Blood will be drawn from a plastic tube (IV) or needle in one arm then go through a machine that removes lymphocytes. The remaining blood will be returned to the participant s other arm. Participants will stay in the hospital about 2 weeks. There they will get: Two chemotherapy drugs by IV Their changed cells by IV Standard drugs for side effects Participants will have frequent follow-up visits for 1 year, then 5 visits for the next 4 years. Then they will answer questions and have blood tests every year for 15 years. ...

Detailed Description
-----------------
Background: Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of childhood cancer. Survival rates have improved, but outcomes for some subgroups, including infants and young adults remain poor, and survival for patients who relapse is < 50%, despite allogeneic stem cell transplant following second remission. CD19 immune escape has been observed by several groups following CD19-CAR therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 expression observed in these cases. Sequential therapy using CD22-CARs to treat CD19 dim/lo escape is associated with rapid development of resistance due to CD22 downregulation. This trial will test whether simultaneous targeting of CD19 and CD22 using a novel bivalent CD19/22-CAR is safe and feasible. Objectives: -Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells that meet established release specifications in children and young adults with CD19+CD22+ B cell ALL, isolated CNS ALL, or lymphoma following a cyclophosphamide/fludarabine conditioning regimen. Eligibility: -Participants between >= 3 years and <= 39 years of age, with CD19+/CD22+ B cell ALL, isolated CNS ALL, or lymphoma who have relapsed or have refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options who meet standard Phase I eligibility criteria. Design: Phase I, 3 + 3 dose escalation design using the following dose levels: -1: 1 x 10^5 transduced T cells/kg (+/- 20%); 1: 3 x 10^5 transduced T cells/kg (+/- 20%); 2: 1 x 10^6 transduced T cells/kg; and 3: 3 x 10^6 transduced T cells/kg (+/- 20%); 4: 1 x 10^7 transduced T cells/kg (+/- 20%). Participants will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m^2/d x 3 on Days -4, -3, -2) and cyclophosphamide (900 mg/m^2/d x 1 on Day -2) followed by infusion of CD19/CD22-CAR T-cells on D0. Participants who are CAR pretreated (with exception for those with an interval HSCT) will receive increased lymphodepleting preparative regimen of fludarabine (30^mg/m2/d x 4 on Days -5, -4, -3, -2) and cyclophosphamide (600 mg/m2/d x 2 on Days -3, -2) followed by infusion of CD19/CD22-CAR T-cells on D0. If fludarabine is unavailable, pentostatin may be given as an alternative. Patients will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, as well as research correlatives.

Official Title
-----------------
Phase 1 Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

Conditions
-----------------
Lymphoma, Non-Hodgkin, Leukemia, Lymphocytic, B Cell, B-Cell Lymphoma, B-Cell Leukemia, Acute Lymphoid Leukemia, B-Non Hodgkin Lymphoma, B-NHL, B-All, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Biological: CD19/CD22 CAR T-Cells
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Diagnosis Participant must have a B cell ALL (inclusive of CML with ALL transformation) or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy regimen and one salvage regimen. In view of the PI and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits SCT at the time of enrollment. Participants who have undergone autologous SCT will be eligible, and participants that have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they have no evidence of GVHD and have been without immunosuppressive agents for at least 30 days. Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor. Participants must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis. For those being considered for reinfusions, measurable or evaluable disease is not required at the time of reinfusion. CD22/CD19 Expression --CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 90% by flow cytometry. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each participant. In general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples. CD22+ B cell malignancy is required and CD22 expression levels will be documented when available, but a specific level of expression is not an eligibility requirement; it may be documented as positive or negative. Age: --Greater than or equal to 3 years of age (and at least 15 kg) and less than or equal to 39 years of age at time of enrollment (greater than or equal to 3 years to less than or equal to 39 years). NOTE: The first participant in each dose cohort must be greater than or equal to 18 years of age. Clinical Performance --Clinical performance status: Participants greater than or equal to 16 years of age: Karnofsky greater than or equal to 50%; Participants < 16 years of age: Lansky scale greater than or equal to 50%. Subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score. Participants must have adequate organ and marrow function as defined below: leukocytes greater than or equal to 750/mcL* platelets greater than or euqual to 50,000/mcL* total bilirubin less than or equal to 2 X ULN (except in the case of subjects with documented Gilbert s disease > 3x ULN) AST(SGOT)/ALT(SGPT) less than or equal to 10 X institutional upper limit of normal creatinine less than or equal to the maximum for age listed in the table below OR creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. Age: less than or equal to 5. Maximun Serum Creatinine (mg/dL): less than or equal to 0.8 Age: 6 to less than or equal to 10. Maximum Serum Creatinine (mg/dL): less than or equal to 1.0 Age: >10. Maximum Serum Creatinine (mg/dL): less than or equal to 1.2 * if these cytopenias are not judged by the investigator to be due to underlying disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not be excluded because of pancytopenia greater than or equal to Grade 3 if it is due to disease, based on the results of bone marrow studies. Subjects with CNS disease are eligible, with exceptions as noted in the exclusion criteria Contraception: Participants of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen. Cardiac function: Left ventricular ejection fraction greater than or equal to 45% or fractional shortening greater than or equal to 28%, and no clinically significant ECG findings Pulmonary Function Baseline oxygen saturation >92% on room air at rest Participants with respiratory symptoms must have a DLCO/adjusted > 45%. For children who are unable to cooperate for PFTs they must not have dyspnea at rest or known requirement for supplemental oxygen. Ability of subject, parent(s)/guardian(s), Legally Authorized Representative (LAR) or Durable Power of Attorney (DPA) to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Subjects meeting any of the following criteria are not eligible for participation in the study: Recurrent or refractory ALL limited to isolated testicular. Subjects with radiologically detected active CNS lymphoma or isolated CNS disease which are eligible for definitive CNS directed radiation therapy will be excluded. Hyperleukocytosis (greater than or equal to 50,000 blasts/micro L) or rapidly progressive disease that in the estimation of the investigator and sponsor would compromise ability to complete study therapy; Pregnant women are excluded from this study because the study agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding should be discontinued. Subjects will be excluded related to the following prior therapy criteria: Systemic chemotherapy, anti-neoplastic investigational agents, or antibody based therapies =<2 weeks (6 weeks for clofarabine or nitrosoureas) prior to apheresis with the following exception: ---No time restriction with prior intrathecal chemotherapy, steroid therapy, hydroxyurea or ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor for participants with Ph+ ALL) provided there is recovery from any acute toxic effects. Radiation therapy =<3 weeks prior to apheresis with the following exception: ---No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the subject has measurable/evaluable disease outside the radiation window. History of allogeneic stem cell transplantation prior to apheresis that meet the following criteria: Less than 100 days post-transplant Evidence of active graft-versus-host disease (GVHD) Taking immunosuppressive agents within 30 days prior to apheresis Less than 6 weeks post donor lymphocyte infusion (DLI) History of prior CAR therapy or other adoptive cell therapies prior to apheresis that meet the following criteria: Less than 30 days post-infusion Circulating CAR T cells (or genetically modified cells) >5% by flow cytometry in peripheral blood. HIV/HBV/HCV Infection: a. Seropositive for HIV antibody. (Participants with HIV are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy in the future should study results indicate effectiveness.) b. Positive for Hepatitis B surface antigen (HbsAG). c. Evidence of active Hepatisis C (evidenced by detectable HCV RNA) Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject; Second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and subject is in remission; History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 39 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: Dose escalation<br>CD19/CD22-CAR-transduced T cells at escalating doses | Biological: CD19/CD22 CAR T-Cells<br>* CD19/CD22 cells will be infused on Day 0 after induction chemotherapy regimen.<br>Drug: Fludarabine<br>* Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion on Day -2.<br>|
| Experimental: Dose expansion<br>CD19/CD22-CAR-transduced T cells at MTD or highest dose administered | Biological: CD19/CD22 CAR T-Cells<br>* CD19/CD22 cells will be infused on Day 0 after induction chemotherapy regimen.<br>Drug: Fludarabine<br>* Fludarabine is administered as an IV infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on BSA (25 mg/m2/dose)<br>Drug: Cyclophosphamide<br>* Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 900 mg/m2/dose after fludarabine infusion on Day -2.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Safety analyses will consist of tabulations of grades of toxicity by type of toxicity. | End of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasability | Number of patients which can successfully manufacture the targeted dose number | 28 days post treatment completion | 
| Overall survival | Overall survival (OS) will be determined as the time from the start of the preparative regimen until death | Death | 
| Progression-free survival | Preparative regimen until the documentation of disease progression or death due to any cause, whichever occurs first. | Time of relapse | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
B-Non Hodgkin Lymphoma, Acute Lymphocytic Leukemia, Acute Lymphoblastic Leukemia, B-precursor ALL, B-All, Philadelphia chromosome + ALL, Lymphoma, CD-22 Expressing Tumor, CD-19 expressing tumor, Adoptive Immunotherapy