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

Study Overview
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Brief Summary
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Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses. Objective: To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL. Eligibility: People aged 3 to 35 with ALL or related B-cell lymphoma that has not been cured by standard therapy. Design: Participants will be screened. This will include: Physical exam Blood and urine tests Tests of their lung and heart function Imaging scans Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone. Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord. Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells. Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment. Participants will be admitted to the hospital. Their own modified T cells will be returned to their body. Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....

Detailed Description
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Background: Despite improvements in therapy, acute lymphoblastic leukemia (ALL) contributes to significant morbidity and mortality for children and young adults with cancer. CD19-CAR and CD22-CAR therapy have proven highly effective in inducing remission in patients with relapsed/refractory disease. Immune escape has been observed by several groups following CD19-CAR and CD22- CAR therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 and/or CD22 expression observed in these cases. The challenges encountered with currently available CD19- and CD22-directed CAR T cells in B-ALL demonstrates the need for combinatorial treatment strategies simultaneously targeting two antigens, such as CD19 and CD22, to enhance the long-term effectiveness of CARs. We have previously treated patients with B-ALL on a phase 1/2 clinical trial using a bivalent CD19/22 CAR T-cell as a first combinatorial treatment strategy. This CAR T-cell construct is well-tolerated and has yielded responses however there has been limited CAR T cell expansion and persistence. Additionally, the previously tested CD19/CD22 bivalent CAR T-cell construct is limited in its ability to target CD22. This new CD19/22 targeted construct being tested in this clinical trial has improved dual targeting capability based on preclinical data/evaluation. Objectives: Phase I: Assess the safety of administering escalating doses of autologous CD19/CD22- CAR engineered T cells in children and young adults with B cell ALL (stratified by disease burden) or lymphoma following a cyclophosphamide/fludarabine conditioning regimen. Phase II: Determine the efficacy of CD19/CD22 therapy in participants stratified by disease burden. Eligibility: -Participants between >= 3 years and <= 35 years of age, with CD19+/CD22+ B cell 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. Design: Phase I, 3 + 3 dose escalation design across 3 cohorts (B-ALL: A/ B-lymphoblastic lymphoma: A: low-disease burden (<25 % marrow blasts without extramedullary disease) vs. B: high-disease burden (>= 25 % marrow blasts or with EMD): C: B-cell non-Hodgkin lymphoma using the following dose levels: -2: 1 x 10^5 transduced T cells/kg (+/- 20%); -1: 3 x 0^55 transduced T cells/kg (+/- 20%); 1: 1 x 10^6 transduced T cells/kg (+/- 20%); and 2: 3x 10^6 transduced T cells/kg (+/- 20%). Cohorts will enroll concurrently. Participants will be treated based on disease burden and will receive 1 of 2 lymphodepleting preparative regimens: Lymphodepleting preparative regimen number 1: Fludarabine (30 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. Lymphodepleting preparative regimen #2: 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. Determination for use of LD regimen #1 versus #2 will be based on pre-treatment absolute lymphocyte count, pre-existing cytopenias, receipt of prior CAR T-cell therapy, high disease burden and assessment of infection risk. Participants will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, and other biologic correlatives.

Official Title
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Phase 1/2 Dose Escalation Study of CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

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

Intervention / Treatment
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* Biological: CD19/CD22-CAR-transduced T cells
* Drug: cyclophosphamide
* Drug: fludarabine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Diagnosis Participant must: Have pathology confirmed B cell ALL (not isolated to the testis or CNS), CML with ALL transformation, or high-grade lymphoma (e.g., Burkitt s lymphoma, B-lymphoblastic lymphoma, diffuse large B-cell lymphoma, inclusive of low-grade lymphoma that has transformed to high grade disease); and Have relapsed or been refractory after at least one standard chemotherapy regimen and at least one salvage treatment. Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor; and Be ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have recurred after SCT; and Have no evidence of graft-versus- host disease (GVHD) and have been without immunosuppressive agents for at least 30 days prior to apheresis, if undergone prior allogeneic SCT; and Be unable to access (in a timely manner), ineligible for, or have relapsed/failed after or not responded to a commercially available CD19 CAR T-cell construct; and Have evidence of at least minimal residual disease or PET-avid disease (lymphoma) at the time of enrollment. CD22/CD19 expression CD19 must be detected on >15% of the malignant cells by immunohistochemistry or > 80% by flow cytometry. CD22 positivity must be confirmed. Age >= 3 years of age and <=35 years of age at time of enrollment. Clinical Performance status: Participants >= 16 years of age: Karnofsky >= 50%; Participants < 16 years of age: Lansky scale >= 50%. Participants must have adequate organ and marrow function as defined below: leukocytes >= 750/mcL* platelets >= 50,000/mcL* total bilirubin <=2 X ULN (except in the case of participants with documented Gilbert s disease > 3x ULN) AST(SGOT)/ALT(SGPT) <=10 x institutional upper limit of normal creatinine <= the maximum for age listed in the table below OR measured creatinine clearance >=60 mL/min/1.73 m^2 for participants with creatinine levels above the max listed below per age. Age (Years) <= 5 || Maximum Serum Creatinine (mg/dL) <= 0.8 Age (Years) 6 to <= 10 || Maximum Serum Creatinine (mg/dL) <= 1.0 Age (Years) >10 || Maximum Serum Creatinine (mg/dL) <= 1.2 a participant will not be excluded because of pancytopenia >= Grade 3 if it is due to underlying bone marrow involvement by leukemia Central nervous system (CNS) Status Participants with leukemia with CNS 1 and 2 disease are eligible in the absence of exclusion criteria Participants of child-bearing or child-fathering potential must be willing to practice effective birth control from the time of enrollment until four months following lymphodepletion (LD) Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and until 1 month after the administration of CAR. Cardiac function: Left ventricular ejection fraction >= 45% or fractional shortening >=28% Pulmonary Function Baseline oxygen saturation >92% on room air at rest Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document. Ability and willingness of participant or Legally Authorized Representative (LAR) to co- enroll on 15-C-0028: Follow-up Evaluation for Gene-Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials. EXCLUSION CRITERIA: Participants meeting any of the following criteria are not eligible for participation in the study: Participants with CNS3 disease, neurologic signs of CNS disease, radiologically detected active CNS lymphoma Hyperleukocytosis (>= 50,000 blasts/microL) Positive serum or urine beta-HCG pregnancy test performed at screening. Participants will be excluded based on prior therapy if they fail to meet following washout criteria: Therapy: Systemic Chemotherapy, anti-neoplastic agents, antibody- based therapies Washout*: >=2 weeks Exceptions: 6 weeks for clofarabine or nitrosoureas; No washout for prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) 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 Therapy: Radiation Washout*: >=3 weeks Exceptions: No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window Therapy: Allogeneic Stem Cell Transplant Washout*: >= 100 days since SCT; >= 30 days since completion of immunosuppression; >= 6 weeks since donor lymphocyte infusion (DLI) Exceptions: Cannot have evidence of active graft-versus-host disease (GVHD) Therapy: CAR T-Cell Therapy or other Adoptive Cell Therapy Washout*: > 30 days post infusion Exceptions: For patients previously treated with CAR T-cells without interim HSCT (cohorts B1 and D1) cannot have circulating CAR T cells (or genetically modified cells) >5% by flow cytometry in peripheral blood Washout: Time between therapy and apheresis Positive HIV antibodies consistent with active HIV. Positive hepatitis C antibodies or positive Hepatitis B surface antigen (HbsAG) indicative of current/active HCV/HBV. Active second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and participant 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. Uncontrolled, symptomatic, intercurrent 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 participant.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 35 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Phase I Dose Escalation-with standard LD - CLOSED<br>CD19/CD22-CAR-transduced T cells at escalating dose + standard LD | Biological: CD19/CD22-CAR-transduced T cells<br>* CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen<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.<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>|
| Experimental: 1b/Phase 1 Dose Escalation - low disease burden<br>CD19/CD22-CAR-transduced T cells | Biological: CD19/CD22-CAR-transduced T cells<br>* CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen<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.<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>|
| Experimental: 2/Phase I Dose Escalation- with intensified LD - CLOSED<br>CD19/CD22-CAR-transduced T cells + standard LD | Biological: CD19/CD22-CAR-transduced T cells<br>* CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen<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.<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>|
| Experimental: 2b/Phase 1 Dose Escalation - high disease burden<br>CD19/CD22-CAR-transduced T cells | Biological: CD19/CD22-CAR-transduced T cells<br>* CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen<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.<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>|
| Experimental: 3/Phase II Dose Expansion- with low disease burden<br>CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD | Biological: CD19/CD22-CAR-transduced T cells<br>* CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen<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.<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>|
| Experimental: 4/Phase II Dose Expansion- with high disease burden<br>CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2 | Biological: CD19/CD22-CAR-transduced T cells<br>* CD19/CD22-CAR-transduced T cells on D0 after lymphodepleting preparative regimen<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.<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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy | Determine the efficacy of CD19/CD22 therapy in participants stratified by disease burden. | Monthly until 3 months post CAR T infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, up to 2 years after the entry date of the last participant. | 
| Safety | Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells in children and young adult with B cell ALL (stratified by disease burden) or lymphoma following a cyclophosphamide/fludarabine LD. | 30 days post CAR T infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility | Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established release criteria. | Up to two years after the last participant has entered. | 
| Adverse Events | Phase II: Assess the safety of CD19/CD22 therapy in participants based on underlying disease burden. | 30 days post CAR T infusion | 
| Persistence and expansion | Evaluate persistence and expansion of C19/CD22-CAR T cells in children and young adults with CD19+CD22+ B-ALL or lymphoma | Up to two years after the last participant has entered. | 
| Progression free survival (PFS) and Overall survival (OS) | Evaluate PFS and OS in participants, separately by phase II cohort | Up to two years after the last participant has entered. | 
| Overall response rate | Phase I: Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with CD19+CD22+ B cell ALL or lymphoma. | Monthly until 3 months post infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, for up to two years from the entry date of the last participant | 
| Assess response and toxicity (CRS grade) | Assess overall response rate and CRS grades (toxicity) in participants who received subsequent infusion | Up to two years after last participant has entered | 

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