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Acute lymphoblastic leukemia (ALL) is the most common cancer in children; about 90% of children and young adults treated for ALL can be cured, but survival drops below 50% if the disease returns. This Phase 1/2 trial tests a new type of chimeric antigen receptor (CAR) T-cell, made from the patient's own blood cells, that targets both CD19 and CD22 -- proteins found on the surface of most types of ALL -- with cyclophosphamide and fludarabine given as part of the regimen. It enrolls people aged 3 to 39 with ALL or related B-cell lymphoma not cured by standard therapy; screening includes a physical exam, blood and urine tests, lung and heart function tests, imaging scans and a bone marrow biopsy.
The summary above is a plain-language rendering of the official record. The original English title is shown for reference.
Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.
* 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
* 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
* Cohorts A1b, B1b, C2b
* CD19 must be detected on \>15% of the malignant cells by immunohistochemistry or \> 80% by flow cytometry.
* CD22 positivity must be confirmed.
* Cohorts D1b, 2 B-ALL
* CD19 or CD22 positivity must be confirmed
* Age \>= 3 years of age and \<=39 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 12 months following completion of study treatment for women and for 4 months following completion of study treatment for men.
* 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, progressing neurologic signs\* of CNS disease, radiologically detected active CNS lymphoma (\*resolving manifestation or persistent and/or irreversible findings from prior CNS involvement (e.g., blindness) is not exclusionary)
* 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) requiring systemic immunosuppression
* Therapy: CAR T-Cell Therapy or other Adoptive Cell Therapy
* Washout\*: \> 30 days post infusion
* 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.