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

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 or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.
• Phase II: Determine the efficacy of CD19/CD22 therapy in participants with B-ALL/ B-LBL..

Eligibility:

-Participants between >= 3 years and <= 39 years of age, with CD19+ and/or 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 4 cohorts (B-ALL/B-cell 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 D: CD19+ or CD22+ single antigen positivity using the following dose levels: -2: 1 x 10^5 transduced T cells/kg (+/- 20%); -1: 3 x 10^5 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 # 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.

• 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.