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

• Status: Not yet recruiting
• Trial end date: 2029-07-01
• Target enrollment: 0
• Participant gender: All

Summary

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 who are CAR-naive/have received interim hematopoietic stem-cell transplantation (HSCT) or who are CAR-pre-treated with CD19+CD22+ B cell ALL or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.

• Phase II: Determine the efficacy of CD19/CD22 therapy in participants who are CAR- na(SqrRoot) ve/interim HSCT or who are CAR pre-treated.

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 4 cohorts (B-ALL: A: CAR-naive/interim HSCT vs. B: CAR-pre-treated and B-lymphoma: C: CAR-naive/interim HSCT vs. D: CAR-pre-treated) using the following dose levels: -1: 3 x 10^5 transduced T cells/kg (+/- 20%); 1: 1 x 10^6 transduced T cells/kg (+/- 20%); 2: 3 x 10^6 transduced T cells/kg (+/- 20%); and 3: 1 x 10^7 transduced T cells/kg (+/- 20%). Cohorts will enroll concurrently.

• Participants will be treated based on prior therapy:

• CAR naive participants (including those who have received an interval HSCT after a prior CAR T-cells): 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.

• CAR pre-treated participants: 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.

• Participants will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, and other biologic correlatives.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Cyclophosphamide; Fludarabine

Criteria

• INCLUSION CRITERIA:

Diagnosis

• Participant must have:

• Pathology confirmed B cell ALL (inclusive of CML with ALL transformation) or high- grade lymphoma (e.g., Burkitt s lymphoma, B-lymphoblastic lymphoma, diffuse large B- cell lymphoma)

---Patients with low-grade lymphoma (e.g., follicular lymphoma or mantle cell lymphoma) will be excluded unless there is transformation to high-grade disease

• Participants must have a disease that is relapsed or refractory after at least one standard chemotherapy regimen and at least one salvage treatment and must either be ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have recurred after SCT.

• 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 graft-versus- host disease (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, defined by any evidence of minimal residual disease or PET-avid disease (lymphoma).

• CD22/CD19 expression

• CD9 must be detected on >15% of the malignant cells by immunohistochemistry or > 80% by flow cytometry. In general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples, and the most easily available tissue sample in each participant will be used.

• CD22 must be detected and expression levels will be documented when available, but a specific level of expression is not an eligibility requirement; it may be documented as positive.

• 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 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 >= 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

1. Participants with leukemia with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

• CNS 1, defined as absence of blasts in CSF on cytospin preparation, regardless of the number of WBCs;

• CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

• CNS 2a: < 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts;

• CNS 2b: >=10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts;

• CNS 2c: >=10/uL RBCs; >=5/uL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm.

• 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 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

• 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 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:

• Recurrent or refractory ALL limited to isolated testicular or isolated CNS disease.

• Participants with radiologically detected active CNS lymphoma or isolated CNS disease

• Hyperleukocytosis (>= 50,000 blasts/microliter)

• Participant pregnancy (confirmed with beta-HCG serum or urine pregnancy test performed at screening).

• Participants 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 (no dose increases within prior 2 weeks) or ALL maintenance-type chemotherapy7(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 participant has measurable/evaluable disease outside the radiation window.

History of allogeneic stem cell transplantation prior to apheresis that meet the any of 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 either of the two the following criteria:

• Less than 30 days post-infusion

• Circulating CAR T cells (or genetically modified cells) >5% by flow cytometry in peripheral blood

• Current/active HIV infection, as measured by seropositivity for HIV antibody.

• Current/active HBV/HCV Infection as measured by seropositivity for hepatitis C or positive for Hepatitis B surface antigen (HbsAG).

• 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;