New CAR T-cell therapy for children and young adults with certain blood cancers

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

This study is testing a new CAR T-cell therapy that uses modified cells from children's and young adults' own blood to see if it can help treat certain tough-to-treat blood cancers.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 126 (estimated)
• Ages: 3 Years to 39 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: CAR T, chemotherapy, Radiation, methotrexate, chimeric antigen receptor, cyclophosphamide, fludarabine
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT05442515 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate a novel chimeric antigen receptor (CAR) T-cell therapy targeting both CD19 and CD22 proteins in children and young adults with recurrent or refractory B-cell malignancies, including acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma. Participants aged 3 to 39 will undergo screening and receive genetically modified T-cells derived from their own blood, combined with chemotherapy agents cyclophosphamide and fludarabine. The study will assess the safety and efficacy of this dual-targeting approach to improve treatment outcomes for patients who have not responded to standard therapies.

Who should consider this trial

Good fit: Ideal candidates are children and young adults aged 3 to 39 with relapsed or refractory B-cell malignancies who have failed prior treatments.

Not a fit: Patients with isolated testicular or CNS involvement of ALL or those who are not eligible for the study criteria may not benefit from this trial.

Why it matters

Potential benefit: If successful, this therapy could significantly improve remission rates and survival for patients with relapsed or refractory B-cell malignancies.

How similar studies have performed: Previous studies using CAR T-cell therapies targeting CD19 and CD22 have shown promising results, indicating potential for success with this novel dual-targeting approach.

Eligibility criteria

* 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 \<=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)
  * 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.

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Nirali N Shah, M.D. — National Cancer Institute (NCI)
• Study coordinator: NCI Pediatric Leukemia, Lymphoma Transpl

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