Using modified T cells to treat children with relapsed or refractory blood cancers

Phase I/II Study of Anti-CD19 Chimeric Antigen Receptor-Expressing T Cells in Pediatric Patients Affected by Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia and Diffuse Large B Cell Lymphoma (DLBCL) or Primary Mediastinal B Cell Lymphoma (PML)

This study is testing a new treatment using modified T cells to see if it can help children with tough-to-treat blood cancers like leukemia and lymphoma feel better.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 32 (estimated)
• Ages: 1 Year to 25 Years
• Sex: All
• Sponsor: Bambino Gesù Hospital and Research Institute (Academic / other)
• Drugs / interventions: chemotherapy, Radiation, prednisone, CAR T, chimeric antigen receptor
• Locations: 1 site (Roma)
• Trial ID: NCT04787263 on ClinicalTrials.gov

What this trial studies

This study evaluates the safety and feasibility of administering autologous T cells modified to target the CD19 antigen in pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and aggressive B-cell non-Hodgkin lymphoma (B-NHL). Following a lymphodepleting chemotherapy regimen, the modified T cells will be administered to assess their efficacy at a defined optimal dose. The study includes a phase I component to establish safety and a phase II extension to evaluate treatment effectiveness. The goal is to manufacture CAR T cells that meet specific release criteria for this patient population.

Who should consider this trial

Good fit: Ideal candidates are pediatric patients aged 1 to 25 years with relapsed or refractory CD19+ B-ALL, DLBCL, or PML.

Not a fit: Patients who do not express the CD19 antigen or are beyond the specified age limits may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for children with difficult-to-treat blood cancers.

How similar studies have performed: Other studies using CAR T cell therapy targeting CD19 have shown promising results, indicating potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

1. Diagnosis of CD19 expressing B-ALL or DLBCL or PML and one of the following:

   1. Patients in 1st relapse, with High-Risk (HR) features including: MLL- rearrangements, E2A/TCF3-PBX1, TCF3-HLF \[t(17;19)\], hypodiploidy (i.e., \<44 chromosomes), TP53 alterations, early (i.e., \<30 months from diagnosis)/very early (i.e., \<18 months from diagnosis) isolated or combined bone marrow relapse
   2. MRD \> 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL
   3. Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy
2. Age: 1 year - 25 years for Bcp-ALL and 1-35 years for B-NHL.
3. Voluntary informed consent is given. For subjects \< 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
4. Clinical performance status: Patients \> 16 years of age: Karnofsky greater than or equal to 60%; Patients \< 16 years of age: Lansky scale greater than or equal to 60%.
5. Patients 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 the preparative regimen.
6. Females of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects on the fetus.

Exclusion Criteria:

1. Pregnant or lactating women
2. Severe, uncontrolled active infections
3. HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood)
4. Life-expectancy \< 6 weeks
5. Hepatic function: Inadequate liver function defined as total bilirubin \> 4x upper limit of normal (ULN) or transaminase (ALT and AST) \> 6 x ULN
6. Renal function: serum creatinine \> 3x ULN for age.
7. Blood oxygen saturation \< 90%.
8. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO.
9. Congestive heart failure, cardiac arrhythmia, psychiatric 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 subject.
10. BM blasts \> 50% pre-infusion.
11. Hyperleukocytosis (greater than or equal to 20,000 blasts/microliter) or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy
12. Presence of active, grade 2-4 acute or moderate-severe chronic GvHD
13. Recurrent or refractory ALL with testicular involvement
14. Concurrent or recent prior therapies, before infusion:

    1. Systemic steroids (at a dose \> 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary.
    2. Systemic chemotherapy in the week preceding infusion.
    3. Anti-thymocyte globulin (ATG) in the 4 weeks preceding infusion.
    4. Immunosuppressive agents in the 1 week preceding infusion.
    5. Radiation therapy must have been completed at least 3 weeks prior to enrollment.
    6. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy);
    7. Exceptions:

    i. There is no time restriction with respect to prior intrathecal chemotherapy, provided that there is complete recovery from any acute toxic effects of such; ii. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided that they meet all other eligibility criteria; iii. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided that there has been no increase in dose for at least 2 weeks prior to starting apheresis;
15. Patient-derived CD19-CAR_Lenti production failure: vitality of the fresh product \<80%, CD3+ cells \<80%, CD3+ CAR+ cells \<10%, non-sterility in IPC at day 5, endotoxin contamination (\> 5 EU/ml) in IPC at day 5, mycoplasma contamination in IPC at day 5, failure of the visual inspection.

Where this trial is running

Roma

• IRCCS Ospedale Pediatrico Bambino Gesù — Roma, Italy (Recruiting)

Study contacts

• Study coordinator: Franco Locatelli, MD, PhD

Conditions Acute Lymphoblastic Leukemia; Diffuse Large B Cell Lymphoma; Primary Mediastinal Lymphoma