CD19 CAR T cell therapy for adults with relapsed or refractory CD19-positive acute lymphoblastic leukemia

Phase Ia Study of a LentiGen® CD19 Chimeric Antigen Receptor (CAR) T Cells in Adult Patients With Relapsed/Refractory CD19 Positive Acute Lymphoblastic Leukemia (ALL) Using a Closed Transduction System

This will try a single IV dose of CD19 CAR T cells after chemotherapy in adults 18–75 with relapsed or refractory CD19-positive ALL to see if it is safe and tolerable.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: King Faisal Specialist Hospital & Research Center (Academic / other)
• Drugs / interventions: CAR T, CAR-T, CART, chemotherapy, Radiation, methotrexate, cyclophosphamide, fludarabine, prednisone
• Locations: 1 site (Riyadh, Riyadh Region)
• Trial ID: NCT07361029 on ClinicalTrials.gov

What this trial studies

This Phase Ia, open-label, single-center dose-finding trial administers CD19-targeted CAR T cells to adults with relapsed/refractory CD19-positive ALL following a chemotherapy lymphodepletion regimen. Approximately 24 patients are planned across four dose-escalation cohorts, with three patients initially treated per cohort and dose-escalation decisions made by a Data Safety Monitoring Board. The starting dose is 5 x 10^5 cells/kg given as a single IV infusion, with predefined spacing between treated patients within each cohort to monitor safety. Safety, maximum tolerated dose, and pharmacokinetics/pharmacodynamics will be closely monitored throughout the trial.

Who should consider this trial

Good fit: Adults aged 18–75 with relapsed or refractory CD19-positive B-ALL qualifying by criteria such as second or greater bone marrow relapse, primary or chemo-refractory disease, Ph+ disease after failed or intolerant TKI therapy, ineligibility for allogeneic stem cell transplant, relapse after alloSCT (≥12 weeks), or relapse after prior CAR T while still CD19-positive are the intended participants.

Not a fit: Patients with CD19-negative disease, uncontrolled infection, active severe graft-versus-host disease, significant organ dysfunction, or those outside the 18–75 age range are unlikely to benefit from this CAR T approach.

Why it matters

Potential benefit: If successful, this therapy could produce meaningful remissions in adults with relapsed or refractory CD19-positive ALL who have few other options.

How similar studies have performed: Other CD19-directed CAR T products have achieved high remission rates in relapsed/refractory B-ALL, so this approach builds on an established but still investigational modality.

Eligibility criteria

Inclusion Criteria:

* Patients aged between 18 to 75 years old (patients is older than 18.0 and less than 75.0 years old) 2. Signed informed consent form 3. Ability to comply with the study protocol 4. Relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL):

  1. Second or greater bone marrow (BM) relapse; or
  2. Primary refractory, defined as not achieving complete remission (CR) after 2 cycles of a standard chemotherapy regimen, or Chemo-refractory, defined as not achieving CR after 1 cycle of standard chemotherapy for relapsed leukemia; or
  3. Philadelphia chromosome-positive ALL intolerant of or with 2 failed lines of tyrosine kinase inhibitor (TKI) therapy; or
  4. Relapsed patients ineligible for Allogeneic Stem Cell Transplant (AlloSCT) due to lack of a suitable donor.
  5. Relapsed after AlloSCT. at least 12 weeks after alloSCT or relapse happened after withdrawing the post-transplant immunosuppression
  6. Relapsed after prior CAR T cell and still CD19 positive. . (Patients with a history of ≥grade CRS, ≥ grade 3 ICANS, or severe hypersensitivity reactions following prior CAR T-cell therapy should be excluded.) 5. BM with ≥5% lymphoblasts by morphologic assessment at screening 6. For relapsed patients, documentation of CD19 tumor expression in BM or peripheral blood by flow cytometry or immunohistochemistry within 1 month of study entry 7. Patients with a history of CNS or meningeal involvement must be in a documented clinical remission prior to registration.

     8\. Alanine aminotransferase (ALT) ≤5 times the upper limit of normal for age 9. Bilirubin ≤2 x ULN 10. Patients with good renal function defined as Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 cc/min.

     11\. Absolute Neutrophil Count (ANC): Patients must have an ANC ≥ 1.0 x 109

     /L without the use of growth factors 12. Platelet Count: Patients must have a platelet count ≥ 50 x 109/L without transfusion support within 7 days of screening.

     13\. Absolute Lymphocyte Count: Patients must have an absolute lymphocyte count ≥ 0.5 x 109/L.

     14\. Definition of Adequate Organ Function:
     * Renal Function: Glomerular Filtration Rate (GFR) \> 60mL/min.
     * Hepatic Function: AST/ALT ≤ 5 x ULN and bilirubin ≤ 2 x ULN. Total bilirubin 1.5 ULN (except Gilbert's syndrome).
     * Pulmonary Function: Adequate respiratory function defined as oxygen saturation ≥ 93% on room air.
     * Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 45% by echocardiogram or MUGA scan and QTcF ≤ 480 ms. 15. Minimum level of pulmonary reserve defined as grade ≤1 dyspnea and pulse oxygenation \>93% on room air 16. Left ventricular ejection fraction ≥45% confirmed by echocardiogram within 30 days of screening 17. Karnofsky ≥ 70% and /or ECOG 0-2 at the time of screening 18. Women of child bearing age should have negative serum pregnancy test within 7 days prior to enrollment 19. If sexually active:

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  1. Females should use effective birth control 1 month prior to screening until 12 months after CAR T cell infusion
  2. Males to use condom for six months after infusion 20. Meet institutional criteria to undergo leukapheresis or have an acceptable, stored leukapheresis product

Exclusion Criteria:

1. Clinically Active central nervous system (CNS) involvement by malignancy
2. History or presence of uncontrolled underlying seizure disorder not related to B-ALL
3. History of or active clinically significant cardiovascular dysfunction, including any of the following:

   * History of stroke within 24 months prior to the CD19 CAR T cells infusion or with ongoing sequelae
   * History of transient ischemic attack within 12 months prior to the CD19 CAR T cells infusion
   * History of myocardial infarction within 36 months prior to the CD19 CAR T cells infusion
   * Symptomatic congestive heart failure (NYHA class III/IV), unstable angina pectoris, cardiac arrhythmia requiring therapy
   * Uncontrolled arrhythmias, or history of or active ventricular arrhythmia requiring medication
   * Active or history of coronary heart disease that remains symptomatic
   * Active or history of unstable or stable angina
   * Left ventricular ejection fraction (LVEF) \< 45% confirmed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) scan
4. Creatinine clearance \< 60
5. Concomitant genetic syndromes associated with Bone Marrow (BM) failure states, such as Fanconi anemia, Kostmann syndrome, Schwachman syndrome, or any other BM failure syndrome; patients with Down syndrome are not excluded
6. Burkitt lymphoma/leukemia
7. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and no evidence of active disease
8. Treatment with any prior gene therapy product (except prior CAR-T cell therapy)
9. Positive HIV test within 8 weeks of screening
10. Serologic status reflecting active hepatitis B or C infection: Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.)
11. Received an investigational medicinal product on trial within the 30 days prior to screening
12. Pregnant
13. Lactating
14. Women of child-bearing potential and all male participants, unless using highly effective methods of contraception for 1 year after CAR-T infusion
15. Therapeutic systemic doses of steroids (\>=0.5mg/kg prednisone equivalent) must be stopped \>72 hours prior to lymphodepletion
16. TKIs and hydroxyurea must be stopped \>72 hours prior to lymphodepletion
17. The following drugs must be stopped \>1 week prior to lymphodepleting chemotherapy:

    vincristine, 6- mercaptopurine, 6-thioguanine, methotrexate 2 weeks prior to CART infusion: salvage chemotherapy (e.g., clofarabine, cytosine arabinoside \>100 mg/m2

    , anthracyclines, cyclophosphamide, methotrexate ≥25 mg/m2

    ), excluding the required lymphodepleting chemotherapy drugs
18. Pegylated asparaginase must be stopped \>4 weeks prior to CAR T cell infusion
19. CNS disease prophylaxis and/or intrathecal chemotherapy must be stopped \>1 week prior to CAR T cell infusion
20. Radiation therapy at non-CNS site must be completed \>2 weeks prior to CAR T Cell infusion
21. CNS-directed radiation must be completed \>8 weeks prior to CAR T cell infusion
22. Known History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study (including, but not limited to, cyclophosphamide and fludarabine used in the lymphodepleting chemotherapy, DMSO used as a cryoprotectant in the cell media, etc.)
23. Autologous transplant within 6 weeks of planned CAR-T cell infusion
24. Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy.
25. Primary Immunodeficiency Patients:

    • Patients with known primary immunodeficiency disorders are excluded due to increased risk of adverse outcomes.
26. Recent Live Vaccine Administration:

    * Patients who have received a live vaccine within 4 weeks prior to enrolment are excluded.
    * Additionally, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy

Where this trial is running

Riyadh, Riyadh Region

• King Faisal Specialist Hospital and Research Center — Riyadh, Riyadh Region, Saudi Arabia (Recruiting)

Study contacts

• Study coordinator: Riad El Fakih

Conditions Relapsed Refractory Acute Lymphoblastic Leukemia; CD19 CAR T; relapsed/refractory acute lymphoblastic leukemia.