Using modified T cells to treat pediatric acute myeloid leukemia

Phase 1 Study of Lentivirally Transduced T Cells Engineered to Contain Anti-CD123 Linked to TCRζ and 4-1BB Signaling Domains in Pediatric Subjects With Refractory or Relapsed Acute Myeloid Leukemia

This study is testing a new type of immune cell treatment for children with hard-to-treat leukemia to see if it is safe and effective.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: 1 Year to 29 Years
• Sex: All
• Sponsor: University of Pennsylvania (Academic / other)
• Drugs / interventions: CAR T, chemotherapy
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT04678336 on ClinicalTrials.gov

What this trial studies

This Phase 1 open-label study evaluates the safety and preliminary efficacy of CART123 cells, which are lentivirally transduced T cells expressing anti-CD123 chimeric antigen receptors, in pediatric patients with relapsed or refractory Acute Myeloid Leukemia (AML). The study employs a 3+3 dose escalation design to determine the maximum tolerated dose of CART123 cells, starting from an initial dose of 2x10^6 cells/kg. The trial aims to assess the feasibility of this innovative treatment approach in a vulnerable patient population.

Who should consider this trial

Good fit: Ideal candidates are pediatric patients aged 1 to 29 years with relapsed or refractory acute myeloid leukemia.

Not a fit: Patients with early-stage AML or those who do not meet the specific eligibility criteria 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 forms of acute myeloid leukemia.

How similar studies have performed: Other studies using CAR T-cell therapies have shown promising results in similar patient populations, indicating potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

1. Male and female patients ≥ 1 and ≤ 29 years of age at time of consent.
2. AML in second or greater relapse, post-transplant relapse, or chemotherapy-refractory disease. Specifically:

   1. Second or greater relapse defined as flow cytometric confirmation of myeloid leukemia of at least 0.1% after second documented complete remission; OR
   2. Any detectable disease post-allogeneic transplant with flow cytometric confirmation (MRD) of myeloid leukemia of at least 0.1% (as confirmed by Hematologics); OR
   3. Refractory disease, defined as persistent bone marrow involvement with \>5% blasts after two courses of induction chemotherapy for patients at initial presentation or \>5% bone marrow blasts after one course of re-induction chemotherapy for patients who have relapsed after previously achieving a CR.
3. Subjects must have a suitable stem cell donor identified with projected ability to proceed to transplant within 6-8 weeks of CART123 infusion.
4. Adequate organ function defined as:

   1. A serum creatinine based on age/gender
   2. Adequate liver function

   i. ALT ≤ 5 x ULN

   ii. Total bilirubin ≤ 3 x ULN

   iii. ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to AML infiltration of the liver.

   c. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and \< Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator

   d. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO, or adequate ventricular function documented by a scan or a cardiologist. In cases where quantitative assessment of LVSF/LVEF is not possible, a statement by the cardiologist that the ECHO shows qualitatively normal ventricular function will suffice.
5. Adequate performance status defined as Lansky or Karnofsky score ≥ 50
6. Signed informed consent must be obtained.
7. No contraindications for leukapheresis (unless apheresis product previously acquired).
8. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

1. Pregnant or lactating (nursing) women.
2. Patients with relapsed AML with t(15:17).
3. Patients \< 6 months from alloHSCT.
4. HIV infection.
5. Active hepatitis B or hepatitis C infection.
6. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy
7. Patients requiring chronic treatment with systemic steroids or immunosuppressant medications. Low-dose physiologic replacement therapy with corticosteroids, topical steroids and inhaled steroids are acceptable. For additional details regarding use of steroids and immunosuppressant medications (including washout requirements prior to CAR T cell administration).
8. Any uncontrolled active medical disorder that would preclude participation as outlined.
9. Uncontrolled active infection
10. Subjects with CNS3 disease that is progressive on therapy or with CNS parenchymal lesions that may increase the risk of CNS toxicity. Subjects with adequately treated CNS leukemia are eligible.
11. Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
12. Patients with any prior history of myeloproliferative neoplasm.
13. Patients with somatic JAK2 V617F mutation by PCR or next generation sequencing.

Where this trial is running

Philadelphia, Pennsylvania

• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Study coordinator: Shamar Durham

Conditions Acute Myeloid Leukemia, in Relapse; Acute Myeloid Leukemia, Pediatric; Acute Myeloid Leukemia, Refractory; refractory; relapsed; Acute; Myeloid; leukemia