CAR T-cell therapy targeting CD4 for patients with relapsed AML

Chimeric Antigen Receptor T Cell Redirected to Target CD4 Positive Relapsed Refractory AML as a Bridge to Allogeneic Stem Cell Transplant

This study is testing a new type of CAR T-cell therapy for patients with relapsed acute myeloid leukemia to see if it can help get rid of their cancer and prepare them for a stem cell transplant.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 12 Years and up
• Sex: All
• Sponsor: Indiana University (Academic / other)
• Drugs / interventions: chemotherapy, Prednisone, chimeric antigen receptor
• Locations: 4 sites (Miami, Florida and 3 other locations)
• Trial ID: NCT06197672 on ClinicalTrials.gov

What this trial studies

This Phase 1 clinical trial evaluates the safety and efficacy of CD4-redirected chimeric antigen receptor (CAR) T-cells in patients with relapsed or refractory acute myeloid leukemia (AML). The study follows a dose-escalation protocol and aims to recruit 20 subjects at Indiana University, expecting to treat around 15 patients after accounting for dropouts. Participants will undergo leukapheresis to obtain peripheral blood mononuclear cells, followed by conditioning chemotherapy, and then receive an infusion of engineered CD4CAR T-cells if their tumor burden is sufficiently reduced. The primary goal is to assess the elimination of residual disease to qualify patients for subsequent stem cell transplant.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 12 and older with CD4+ acute myeloid leukemia who have failed standard first-line treatments.

Not a fit: Patients who have not been diagnosed with CD4+ AML or those who are not refractory to standard treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could provide a new treatment option for patients with relapsed or refractory AML, potentially leading to better outcomes and eligibility for stem cell transplantation.

How similar studies have performed: While CAR T-cell therapies have shown promise in other hematological malignancies, this specific approach targeting CD4 in AML is novel and has not been extensively tested.

Eligibility criteria

Inclusion Criteria:

1. ≥ 12 years old at the time of informed consent
2. Ability to provide written informed consent and HIPAA authorization.
3. Diagnosis of AML that is CD4+ and must have failed standard induction/ first line treatment such as intensive induction or less intensive hypomethylation and venetoclax first line. In the specific case of azacitidine and venetoclax (aza/ven), BM biopsy for response assessment on days 21-28 of first cycle. If disease progression by increasing number of blasts is documented, patient will be eligible. If no morphologic remission (persistent BM blasts above 5%) but evidence of efficacy exists, a second cycle without interruption will be given with the goal of achieving morphologic remission and repeat BM biopsy on days 21-28 of this cycle. If residual disease or disease progression is captured, then they will be considered refractory and will qualify for this trial. This is unless the patient now qualifies for a more intensive induction therapy that they did not qualify for when aza/ven was initially chosen as first-line treatment. Given the low response rate for aza/ven in the RR-AML, CR of only 13%, this combination would not be a prerequisite to qualify for the study.
4. If these patients who fail first line treatment have an FDA approved treatment options available (including targeted and non-targeted treatment) for a second line treatment, they do not qualify for the trial until they also are deemed nonresponsive to those. If an approved second line is not available, patients will be eligible after first line failure.
5. Creatinine clearance of \> 60ml/min (or otherwise non clinically significant, per study investigator)
6. alanine aminotransferase/ aspartate aminotransferase ALT/AST \< 3 x ULN
7. Bilirubin \< 2 x ULN (UPPER LIMIT OF NORMAL)
8. Pulmonary Function Test (PFT) with a DIFFUSE LUNG CAPACITY , DLCO, of ≥ 60% (if not completed within 6 months from Day 0)
9. Adequate echocardiogram with EJECTION FRACTION, EF, of ≥50%
10. Adequate venous access for apheresis and no other contraindications for leukapheresis
11. Confirmation of a bone marrow donor for post CD4CAR transplant to proceed to transplant if eligible post treatment.

Exclusion Criteria:

1. CD4 negative AML
2. Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential (see definition below) must have a negative serum or urine pregnancy test prior to initiation of conditioning chemotherapy, per research sites' clinical policy.
3. Uncontrolled active infection necessitating systemic therapy.
4. Active hepatitis B hb, or hepatitis C, HC, infection. Active hepatitis C is defined as the hepatitis C antibody is positive while quantitative HCV RNA results exceed the lower detection limit.

   Note the following subjects will be eligible:
   * Subjects with a history of hepatitis B but have received antiviral therapy and have non-detectable viral DNA for 6 months prior to enrollment are eligible.
   * Subjects seropositive for HBS antibodies due to hepatitis B virus vaccine with no signs or active infection (Negative HBs Ag, HBc and HBe Ags) are eligible.
   * Subjects who had hepatitis C but have received antiviral therapy and show no detectable hepatitis C virus (HCV) viral RNA for 6 months are eligible.
   * If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
5. Concurrent use of systemic glucocorticoids in greater than replacement doses or steroid dependency defined in rheumatological and pulmonary diseases as uninterrupted corticosteroid intake for more than a year at a dosage of 0.3 mg/kg/day or greater, and where the underlying disease worsens on temporary stoppage of steroid therapy, with symptoms of steroids withdrawal (eg, lethargy, headache, weakness, pseudo rheumatism, emotional disturbances, etc) precipitated by the temporary stoppage unless tapering can occur safely without compromising the underlying disease, the withdrawal tolerance and can happen in a timeframe appropriate to enroll in this trial without safety concerns

   Subjects who receive daily corticosteroids in replacement doses can be included in the study. The replacement doses are defined as following:
   1. Hydrocortisone 25mg/day or less
   2. Prednisone 10mg/day or less
   3. Dexamethasone 4mg or less Note: Recent or current use of inhaled glucocorticoids is not exclusionary, as this route pertains extremely minimal systemic penetration
6. Any previous treatment with any gene therapy products
7. Any uncontrolled active medical disorder that would preclude participation as outlined in the opinion of the treating investigator and/or Principal Investigator
8. HIV infection
9. Subjects who have received or will receive live vaccines within 30 days before the first experimental cell treatment. Inactivated seasonal flu vaccination is allowed.
10. Subjects with active autoimmune diseases who need systematic treatments (such as disease modifying agents, corticosteroids, and immunosuppressive drugs) during the last year.

    Note: Replacement therapy (thyroxine, insulin, or physiological corticosteroid replacement therapy (up to10 mg of oral daily prednisone or equivalent in hydrocortisone and dexamethasone) to treat adrenal dysfunction or pituitary dysfunction) is not considered as systematic therapy. Subjects who need inhalation corticosteroid therapy can be included in this trial. Subjects with vitiligo or in long-term remission of pediatric asthma or allergic diseases can be included in this trial.
11. Subjects with a history of mental disorders or drug abuse that may influence treatment compliance.
12. Active malignancy not related to AML that has required therapy in the last 3 years or is not in complete remission. Exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not require therapy. Other similar malignant conditions may be discussed with and permitted by the Principal Investigator.
13. Participation in another clinical study with an investigational product within the past 6 months provided patient was in fact given that experimental treatment, just being enrolled and treated is not a disqualifier.

Eligibility for Conditioning Chemotherapy:

1. Specific organ function criteria for cardiac, renal, and liver function must be similar to initial inclusion values.
2. Review of co-morbidities to confirm no major changes in health status (examples of major changes include heart attack, stroke, and any major trauma).
3. Planned infusion does was successfully manufactured and met release criteria.
4. Negative pregnancy testing (if applicable).

Eligibility for CD4CAR infusion:

1. Afebrile and not receiving antipyretics, and no evidence of active infection. If fever is attributed to underlying disease, it will not disqualify.
2. Specific organ function criteria for cardiac, renal, and liver function must be similar to initial inclusion values. The following tests do not need repeated: an echocardiogram if within 6 weeks of initial assessment, and the PFT if completed within 6 months from Day 0.
3. If previous history of corticosteroid chemotherapy, subject must be off all but adrenal replacement doses 3 days before the CD4CAR infusion.

Where this trial is running

Miami, Florida and 3 other locations

• University of Miami Sylvester Comprehensive Cancer Center — Miami, Florida, United States (Recruiting)
• Indiana University Melvin and Bren Simon Comprehensive Cancer Center — Indianapolis, Indiana, United States (Recruiting)
• Riley Hospital for Children — Indianapolis, Indiana, United States (Recruiting)
• The University of Texas MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Huda Salman, MD, PhD — Indiana University
• Study coordinator: Cristina Roach, RN

Conditions Acute Myeloid Leukemia; T Cell; Cell Therapy; CAR T; Chimeric Antigen Receptor Therapy