CD33KO-HSPC Infusion Followed by CART-33 Infusion(s) for Refractory/Relapsed AML

Official title

Phase 1 Study of Lentivirally Transduced T Cells Engineered to Contain Anti-CD33 Linked to TCRζ And 4-1BB Signaling Domains In Combination With CD33KO-HSPC In Subjects With Refractory Or Relapsed Acute Myeloid Leukemia

Overview

The purpose of this study is to provide a new type of treatment for AML. This treatment combines a new type of stem cell transplant along with treatment using chimeric antigen receptor (CAR) T cells that have been engineered to recognize and attack your AML cells. The first treatment is a modified stem cell transplant, using blood-forming stem cells donated from a healthy donor. From the same donor, we will also make CAR T-cells, which are leukemia fighting cells, which will be given to the patient via an infusion into the vein after the transplanted stem cells have started to grow healthy blood cells. The modification of the stem cell transplant means that the healthy bone marrow cells will be "invisible" to the CAR T-cells that are trying to kill the leukemia cells.

Interventions

• Biological CD33KO-HSPC; CART33
  CD33KO-HSPC: Stem cell transplant (also known as bone marrow transplant) is a common treatment used for patients with blood cancers, but for this transplant we will first modify the cells, in order to make the CAR T-cell treatment safer for when the patient receives them later. The modification is a type of gene editing - this means changing the DNA of the cells, so that a protein that the bone marrow stem cells usually show on their surface is not shown any more. This makes the bone marrow cell

Primary outcome measures

• Manufacturing feasibility [Time frame: 1 month]
• Occurrence of dose-limiting toxicities related to CD33KO-HSPC [Time frame: 3 months]
• Occurrence of dose-limiting toxicities related to CART-33 [Time frame: 6 months]

Secondary outcome measures (5)

• Efficacy of CD33KO-HSPC [Time frame: 1 month]
• Efficacy of at least 1 dose of CART-33 [Time frame: 6 months]
• Overall Survival (OS) [Time frame: 6 months, 12 months]
• Progression free survival (PFS) [Time frame: 6 months, 12 months]
• Duration of Response (DOR) [Time frame: 15 years]

Eligibility criteria

Inclusion criteria

• Male or female 18 years of age or older
• Subjects with AML unlikely to be cured with currently available therapies

• AML that has not achieved a complete remission or morphologic leukemia free state by ELN criteria; partial remission or refractory disease (including primary refractory) are eligible; OR:
• AML relapsed following allogeneic stem cell transplantation (including MDS evolved to AML post-allogeneic stem cell transplantation). Note: morphologic relapse is not required; persistent/recurrent disease-associated molecular, phenotypic or cytogenetic abnormalities (measurable residual disease, MRD) at any time after allogeneic HCT is eligible; OR:
• Subjects with relapsed disease after prior transplant must be off systemic immunosuppression for at least 1 month at the time of enrollment.
• Subjects must have a suitable stem cell donor.
• Satisfactory organ function

• Creatinine clearance > 40 ml/min
• ALT/AST must be ≤ 5x upper limit of normal unless related to disease and < 20 x upper limit of normal if related to disease
• Direct bilirubin < 2.0 mg/dl, unless subject has Gilbert's syndrome (≤ 3.0 mg/dL)
• Left ventricular ejection fraction ≥ 40% as confirmed by echocardiogram or MUGA
• DLCO > 45% predicted
• ECOG performance status 0-1
• Written informed consent is given
• Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion criteria

• Pregnant or lactating (nursing) women
• Active hepatitis B or hepatitis C or HIV infection
• Concurrent use of systemic steroids or immunosuppressant medications
• Any uncontrolled active medical disorder that would preclude participation as outlined
• Subjects with signs or symptoms indicative of CNS involvement.
• Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
• Class III/IV cardiovascular disability according to New York Heart Association Classification
• Subjects with clinically apparent arrhythmia, or arrhythmias that are not stable on medical management, within 2 weeks of the screening/enrollment visit.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Pennsylvania — Philadelphia

Identifiers

NCT: NCT05945849 · IRB # 854325, UPCC # 26423

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗