Phase 1 Study of Lintivirally Transduced T Cells Engineered to Contain Anti-CD38 Linked to TCRζ and 4-1BB Signaling Domains in Subjects With Acute Myeloid Leukemia and Multiple Myeloma CART 38

What's the purpose of this trial?

This is an open-label Phase 1 study to estimate the safety and manufacturing feasibility of lentivirally transduced T cells expressing anti-CD38 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in patients with Acute Myeloid Leukemia and Multiple Myeloma. This CAR T cell product will be referred to as "CART-38 cells".

This trial is currently open and accepting patients.

What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

Inclusion Criteria:

1. Male or female patients age ≥ 18 years.
2. Patients must have one of the following diagnoses:s:

a. Cohort A: Acute Myeloid Leukemia (AML) which meets one of the following criteria: i. Patients with second or greater relapse defined as flow cytometric confirmation of myeloid leukemia of at least 0.1% after second documented complete remission; OR ii. Patients with detectable disease post-allogeneic transplant with flow cytometric confirmation (MRD) of myeloid leukemia of at least 0.1%; OR iii. Patients with 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 complete remission.

b. Cohort B: Relapsed/refractory multiple myeloma (MM) according to IMWG 2016 criteria99 which meets the following conditions: i. Relapsed/refractory disease after receiving ≥ 3 lines of therapy, to ensure the patient has been exposed to ≥ 1 IMiD®, ≥ 1 proteasome inhibitor, and daratumumab; where refractory MM is defined as the achievement of less than a partial response (\< PR after ≥ 2 cycles) and relapsed MM requires patients be ≤ 12 months from the last dose of their prior treatment regimen to confirmation of relapse) ii. Patients must also have measurable disease as defined by one of the following:

1. Serum M-protein ≥ 0.5 g/dL; 2. Urine M-protein ≥ 200 mg/24 hours; 3. Serum free light chain (FLC) assay; involved FLC level ≥ 100 mg/L provided the serum FLC ratio is abnormal; 4. ≥ 30% clonal plasma cells in the bone marrow aspirate or biopsy sample; 5. Measurable plasmacytomas \> 2 cm in cross sectional diameter.

3. AML only: Documentation of CD38 Expression on leukemic blasts by flow or by immunohistochemistry (IHC). Results must be confirmed after last documented relapse and after any CD38-directed therapy (if applicable).

4. Confirmed availability of cells for a rescue transplant as a therapeutic back-up option as follows:

1. Cohort A (AML): Patients must have a suitable stem cell donor available who may donate cells in the event the subject needs to undergo an allogeneic HSCT. Donor may be matched or mismatched and must be found to be suitable according to the institution's standard criteria; donors must be fully cleared to proceed as the donor.
2. Cohort B (MM): Previously harvested autologous stem cells \> 2x106/kg CD34+ cells.

5. Patients must be \> 3 months from prior autologous transplant and \> 6 months from alloASCT. Patients with detectable disease after prior allogeneic SCT must not have active GVHD or have ongoing immunosuppression requirements.

6. Adequate organ function defined as:

a. Creatinine ≤ 2.5 mg/dl or Creatinine Clearance \> 30ml/min b. ALT/AST ≤ 5x upper limit of normal range c. Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0 mg/dl) d. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen \> 92% on room air e. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA

7. ECOG Performance Status that is either 0 or 1. 8. Signed informed consent form 9. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

1. Active hepatitis B or active hepatitis C
2. Any active, uncontrolled infection
3. Severe, active co-morbidity that in the opinion of the physician-investigator would preclude participation in this study.
4. Class III/IV cardiovascular disability according to the New York Heart Association Classification
5. Patients with known somatic JAK2 V617F mutation by PCR or next generation sequencing.
6. Active acute or chronic GVHD requiring systemic therapy.
7. Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
8. Active CNS disease. Patients with a history of CNS involvement that was successfully treated are eligible. Additional CNS testing such as a lumbar puncture and/or brain imaging is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
9. Pregnant or nursing (lactating) women.
10. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, and unrelated to their cancer or previous cancer treatment.
11. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
12. Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).

Additional Trial Information

Phase 1

Enrollment: 36 patients (estimated)

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