CART-38 for Acute Myeloid Leukemia and Multiple Myeloma

Overseen By Abramson Cancer Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Hepatitis B, Hepatitis C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

36 Participants Needed

Trial Summary

What is 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".

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic steroids or immunosuppressant medications, you may not be eligible to participate.

What data supports the effectiveness of the treatment CART-38 for Acute Myeloid Leukemia and Multiple Myeloma?

Research shows that CART-38 cells, which are engineered T cells targeting the CD38 molecule, have been effective in killing cancer cells in both acute myeloid leukemia and multiple myeloma in preclinical studies. These studies demonstrated that CART-38 cells could reduce tumor size and prolong survival in animal models, indicating potential effectiveness for these conditions. ^{1 2 3 4 5}

Is CART-38 therapy safe for humans?

CART-38 therapy has shown potential in treating certain blood cancers, but it may cause a reduction in blood-forming cells, which requires careful monitoring. In preclinical studies, CART-38 cells were controllable with a safety switch, suggesting a way to manage potential side effects. ^{1 2 6 7 8}

How is the CART-38 treatment different from other treatments for acute myeloid leukemia and multiple myeloma?

CART-38 is a unique treatment because it uses genetically engineered T cells to specifically target the CD38 protein found on cancer cells in acute myeloid leukemia and multiple myeloma, offering a novel approach compared to traditional chemotherapy. This therapy is designed to attack cancer cells more precisely, potentially leading to better outcomes for patients with these conditions. ^{1 2 3 9 10}

Eligibility Criteria

Adults over 18 with Acute Myeloid Leukemia or Multiple Myeloma, who have a backup option for cell transplant and good organ function. They must not be dependent on steroids, pregnant, or have certain heart issues, active infections, CNS diseases, GVHD requiring therapy, autoimmune diseases needing high-dose steroids, or known allergies to the study product components.

Inclusion Criteria

Subjects of reproductive potential must agree to use acceptable birth control methods

My leukemia cells show CD38 expression.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Severe, active co-morbidity that in the opinion of the physician-investigator would preclude participation in this study

I am allergic to some ingredients in the study medication.

I do not have any ongoing, untreated infections.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single fixed dose of CART-38 cells via intravenous infusion following lymphodepleting chemotherapy

1 day

1 visit (in-person)

Dose Limiting Toxicity (DLT) Evaluation

Formal DLT evaluations are performed after the 3rd subject in each disease cohort/dose level reaches the Day 28 safety follow-up visit

28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CART-38

Trial Overview The trial is testing CART-38 cells in patients with AML and MM. These are T cells modified to target CD38 cancer markers using a new method. Different doses of these cells will be given after chemotherapy drugs Cyclophosphamide and Fludarabine to evaluate safety and production feasibility.

Participant Groups

Group I: Cohort B Dose Level 3: Multiple Myeloma (MM) Experimental Treatment 3 Interventions

Cohort B Dose Level 3 - Adult patients ages ≥ 18 with Multiple Myeloma (MM) who have not achieved remission after at least two lines of prior therapy will receive a single fixed dose of 3x10(7) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group II: Cohort B Dose Level 2: Multiple Myeloma (MM) Experimental Treatment 3 Interventions

Cohort B Dose Level 2 - Adult patients ages ≥ 18 with Multiple Myeloma (MM) who have not achieved remission after at least two lines of prior therapy will receive a single fixed dose of 7x10(6) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group III: Cohort B Dose Level 1: Multiple Myeloma (MM) Experimental Treatment 3 Interventions

Cohort B Dose Level 1 - Adult patients ages ≥ 18 with Multiple Myeloma (MM) who have not achieved remission after at least two lines of prior therapy will receive a single fixed dose of 3x10(6) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group IV: Cohort B Dose Level -1: Multiple Myeloma (MM) Experimental Treatment 3 Interventions

Cohort B Dose Level -1 - Adult patients ages ≥ 18 with Multiple Myeloma (MM) who have not achieved remission after at least two lines of prior therapy will receive a single fixed dose of 7x10(5) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group V: Cohort A Dose Level 3 :Relapsed/Refractory Acute Myeloid Leukemia (AML) Experimental Treatment 3 Interventions

Cohort A Dose Level 3: Adult patients ages ≥ 18 with acute myeloid leukemia (AML) will receive a single fixed dose of 3x10(7) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group VI: Cohort A Dose Level 2 :Relapsed/Refractory Acute Myeloid Leukemia (AML) Experimental Treatment 3 Interventions

Cohort A Dose Level 2: Adult patients ages ≥ 18 with acute myeloid leukemia (AML) will receive a single fixed dose of 7x10(6) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group VII: Cohort A Dose Level 1: Relapsed/Refractory Acute Myeloid Leukemia (AML) Experimental Treatment 3 Interventions

Cohort A Dose Level 1: Adult patients ages ≥ 18 with acute myeloid leukemia (AML) who have not achieved remission after at least two lines of prior therapy will receive a single fixed dose of 3x10(6) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Group VIII: Cohort A Dose Level -1 :Relapsed/Refractory Acute Myeloid Leukemia (AML) Experimental Treatment 3 Interventions

Cohort A Dose Level -1: Adult patients ages ≥ 18 with acute myeloid leukemia (AML) will receive a single fixed dose of 7x10(5) CART 38 Cells via intravenous infusion on Day 0, following lymphodepleting chemotherapy with cyclophosphamide or fludarabine based on physician discretion.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

CART-38, a novel CAR T-cell therapy targeting CD38, effectively rejected multiple hematologic malignancies, including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), and multiple myeloma (MM) in xenografted mice, demonstrating its potential efficacy across different age groups.

While CART-38 showed promising results in treating these cancers, it also reduced hematopoietic progenitors in a model of normal human blood cell development, indicating a need for careful monitoring of potential toxicity in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD38 as a pan-hematologic target for chimeric antigen receptor T cells. Glisovic-Aplenc, T., Diorio, C., Chukinas, JA., et al.[2023]

CD38-chimeric antigen receptor-transduced T cells showed strong anti-tumor effects against multiple myeloma and acute myeloid leukemia, effectively killing cancer cells in a dose-dependent manner, indicating their potential as a targeted cancer therapy.

While these engineered T cells can also attack some healthy CD38-positive cells, they do not prevent the growth of hematopoietic progenitor cells, and their activity can be controlled using a suicide gene, suggesting a safety mechanism for managing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Drent, E., Groen, RW., Noort, WA., et al.[2018]

Chimeric antigen receptor (CAR) T-cell therapy has shown significant efficacy in treating refractory leukemia, particularly with CD19-targeting CAR-T cells leading to sustained responses in patients with relapsed acute lymphoblastic leukemia.

Recent advancements in CAR-T cell design, including improved intracellular activating domains and viral vector transduction, have enhanced the effectiveness of these therapies and expanded the range of potential leukemic antigens for targeting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T therapy for leukemia: progress and challenges. Wang, X., Xiao, Q., Wang, Z., et al.[2018]

CAR T-cell therapy shows promise in improving outcomes for patients with acute myeloid leukemia (AML), a condition with historically poor prognosis.

A significant challenge for the effectiveness of CAR T-cell therapy in AML is the identification of specific target antigens on leukemia cells, as well as the risk of immune escape due to changes in these antigens and a suppressive tumor environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. Sauer, T., Rooney, CM.[2020]

Chimeric antigen receptor (CAR)-T cell therapy is a cutting-edge treatment that uses genetically engineered T cells to target and attack tumors more effectively, particularly in patients with blood cancers like acute lymphoblastic leukemia and multiple myeloma.

The paper details the structure and mechanism of action of CAR-T cells, highlighting their potential to improve treatment outcomes and reduce the risk of relapse compared to traditional chemotherapy and immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Application of CAR-T Cells in Haematological Malignancies. Skorka, K., Ostapinska, K., Malesa, A., et al.[2023]

CART33, a chimeric antigen receptor T cell therapy targeting CD33, showed significant effectiveness in eradicating acute myeloid leukemia (AML) in preclinical models, leading to prolonged survival.

To reduce the risk of long-term toxicity associated with permanent CART cell expression, a transiently expressed mRNA anti-CD33 CAR was developed, demonstrating potent but self-limited activity against AML, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Kenderian, SS., Ruella, M., Shestova, O., et al.[2022]

In a study of 145 adult patients undergoing anti-CD19 CAR T cell therapy, 31 patients experienced major cardiovascular events (MACE) within a median of 11 days post-infusion, highlighting a significant risk of cardiovascular complications associated with this treatment.

The analysis identified that higher baseline creatinine levels and severe cytokine release syndrome (Grade 3 or 4) were independently linked to an increased risk of MACE, suggesting the need for careful cardiovascular monitoring in patients receiving CART19 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. Lefebvre, B., Kang, Y., Smith, AM., et al.[2022]

In a phase-1/2 trial involving 13 adult patients with refractory acute lymphoblastic leukemia, third-generation CAR T cells (CARTs) demonstrated promising efficacy, with 80% of evaluable patients achieving complete remission, including 50% with no detectable residual disease.

The treatment was associated with remarkably low toxicity, as none of the patients experienced severe side effects like neurotoxicity or high-grade cytokine release syndrome, indicating a favorable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. Schubert, ML., Schmitt, A., Hückelhoven-Krauss, A., et al.[2023]

In a phase 1 study involving 57 patients with relapsed/refractory multiple myeloma, LCAR-B38M CAR T cell therapy showed an impressive overall response rate of 88%, with 68% of patients achieving a complete response.

While the therapy had a manageable safety profile, with common adverse events including leukopenia and cytokine release syndrome, it demonstrated durable responses with a median progression-free survival of 15 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. Zhao, WH., Liu, J., Wang, BY., et al.[2020]

The newly developed CD38-CAR-T cells, utilizing a nanobody targeting CD38, effectively proliferated and produced inflammatory cytokines, demonstrating strong potential for treating multiple myeloma by lysing CD38+ cancer cells.

In vivo studies showed that these CD38-CAR-T cells inhibited tumor growth in mice, indicating their efficacy as a promising therapeutic strategy for multiple myeloma with minimal off-target effects on healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Multiple Myeloma Activity of Nanobody-Based Anti-CD38 Chimeric Antigen Receptor T Cells. An, N., Hou, YN., Zhang, QX., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

CD38 as a pan-hematologic target for chimeric antigen receptor T cells. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

CAR-T therapy for leukemia: progress and challenges. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

The Application of CAR-T Cells in Haematological Malignancies. [2023]

6. England pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular Effects of CAR T Cell Therapy: A Retrospective Study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. [2023]

9. England pubmed.ncbi.nlm.nih.gov

A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. [2020]

10. United States pubmed.ncbi.nlm.nih.gov

Anti-Multiple Myeloma Activity of Nanobody-Based Anti-CD38 Chimeric Antigen Receptor T Cells. [2019]