CAR T-Cell Therapy for Leukemia and Lymphoma

(SAGAN Trial)

Recruiting at 1 trial location

Overseen By Carlos Ramos, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Investigational agents, Tumor vaccines

Disqualifiers: Active infection, Other cancer, Pregnancy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 6 weeks

64 Participants Needed

Trial Summary

What is the purpose of this trial?

Subjects on this study have a type of lymph gland cancer called Non-Hodgkin Lymphoma, acute lymphocytic leukemia, or chronic Lymphocytic Leukemia (these diseases will be referred to as "lymphoma" or "leukemia"). The lymphoma or leukemia has come back or has not gone away after treatment. The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, hoping that they will work together. Both antibodies and T cells have been used to treat patients with cancer. They have shown promise, but have not been strong enough to cure most patients. T cells can kill tumor cells but normally there are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study is called anti-CD19. It first came from mice that have developed immunity to human lymphoma. This antibody sticks to lymphoma cells because of a substance on the outside of these cells called CD19. CD19 antibodies have been used to treat people with lymphoma and leukemia. For this study, anti-CD19 has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. In the laboratory, the investigators found that T cells work better if they also add proteins that stimulate T cells, such as one called CD28. Adding the CD28 makes the cells last longer in the body but not long enough for them to be able to kill the lymphoma cells. The investigators believe that if they add an extra stimulating protein, called CD137, the cells will have a better chance of killing the lymphoma cells. The investigators are going to see if this is true by putting the CD19 chimeric receptor with CD28 alone into half of the cells and the CD19 chimeric receptor with CD28 and CD137 into the other half of the cells. These CD19 chimeric receptor T cells with CD28 and with or without CD137 are investigational products not approved by the FDA. The purpose of this study is to find the biggest dose of chimeric T cells that is safe, to see how long the T cell with each sort of chimeric receptor lasts, to learn what the side effects are and to see whether this therapy might help people with lymphoma or leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does allow treatment with PD1/PDL1 inhibitors if medically indicated. It also excludes those currently receiving investigational agents or tumor vaccines within the previous 6 weeks.

What data supports the effectiveness of the treatment CD19.CAR/28 and CD19.CAR/28137 T cells for leukemia and lymphoma?

Research shows that CD19-targeted CAR T cells have been highly effective in treating B-cell acute lymphoblastic leukemia (B-ALL), achieving complete remission in up to 90% of patients who did not respond to chemotherapy. This suggests that the treatment could be a promising option for patients with similar types of leukemia and lymphoma. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for treating leukemia and lymphoma?

CAR T-cell therapy for leukemia and lymphoma has shown some side effects, such as cytokine release syndrome (CRS) and neurotoxicity, but these are generally manageable with proper care. Studies have reported that the treatment is well-tolerated, with no serious adverse events directly linked to the therapy, and side effects can often be controlled with medications like tocilizumab and steroids. ^{1 6 7 8 9}

How is CAR T-cell therapy for leukemia and lymphoma different from other treatments?

CAR T-cell therapy is unique because it uses the patient's own T-cells, which are modified to specifically target and attack cancer cells expressing the CD19 protein, offering a promising option for patients with chemotherapy-resistant leukemia and lymphoma. This approach has shown high success rates in inducing remission, especially in cases where traditional treatments have failed. ^{3 5 9 10 11}

Research Team

Carlos Ramos, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for people up to 75 years old with certain types of blood cancers like B-cell lymphoma, ALL, or CLL that have come back or didn't respond to treatment. They should be fit enough for the study and not have infections needing antibiotics, HIV/HTLV, or a history of severe reactions to mouse proteins.

Inclusion Criteria

TREATMENT: Bilirubin less than 3 times the upper limit of normal.

TREATMENT: AST less than 5 times the upper limit of normal.

PROCUREMENT: Hgb greater than or equal to 7.0 (can be a transfused value).

Exclusion Criteria

TREATMENT: History of hypersensitivity reactions to murine protein-containing products.

I am currently on antibiotics for an active infection.

I have no cancer history, except for certain skin, breast, or cervix cancers treated over 2 years ago.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an infusion of CD19 CAR T Cells, with potential pre-treatment using cyclophosphamide and fludarabine if necessary

6 weeks

1 visit (in-person) for infusion, followed by monitoring

Evaluation

6-week evaluation period to assess treatment benefit, with potential for additional doses if beneficial

6 weeks

1 visit (in-person) for evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment, with long-term follow-up for gene transfer side effects

15 years

Treatment Details

Interventions

• CD19.CAR/28 and CD19.CAR/28137 T cells
• Cyclophosphamide
• Fludarabine

Trial Overview The trial tests two modified T-cell therapies against aggressive blood cancers. One therapy includes CD19.CAR/28 T cells; the other adds CD137 to enhance effectiveness. The goal is to find the safest high dose, understand side effects, and see if these therapies can help patients.

Participant Groups

Group I: Dose Expansion: CD19 CAR T Cells for B-cell NHL/CLL Experimental Treatment 1 Intervention

Each patient will receive the maximum tolerated dose (MTD) of CD19 CAR T Cells administered as an infusion. Each infusion will consist of CD19.CAR/28 T cells and CD19.CAR/28137 T cells.

Group II: Dose Expansion: CD19 CAR T Cells for B-cell ALL Experimental Treatment 1 Intervention

Each patient will receive the maximum tolerated dose (MTD) of CD19 CAR T Cells administered as an infusion. Each infusion will consist of CD19.CAR/28 T cells and CD19.CAR/28137 T cells.

Group III: Dose Escalation: CD19 CAR T Cells for B-cell NHL/CLL Experimental Treatment 1 Intervention

Each patient will receive a dose of CD19 CAR T Cells administered as an infusion. Each infusion will consist of CD19.CAR/28 T cells and CD19.CAR/28137 T cells.

Group IV: Dose Escalation: CD19 CAR T Cells for B-cell ALL Experimental Treatment 1 Intervention

Each patient will receive a dose of CD19 CAR T Cells administered as an infusion. Each infusion will consist of CD19.CAR/28 T cells and CD19.CAR/28137 T cells.

CD19.CAR/28 and CD19.CAR/28137 T cells is already approved in United States for the following indications:

Approved in United States as CD19.CAR/28 T cells for:

• Non-Hodgkin Lymphoma
• Acute Lymphocytic Leukemia
• Chronic Lymphocytic Leukemia

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Findings from Research

CD37CAR T cells have shown comparable efficacy to CD19CAR T cells in controlling tumor growth in both in vitro and in vivo models, making them a promising alternative for treating B-cell lymphomas.

Unlike CD19CAR T cells, CD37CAR T cells effectively target tumors that have lost CD19 expression, demonstrating their potential to overcome resistance in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma. Köksal, H., Dillard, P., Josefsson, SE., et al.[2020]

In a study involving five adults with relapsed B cell acute lymphoblastic leukemia (B-ALL), treatment with autologous T cells modified to express a CD19-specific CAR (19-28z) led to rapid tumor eradication and complete remissions without minimal residual disease (MRD), indicating strong efficacy of this therapy.

The treatment was generally well tolerated, although patients with higher tumor burdens experienced significant cytokine elevations, which required management with steroids, highlighting the need for monitoring and potential intervention during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Brentjens, RJ., Davila, ML., Riviere, I., et al.[2023]

CAR T-cells are engineered T-cells that target the CD19 antigen, showing promising initial results in treating various B-cell malignancies, including acute lymphocytic leukaemia and chronic lymphocytic leukaemia.

While the treatment shows potential, there are significant differences in patient responses and notable side effects that require careful management, highlighting the need for personalized approaches in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. Heijink, DM., Kater, AP., Hazenberg, MD., et al.[2017]

CD19 is a highly effective target for CAR T-cell therapies, showing significant responses in patients with relapsed B-cell malignancies, particularly chronic lymphocytic leukemia and acute lymphoblastic leukemia.

While treatment with CD19-CAR T cells can lead to severe systemic inflammatory reactions, these are generally reversible with proper medical care, highlighting the importance of monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-CAR trials. Ramos, CA., Savoldo, B., Dotti, G.[2022]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving complete remission in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), compared to a 30% response rate with traditional chemotherapy.

The therapy involves genetically modifying T cells to express a chimeric antigen receptor, allowing them to effectively target and eliminate cancer cells, although it is important to note that there are unique toxicities associated with this treatment that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Davila, ML., Brentjens, RJ.[2023]

Adoptive cellular therapy using CD19 CAR T cells has shown remarkable efficacy in achieving remission in 67-90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), indicating a promising treatment option for this high-risk group.

While CD19 CAR T-cell therapy can lead to significant toxicities such as cytokine release syndrome and neurologic dysfunction, these effects are generally manageable with supportive care, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Tasian, SK., Gardner, RA.[2020]

In a phase 1 clinical trial involving 14 patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), the novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy demonstrated a strong safety profile, with no serious adverse events directly linked to the treatment and only mild cytokine release syndrome observed.

Efficacy results showed that 38% of patients with ALL achieved complete remission or incomplete count recovery, and 50% of patients with diffuse large B-cell lymphoma (DLBCL) also achieved complete remission, indicating promising antitumor activity of the SB-based CAR constructs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. Singh, H., Srour, SA., Milton, DR., et al.[2023]

CD19CAR-T cell therapy is effective in treating relapsed and refractory B-lineage acute lymphoblastic leukemia, with four out of five patients achieving complete remission and minimal residual disease negativity.

The therapy can be safely administered with real-time monitoring of a 6-cytokine pattern, allowing for effective management of side effects like cytokine release syndrome and neurotoxicity using tocilizumab and steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children. Shen, D., Song, H., Xu, X., et al.[2021]

Adoptive cellular therapy using CAR-modified T cells targeting CD19 has shown significant clinical efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in both children and adults, with some patients also benefiting from treatment for chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).

Current research is expanding the use of CAR T-cell therapies to other cancers, including multiple myeloma and solid tumors, while also addressing challenges such as severe cytokine release syndrome and neurologic toxicities associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Geyer, MB., Brentjens, RJ.[2022]

Anti-CD19 CAR T-cell therapy has shown remarkable efficacy in treating relapsed or refractory aggressive B-cell lymphomas, leading to durable remissions in patients who previously had no effective treatment options.

Three CAR T-cell therapies (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) are approved for use, each differing in their design, manufacturing processes, and safety profiles, highlighting the need for personalized approaches in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Abramson, JS.[2021]

The study found that high levels of leukemia blast contamination in the starting material did not negatively impact the manufacturing of CAR T-cells or their ability to expand, suggesting that CAR T-cell therapy can be safely produced even from contaminated samples.

Using a specific CAR design with a short linker (CAR.CD19 SL) enhances the ability of CAR T-cells to target and kill CD19+ leukemia cells, providing a potential safety advantage in preventing leukemic relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. Quintarelli, C., Guercio, M., Manni, S., et al.[2022]

References

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

Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma. [2020]

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

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. [2017]

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

CD19-CAR trials. [2022]

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

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]

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

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. [2023]

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

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children. [2021]

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

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]

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

Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. [2022]