CAR-T Therapy for Leukemia

Overseen By Kelly Hoye

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Corticosteroids, Investigational drugs

Disqualifiers: Pregnancy, Active HIV, HBV, HCV, 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: 8

Duration: 2-14 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for leukemia called iC9-CAR19 cells, a type of CAR-T therapy. The goal is to determine if combining antibodies (proteins that fight disease) and T cells (blood cells that kill infected or cancerous cells) can safely and effectively treat leukemia. Researchers have added a special "safety switch" to the treatment to help manage side effects. People with relapsed or hard-to-treat precursor B cell acute lymphoblastic leukemia (ALL) may be suitable candidates, especially if previous treatments have failed. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but certain drugs must be stopped before lymphodepleting chemotherapy, such as tyrosine kinase inhibitors and some chemotherapy drugs. Maintenance doses of specific chemotherapy drugs are allowed, and corticosteroids are permitted only under certain conditions.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using iC9-CAR19 cells to treat leukemia can be safe for adults. These cells include a special safety feature called iC9, which helps control unwanted effects. Early data indicate that while many patients have experienced side effects like nerve damage and a strong immune reaction, the iC9 feature can help manage these effects. This feature can temporarily deactivate the CAR-T cells if needed, reducing severe reactions. Studies suggest that these cells are generally well-tolerated when administered in the right amount. However, there remains a risk of mild to severe side effects, so close monitoring of patients is important. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for leukemia?

Unlike the standard chemotherapy and targeted therapies for leukemia, iC9-CAR19 cells represent a cutting-edge approach by using genetically engineered T cells to specifically target and destroy cancerous B cells. This treatment is unique because it incorporates a safety switch, the inducible caspase 9 (iC9), which can be activated to control and mitigate severe side effects, making it potentially safer than traditional CAR-T therapies. Researchers are excited because this approach not only offers precision targeting of leukemia cells but could also provide a safer alternative with its built-in safety mechanism, potentially improving outcomes for both adult and pediatric patients.

What evidence suggests that iC9-CAR19 cells might be an effective treatment for leukemia?

In this trial, participants will receive modified T cells known as iC9-CAR19 cells, which have shown promise in previous studies for treating leukemia. These cells contain a part of an antibody that attaches to leukemia cells, aiding in their detection and destruction. Some patients, however, have experienced side effects like cytokine release syndrome, where excessive signaling proteins cause severe symptoms. To manage this, researchers have added a safety switch called inducible caspase 9 (iC9) to the cells to help control these effects. Early results suggest that this treatment can be safe and effective, with the safety switch providing an extra layer of security. ^{2 3 4 5 6}

Who Is on the Research Team?

Natalie S. Grover

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for people aged 3-70 with relapsed/refractory B cell ALL, who've had some prior treatment. They must have a certain level of health and organ function, agree to contraception methods if applicable, and not be pregnant or breastfeeding. Those with severe infections or other active cancers aren't eligible.

Inclusion Criteria

I am mostly independent in my daily activities.

Written informed consent for procurement signed by subject or legal guardian of a pediatric subject and HIPAA authorization

I have Ph+ ALL and have not responded to at least 2 treatments, had a relapse after a stem cell transplant, or have minimal residual disease.

Exclusion Criteria

I haven't had any cancer except for skin cancer in the last 5 years.

My tumor is not located where it could block my airway if it grows.

My aggressive leukemia is worsening with over half of my white blood cells being cancerous.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Procurement

Peripheral blood is collected for cell procurement, and leukapheresis may be performed if necessary.

1-2 weeks

Up to 3 visits (in-person)

Lymphodepleting Regimen

Subjects receive a lymphodepleting regimen of fludarabine and cyclophosphamide.

1 week

4 visits (in-person)

Treatment

Administration of iC9-CAR19 T cells post lymphodepletion.

2-14 days

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

Weekly visits (in-person)

Long-term Follow-up

Subjects are followed for up to 15 years for RCR evaluation or until death.

15 years

What Are the Treatments Tested in This Trial?

Interventions

• iC9-CAR19 cells

Trial Overview The study tests autologous T cells modified with a CD19 antigen (iC9-CAR19 cells) to treat leukemia. It includes an 'off switch' to reduce side effects like cytokine release syndrome. The goal is to find the safest dose that works best against cancer.

How Is the Trial Designed?

Group I: iC9-CAR19 cells Experimental Treatment 4 Interventions

The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10\^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10\^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10\^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.

Group II: Expansion Cohort Second Administration of iC9-CAR19 cells Experimental Treatment 4 Interventions

After the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells. Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS, did not respond to the initial dose of the standard of care treatment will be enrolled in a sub-study of rimiducid.

iC9-CAR19 cells is already approved in United States for the following indications:

Approved in United States as iC9-CAR19 cells for:

• Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

Published Research Related to This Trial

Adoptive T-cell therapy shows promise for treating various cancers and infections, but safety concerns remain due to potential on-target and off-target toxicities, which can sometimes be fatal.

The inducible caspase 9 (iCasp9) safety switch offers a solution by allowing for the rapid elimination of modified T cells if adverse effects occur, enhancing the safety of T-cell therapies, especially in cases like graft-versus-host disease in stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive T-cell therapy: adverse events and safety switches. Tey, SK.[2022]

In a study of 59 children receiving CAR-T therapy for B-cell acute lymphoblastic leukemia, 40.7% required admission to the Pediatric Intensive Care Unit (PICU), primarily due to cytokine release syndrome (CRS), indicating that while CAR-T is effective, it can lead to serious side effects that need intensive monitoring.

Despite the high rate of PICU admissions and associated complications, including severe neurotoxicity in some patients, supportive treatments like tocilizumab were effective in managing these toxicities, resulting in a high survival rate among the patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors and outcome of Chimeric Antigen Receptor T-Cell patients admitted to Pediatric Intensive Care Unit: CART-PICU study. Caballero-Bellón, M., Alonso-Saladrigues, A., Bobillo-Perez, S., et al.[2023]

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]

CAR T cell therapy, which modifies T cells to target the CD19 antigen on B cells, has shown significant clinical effectiveness in treating various B cell malignancies, including chronic lymphocytic leukemia and acute lymphoblastic leukemia, with some patients experiencing long-term remissions.

The FDA has recognized the potential of CD19-directed CAR T cells by granting 'breakthrough' designation for their use in treating relapsed or refractory acute lymphoblastic leukemia in both adults and children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T Cells: A New Tool in the Fight against B Cell Malignancies. Miller, BC., Maus, MV.[2023]

The study developed a novel CAR T-cell therapy targeting CD33 in acute myeloid leukemia (AML) that incorporates an inducible Caspase9 (iC9) suicide gene system, allowing for controlled elimination of T-cells to manage adverse effects like myelosuppression.

In preclinical models, these iC9 CAR T-cells effectively controlled leukemia growth and could be partially eliminated by 76% using a chemical inducer, suggesting a promising approach to enhance safety while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy. Minagawa, K., Al-Obaidi, M., Di Stasi, A.[2019]

In a study of 27 pediatric patients receiving CD19 CAR-T therapy for relapsed or refractory B-cell acute lymphoblastic leukemia, only 22% experienced infections in the first 100 days, indicating a lower infection rate than previously reported.

The most common infections were bacterial bloodstream infections, but importantly, there were no infection-related deaths, suggesting that the antimicrobial prophylaxis used was effective in managing infection risks in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia. Diamond, Y., Gilsenan, M., Wang, SS., et al.[2023]

CAR-T cell therapy has shown great promise in treating hematological cancers, with two Anti-CD19 CAR-T therapies already approved for CD19-positive leukemia and lymphoma.

However, the therapy can cause serious side effects like cytokine release syndrome and on-target off-tumor toxicity, leading to some patients discontinuing treatment; researchers are exploring various safety strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Yu, S., Yi, M., Qin, S., et al.[2020]

The study explores the use of an inducible caspase 9 (iC9) suicide gene in CAR-T cells to enhance safety by allowing for the elimination of malignant CAR+ B cells, which can arise during treatment manufacturing.

In both in vitro and animal models, the activation of the iC9 suicide gene with the small molecule AP1903 effectively eliminated CAR+ leukemia and lymphoma cells, suggesting a promising strategy to mitigate adverse effects associated with CAR-T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies. Guercio, M., Manni, S., Boffa, I., et al.[2022]

Immunotherapy using CD19.CAR-T cells is highly effective for treating B cell malignancies, but it can lead to serious side effects like B cell aplasia and cytokine release syndrome (CRS).

The study shows that an inducible caspase-9 (iC9) safety switch can selectively eliminate CD19.CAR-T cells in a controlled manner, allowing for management of CRS while preserving antitumor activity and enabling normal B cell recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inducible Caspase-9 Selectively Modulates the Toxicities of CD19-Specific Chimeric Antigen Receptor-Modified T Cells. Diaconu, I., Ballard, B., Zhang, M., et al.[2019]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34737753/

Inclusion of the Inducible Caspase 9 Suicide Gene in CAR ... Altogether, our data indicate that the inclusion of the iC9 suicide gene may result in a safe CAR-T cell product, even when manufacturing starts ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03016377

NCT03016377 | Administration of Autologous CAR-T CD19 ... The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and tolerable (there are not too many unwanted effects).

3. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118706575

Safety and Antitumor Effects of CD19-Specific Autologous ... Conclusions: iC9-CAR19 cells can be safely administered to adult patients with relapsed and refractory B-ALL. The use of iC9 as a safety switch ...

4. ashpublications.org ashpublications.org/blood/article/137/23/3306/475336/Utility-of-a-safety-switch-to-abrogate-CD19-CAR-T

Utility of a safety switch to abrogate CD19.CAR T-cell ... T cells engineered with safety switches, like the inducible caspase-9 (iC9), have been explored clinically to mitigate graft-versus-host ...

5. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03696784/

Clinical Trial: NCT03696784 In this study, to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells have a safety switch that, when ...

6. ash.confex.com ash.confex.com/ash/2020/webprogram/Paper139051.html

1441 Safety and Antitumor Effects of CD19-Specific ... Conclusions: iC9-CAR19 cells can be safely administered to adult patients with relapsed and refractory B-ALL. The use of iC9 as a safety switch ...