CAR-T Cell Therapy for B-Cell Lymphoma

Overseen By Kelly Hoye

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must be taking: Anti-CD20 antibodies

Must not be taking: Corticosteroids, CYP1A2 inhibitors

Disqualifiers: Pregnancy, HIV, HBV, HCV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment that combines antibodies and T cells to combat B-cell lymphoma, a type of cancer. The treatment, known as iC9-CAR19 T cells (also referred to as ATLCAR.CD19 or iC9-CAR19 cells), modifies T cells to better target and destroy cancer cells. The study also explores managing potential side effects using a safety switch that can deactivate the modified T cells if necessary. This trial may suit individuals with B-cell lymphoma who have not responded to at least two previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong inhibitors of CYP1A2 or chemotherapy within specific timeframes before the treatment. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the iC9-CAR19 T cell treatment can be safe for patients with certain cancers, such as B-cell lymphoma. This treatment uses modified T cells to find and attack cancer cells with a marker called CD19. However, earlier studies reported side effects, including cytokine release syndrome (which can cause fever and low blood pressure) and neurotoxicity (which affects the brain).

To manage these side effects, the treatment includes a safety switch. If serious side effects occur, a drug called AP1903 can be administered to inactivate the T cells, reducing their activity and side effects. Earlier studies found that doses of 1×10^6 CAR19+ T cells per kilogram of body weight were safe and showed promising growth in the body.

While the treatment shows promise, it is important to be aware of the potential risks and the safety measures in place. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for B-cell lymphoma?

Unlike the standard treatments for B-cell lymphoma, which often include chemotherapy and radiation, iC9-CAR19 T cells offer a novel approach by using genetically modified T cells to target and destroy cancerous B cells. This treatment is unique because it includes a safety switch mechanism, activated by the agent AP1903, which can trigger cell death if severe side effects like cytokine release syndrome or neurotoxicity occur. Researchers are excited about iC9-CAR19 T cells because their targeted action and built-in safety feature could lead to more effective and safer cancer therapies compared to conventional methods.

What evidence suggests that iC9-CAR19 T cells might be an effective treatment for B-cell lymphoma?

Research has shown that CD19-directed CAR T-cell therapy yields promising results for individuals with relapsed or refractory B-cell non-Hodgkin lymphoma. Studies have found that about 30-40% of patients respond well to this treatment. The therapy modifies T cells to locate and attack cancer cells, often leading to remission. However, cancer may return in about half of the patients. In this trial, participants will receive iC9-CAR19 T cells, which include a built-in safety switch to manage severe side effects. This feature could enhance the treatment's safety while maintaining its effectiveness. ^{5 6 7 8 9}

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 adults over 18 with certain types of B-cell lymphoma or leukemia who have tried at least two other treatments without success. It's not for pregnant women, those with severe hepatitis B, or HIV/HTLV/HCV infections. Participants must be willing to use birth control and have a Karnofsky score above 60%, indicating they can care for themselves.

Inclusion Criteria

Measurable or assessable disease by specified criteria

Women of childbearing potential must follow contraceptive measures

I have received treatments specific to my type of lymphoma.

Exclusion Criteria

Pregnant or lactating subjects

History of intolerance to fludarabine

I do not have an active infection with any major viruses.

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 cytoreductive regimen of bendamustine and fludarabine or cyclophosphamide and fludarabine

3 days

3 visits (in-person)

Treatment

Administration of iC9-CAR19 T cells post lymphodepletion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

What Are the Treatments Tested in This Trial?

Interventions

• iC9-CAR19 T cells

Trial Overview

The study tests iC9-CAR19 T cells designed to target CD19 on cancer cells, combined with chemotherapy drugs like Bendamustine and Fludarabine. If severe side effects occur, AP1903 is used to activate a 'safety switch' in the T cells to reduce their activity.

How Is the Trial Designed?

Group I: Single Arm iC9.CAR19 T cells Experimental Treatment 5 Interventions

The safety of iC9-CAR19 cells will be investigated using the 3+3 design. Dose level (DL) Dose (#transduced cells/kg) -1 1 x 10\^5 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. Lymphodepleting chemotherapy of IV bendamustine 70 mg/m2 and IV fludarabine 30 mg/m2/day for 3 consecutive days will be given within 2-14 days prior to cell infusion. AP1903 (0.4 mg/kg), a dimerizing agent to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).

Group II: Expansion Cohort iC9-CAR19 cells Experimental Treatment 5 Interventions

After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects).

iC9-CAR19 T cells is already approved in United States, European Union for the following indications:

Approved in United States as Yescarta (axicabtagene ciloleucel) for:

• Large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Yescarta (axicabtagene ciloleucel) for:

• Diffuse large B-cell lymphoma
• Primary mediastinal large B-cell lymphoma

Approved in United States as Kymriah (tisagenlecleucel) for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Kymriah (tisagenlecleucel) for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma

Approved in United States as Breyanzi (lisocabtagene maraleucel) for:

• Large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Breyanzi (lisocabtagene maraleucel) for:

• Diffuse large B-cell lymphoma
• Primary mediastinal large B-cell lymphoma

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

M.D. Anderson Cancer Center

Collaborator

Trials

3,107

Recruited

1,813,000+

UNC Chapel Hill University Cancer Research Fund

Collaborator

Trials

1

Recruited

30+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

The V Foundation

Collaborator

Trials

10

Recruited

320+

Published Research Related to This Trial

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]

Anti-CD19 CAR-T cell therapy successfully achieved a complete response in a patient with relapsed/refractory follicular lymphoma, demonstrating its efficacy in treating this type of lymphoma.

The therapy not only addressed the lymphoma but also allowed for subsequent curative treatment of gastric adenocarcinoma, indicating its potential for use in patients with multiple malignancies while maintaining a good quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of a case with synchronous follicular lymphoma and gastric adenocarcinoma with CD19 CAR T cells and literature review. Liu, J., Cao, F., Li, Z., et al.[2022]

Anti-CD19 CAR-modified T cells have demonstrated a 48% overall response rate in treating B-cell malignancies, with complete responses observed in 24% of patients across six phase I clinical trials involving 50 patients.

The study found that conditioning chemotherapy significantly improves progression-free survival (PFS), making it a crucial factor for enhancing the efficacy of CAR T-cell therapy, while the treatment was generally well tolerated with temporary adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. Zhu, Y., Tan, Y., Ou, R., et al.[2022]

CD19-directed CAR T-cell therapy has significantly transformed the treatment approach for aggressive B-cell non-Hodgkin lymphoma, offering new hope for patients.

There are currently three commercially available CAR T-cell therapies targeting CD19, indicating a growing acceptance and application of this innovative immunotherapy in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy for Relapsed/Refractory Aggressive Large B-Cell Lymphoma. Gideon, J.[2023]

Anti-CD19 CAR T-cell therapy has demonstrated significant clinical activity in treating B-cell non-Hodgkin lymphoma (NHL), with objective response rates ranging from 50-83% for relapsed diffuse large B-cell lymphoma (DLBCL), 83-93% for follicular lymphoma (FL), and 93% for mantle cell lymphoma (MCL).

This therapy represents a promising treatment option for patients with poor-risk refractory B-cell NHLs, highlighting its potential efficacy in difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. Chavez, JC., Yassine, F., Sandoval-Sus, J., et al.[2022]

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]

Anti-CD19 CAR T cell therapy has shown promising results in treating advanced-stage B-cell malignancies, with some patients achieving long-term remissions after treatment, indicating its potential as a new standard therapy.

While the therapy demonstrates strong efficacy by specifically targeting CD19, some patients have experienced acute adverse effects linked to increased inflammatory cytokines, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Kochenderfer, JN., Rosenberg, SA.[2021]

CD19-directed CAR T-cell therapy has shown promising results in treating relapsed/refractory B-cell non-Hodgkin lymphoma, with 30-40% of patients achieving durable responses in pivotal phase I/II trials, leading to FDA and EMA approvals for specific therapies.

Despite its effectiveness, the therapy is associated with significant toxicities, such as cytokine release syndrome and neurotoxicity, which can limit its use and present challenges in patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-directed CAR T-cell therapy in B-cell NHL. Kersten, MJ., Spanjaart, AM., Thieblemont, C.[2021]

In a phase 1 study involving 12 pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the autologous CD19-CAR T-cell therapy was well tolerated, with low rates of cytokine release syndrome (6 patients) and neurotoxicity (3 patients).

75% of the patients achieved a minimal residual disease-negative complete response in the bone marrow, although higher disease burden before treatment was linked to more side effects and lower response rates, emphasizing the importance of pre-infusion disease status on treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Talleur, AC., Qudeimat, A., Métais, JY., et al.[2022]

CAR-T-cell therapy has shown significant promise in treating relapsed or refractory B-cell malignancies, such as B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, by targeting specific antigens like CD19 and BCMA.

The review highlights both the efficacy and toxicity of CD19- and BCMA-targeted CAR-T-cell therapies, indicating that while these treatments can be effective, they also come with potential side effects that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Roex, G., Feys, T., Beguin, Y., et al.[2020]

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Project Details

We hypothesize that targeting CD70 with iC9/CAR27D10ζ/IL-15 NK cells will greatly improve outcomes in patients with NHL after CAR19 T-cell failure and that by ...