CART Therapy for Multiple Myeloma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Disqualifiers: Pregnancy, Hepatitis, HIV, Heart failure, Autoimmune, CNS involvement

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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called CART-BCMA, a type of CAR-T cell therapy, for individuals with multiple myeloma, a type of blood cancer. The trial aims to determine the safety and behavior of this treatment in the body, either alone or combined with another treatment, huCART19. Participants will receive the treatment in various ways, such as split doses or single doses, to identify the most effective method. The trial seeks individuals who have tried one or two treatments for high-risk multiple myeloma and have not achieved complete remission but are still responding to their current treatment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants must be clinically stable on their current regimen, which suggests you may continue your existing treatment if it meets the trial's criteria.

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

Research has shown that the CART-BCMA treatment has been safe in previous studies for patients with relapsed or refractory multiple myeloma. Most patients responded well, although some experienced side effects. For instance, 76% of patients treated with a similar therapy developed cytokine release syndrome (CRS), which can cause flu-like symptoms. A smaller percentage, 4.5%, experienced ICANS, a temporary side effect affecting the brain. These are known and monitored side effects of CAR T-cell therapies.

For huCART19, studies have also shown it to be safe. When combined with CART-BCMA, the safety results are similar to using CART-BCMA alone, indicating that adding huCART19 does not seem to increase the risk of side effects.

In summary, while some known side effects require monitoring, both CART-BCMA and its combination with huCART19 have generally been well-tolerated in past research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for multiple myeloma, such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, CART-BCMA offers a unique approach by harnessing the body's own immune cells. Researchers are excited about this treatment because it uses CAR T-cell therapy, which involves genetically modifying a patient's T-cells to specifically target the BCMA protein present on myeloma cells. This targeted mechanism allows for potentially more precise and effective destruction of cancerous cells. Furthermore, the combination with huCART19 adds another layer of immune targeting, which could enhance the overall efficacy and durability of the response against the cancer. These innovative features provide hope for improved outcomes in patients who have relapsed or not responded to existing treatments.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

Research has shown that CART-BCMA therapy, which participants in this trial may receive, is highly effective in treating multiple myeloma, particularly for patients unresponsive to other treatments. One study found that over 90% of patients experienced tumor reduction or remission. This trial will also assess the combination of CART-BCMA with huCART19, which has demonstrated promising safety and effectiveness against myeloma. Although most patients eventually experience cancer recurrence, targeting two cancer markers simultaneously may delay this process. Overall, these treatments have shown significant promise in early studies for managing difficult-to-treat multiple myeloma. ^{1 2 6 7 8}

Who Is on the Research Team?

Alfred Garfall, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults with high-risk multiple myeloma who have started treatment within the last year and seen some improvement but not a complete cure. They shouldn't have had stem cell transplants or certain chemotherapies, and their vital organs must be functioning well. Participants need to agree to birth control methods if applicable.

Inclusion Criteria

My vital organs are functioning well.

Subjects must have signed written, informed consent

Your beta-2-microglobulin level is higher than 5.5 mg/L and your LDH level is higher than the normal range.

Exclusion Criteria

I do not have active hepatitis B, C, HIV, or any uncontrolled infection.

My myeloma has affected or is affecting my brain or spinal cord.

Any uncontrolled medical or psychiatric disorder that would preclude participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase A: Safety Run-in

Safety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine

4-6 weeks

Phase B: Randomization

Randomization Phase where patients receive either CART-BCMA alone or CART-BCMA + huCART19 as split-dose infusions after lymphodepleting chemotherapy

4-6 weeks

Phase C: Single-dose Infusion

Single-dose infusion phase to test the safety of single-dose infusion of CART-BCMA alone and CART-BCMA + huCART19 after lymphodepleting chemotherapy

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• CART-BCMA
• huCART19

Trial Overview

The study tests a single-dose infusion of CART-BCMA alone or combined with huCART19 in patients after initial therapy success. It explores different chemotherapy regimens, combination treatments, and dosing strategies to improve outcomes for those at high risk.

How Is the Trial Designed?

Group I: Phase C Experimental Treatment 1 Intervention

Single-dose infusion phase to test the safety of single-dose infusion of CART-BCMA alone (Cohort 1) and CART-BCMA + huCART19 (Cohort 2) as single-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients responding to first- or second-line therapy.

Group II: Phase B Experimental Treatment 1 Intervention

Randomization Phase in which patients responding to first or second-line therapy will receive either CART-BCMA alone (Cohort 1) or CART-BCMA + huCART19 (Cohort 2) as split-doses after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.

Group III: Phase A Expansion Experimental Treatment 1 Intervention

Once safety of CART-BCMA/huCART19 combination therapy is established in Phase A, an expansion of Phase A will occur in which the Phase A target population (patients with relapsed/refractory multiple myeloma responding to a standard salvage therapy regimen) will receive both CART-BCMA and huCART19. Enrollment into the Phase A Expansion may occur concurrently with Phase B once opened.

Group IV: Phase A Experimental Treatment 1 Intervention

Safety Run-in to test the safety of CART-BCMA + huCART19 as split-dose infusions after lymphodepleting chemotherapy with cyclophosphamide + fludarabine in patients who have relapsed/refractory myeloma after two prior regimens but who are responding to their current therapy.

CART-BCMA is already approved in United States for the following indications:

Approved in United States as CART-BCMA for:

• Experimental use for desensitization in kidney transplantation

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

In a study involving 35 patients with relapsed or refractory multiple myeloma, the CAR T-cell therapy ARI0002h achieved a remarkable overall response rate of 100% within the first 100 days, with 80% of patients showing a very good partial response or better.

The treatment demonstrated a favorable safety profile, with 80% of patients experiencing only mild cytokine-release syndrome (grade 1-2) and no neurotoxic events reported, suggesting that ARI0002h could be a safe and effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study. Oliver-Caldés, A., González-Calle, V., Cabañas, V., et al.[2023]

In a study of 21 patients with relapsed and refractory multiple myeloma treated with BCMA-chimeric antigen receptor T cells (CART), 17 patients showed effective responses, including 10 achieving complete remission, indicating a promising efficacy of this treatment.

The treatment was associated with manageable adverse reactions, primarily cytokine release syndrome (CRS), which occurred in 20 patients but was mostly mild (Grade 1 or 2), demonstrating that BCMA-CART can be safely administered with proper monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. Zhang, XY., Ding, HY., Gang, DX., et al.[2022]

B-cell maturation antigen (BCMA) CAR T cells are emerging as a highly effective treatment for multiple myeloma, showing promise for inclusion in first-line therapy based on clinical and preclinical data.

Advancements in patient stratification through genomic analysis and improvements in CAR T-cell manufacturing are enhancing early diagnosis, management of side effects, and overall access to this innovative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy in Multiple Myeloma: Mission Accomplished? Rasche, L., Hudecek, M., Einsele, H.[2023]

In a phase II trial involving 69 patients with relapsed or refractory multiple myeloma, the combination of anti-BCMA and anti-CD19 CAR T cells resulted in a high overall response rate of 92%, with 60% achieving a complete response.

The treatment demonstrated a median progression-free survival of 18.3 months and a manageable safety profile, although 95% of patients experienced cytokine release syndrome, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma. Wang, Y., Cao, J., Gu, W., et al.[2022]

In a phase I clinical trial involving 30 multiple myeloma patients, anti-BCMA CAR T cells showed favorable safety with no high-grade cytokine release syndrome and only one case of low-grade neurologic toxicity.

The treatment demonstrated significant efficacy, with 10 out of 15 patients with measurable disease achieving a partial response or better, and 4 patients converting to minimal residual disease-negative complete response, indicating strong antimyeloma activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy. Garfall, AL., Cohen, AD., Susanibar-Adaniya, SP., et al.[2023]

In a phase I study involving 25 patients with relapsed/refractory multiple myeloma, CART-BCMA therapy demonstrated clinical activity, with response rates of 44% in the lowest dose cohort and 64% in the highest dose cohort, indicating its potential effectiveness as a treatment.

While CART-BCMA infusions were associated with some serious side effects like cytokine release syndrome and neurotoxicity, these were mostly reversible, suggesting a manageable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. Cohen, AD., Garfall, AL., Stadtmauer, EA., et al.[2020]

In a first-in-humans clinical trial involving 16 patients with heavily treated multiple myeloma, CAR-BCMA T cells demonstrated an impressive overall response rate of 81%, with 63% achieving very good partial or complete responses.

The treatment was associated with significant anti-myeloma activity, including eradication of bone marrow myeloma and resolution of soft-tissue plasmacytomas, although some patients experienced severe but reversible cytokine-release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. Brudno, JN., Maric, I., Hartman, SD., et al.[2019]

In a clinical trial involving 17 patients with relapsed and refractory multiple myeloma, the biepitope-targeting CAR T therapy (LCAR-B38M) showed a high overall response rate of 88.2%, with 13 patients achieving stringent complete response (sCR).

While the treatment was generally effective, 10 patients experienced mild cytokine release syndrome (CRS) and 6 had severe but manageable CRS, indicating that while adverse effects can occur, they are often clinically manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Xu, J., Chen, LJ., Yang, SS., et al.[2020]

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