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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label phase 1 study to assess the safety and pharmacodynamics of CART-BCMA, with or without huCART19, in patients responding to first- or second-line therapy for high-risk multiple myeloma. The regimen evaluated in this study is based on established safety of CARTBCMA demonstrated in UPCC 14415/IRB#822756 at dose of 5x108 cells, administered as split infusions, following cyclophosphamide 1.5 g/m2 in patients with relapsed/refractory myeloma. This study tests CART-BCMA (1) as consolidation of early therapy for multiple myeloma, (2) with addition of fludarabine to the lymphodepleting chemotherapy regimen, (3) in combination with huCART19, and (4) as a single rather than split-dose infusion.

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.

What data supports the effectiveness of the treatment CART-BCMA for multiple myeloma?

Research shows that CART-BCMA, a type of CAR T-cell therapy, has high response rates in patients with relapsed or hard-to-treat multiple myeloma. In a study, 10 out of 15 patients with measurable disease showed a partial response or better, and some patients even achieved a complete response, indicating its potential effectiveness. ^{1 2 3 4 5}

Is CART therapy safe for treating multiple myeloma?

CART therapy for multiple myeloma has shown generally favorable safety results, with some patients experiencing mild to severe cytokine release syndrome (CRS), which is a manageable immune reaction. Most adverse effects were clinically manageable, and severe reactions were reversible, indicating that the treatment is generally safe for humans. ^{3 4 6 7 8}

How is CART-BCMA treatment different from other treatments for multiple myeloma?

CART-BCMA is a unique treatment for multiple myeloma because it uses genetically modified immune cells (CAR T-cells) to specifically target and attack cancer cells expressing BCMA, a protein found on myeloma cells. This approach can lead to high remission rates, especially in patients who have not responded to other treatments. ^{1 2 3 5 9}

Research Team

Alfred Garfall, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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.

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

Your cells have more than 3 abnormal changes in their structure, except for having extra chromosomes.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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 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 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]

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]

References

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

CAR T-Cell Therapy in Multiple Myeloma: Mission Accomplished? [2023]

2. United States 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. [2022]

3. United States 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. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma]. [2022]

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

Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy. [2023]

6. United States 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. [2019]

7. England 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. [2023]

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

Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. [2020]

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

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. [2020]