TriPRIL CAR T Cell Therapy for Multiple Myeloma

Overseen By Matthew J Frigault, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Marcela V. Maus, M.D.,Ph.D.

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Active infection, Heart failure, CNS pathology, others

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

Compensation: Varies

Number of Visits: 9

Duration: 1 day

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called TriPRIL CAR T Cell therapy for individuals with multiple myeloma that hasn't responded to other treatments. Researchers aim to evaluate its effectiveness and potential side effects. The trial consists of two steps: a dose escalation phase to determine the optimal dose and a dose expansion phase to further study its effects. Suitable candidates have multiple myeloma and have tried at least three different treatment regimens, including specific types of drugs, without success. 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 must stop taking your current medications. However, you cannot have had any systemic treatment for multiple myeloma within 14 days before a key procedure, and certain medications that interfere with the study may need to be stopped. It's best to discuss your specific medications with the trial's principal investigator.

Is there any evidence suggesting that TriPRIL CAR T Cells are likely to be safe for humans?

Research shows that TriPRIL CAR T Cell therapy can cause some side effects. One common side effect is cytokine release syndrome (CRS), a strong immune reaction reported in 84% of patients. Another side effect is neurotoxicity, affecting the nervous system and observed in 18% of patients. These side effects are typical for CAR T cell treatments, a type of gene therapy used to fight cancer.

The treatment is currently being tested in early studies (Phase 1), which mainly focus on safety. Researchers closely monitor and study all side effects. Safety data from similar CAR T therapies in multiple myeloma patients suggest that while risks exist, medical care can manage the treatment.

This therapy targets individuals with relapsed or hard-to-treat multiple myeloma. Those considering joining such a study should discuss potential risks and benefits with a healthcare professional. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for multiple myeloma, such as chemotherapy and immunomodulatory drugs, TriPRIL CAR T Cell therapy offers a personalized approach by engineering a patient's own T-cells to target and attack cancer cells. This innovative therapy harnesses a new mechanism of action by specifically targeting cancer cells, potentially leading to more precise and effective treatment outcomes. Researchers are excited about TriPRIL CAR T Cells because they could provide a more targeted and potent approach to fighting multiple myeloma, with the potential for fewer side effects and longer-lasting remission compared to traditional therapies.

What evidence suggests that TriPRIL CAR T Cells might be an effective treatment for multiple myeloma?

Research has shown that CAR T-cell therapies, such as TriPRIL, hold promise for treating multiple myeloma. Studies have found that targeting BCMA, a protein often present on multiple myeloma cells, with CAR T-cells has led to strong responses. For instance, some CAR T-cell treatments demonstrated a complete response rate of 73%, indicating that many patients had no detectable cancer after treatment. These treatments work by reprogramming a patient's immune cells to better locate and attack cancer cells. In this trial, participants will receive TriPRIL CAR T Cells, which may offer similar benefits by effectively targeting and reducing cancer cells in multiple myeloma. ^{1 2 4 5 6}

Who Is on the Research Team?

Matthew Frigault, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed or refractory multiple myeloma who have tried at least three prior treatments, including specific inhibitors and antibodies. They must be in relatively good health (ECOG 0-2), not pregnant, willing to use birth control, and able to consent. People with certain heart conditions, active infections, recent other cancer treatments or stem cell transplants can't join.

Inclusion Criteria

I am able to care for myself and perform daily activities.

My organs and bone marrow are working well.

My cell sample for treatment has been accepted by the lab.

Exclusion Criteria

I have recovered from previous cancer treatment side effects, except for hair loss or mild nerve issues.

I had a stem cell transplant using my own cells within the last 3 months.

My cancer has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis

White blood cells are collected from participants

1 day

1 visit (in-person)

Lymphodepletion

Participants receive 3 days of chemotherapy to decrease the number of lymphocytes

1 week

3 visits (in-person)

Treatment

Participants receive one infusion of TriPRIL CAR T Cells

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• TriPRIL CAR T Cells

Trial Overview The study tests TriPRIL CAR T Cells designed to treat multiple myeloma that's come back or hasn't responded to treatment. Participants also receive Fludarabine and Cyclophosphamide chemotherapy drugs as part of the process before getting the new therapy.

How Is the Trial Designed?

Group I: TriPRIL CAR T Cells-Dose Expansion Experimental Treatment 3 Interventions

Prior to receiving TriPRIL CAR T Cells, participants will undergo two preparatory processes: * Leukapheresis: White blood cells will be collected and manufacture TriPRIL CAR T cells at a GMP manufacturing facility. * Lymphodepletion: On days, -5, -4. -3 participants will receive 3 days of chemotherapy to decrease the number of lymphocytes TriPRIL CAR T Cells will be administered intravenously on day 0 using the respective dose (at or below the Maximum Tolerated Dose-MTD), as determined during the dose escalation part.

Group II: TriPRIL CAR T Cells-Dose Escalation Experimental Treatment 3 Interventions

Prior to receiving TriPRIL CAR T Cells, participants will undergo two preparatory processes: * Leukapheresis: White blood cells will be collected and manufacture TriPRIL CAR T cells at a GMP manufacturing facility. * Lymphodepletion: On days, -5, -4. -3 participants will receive 3 days of chemotherapy to decrease the number of lymphocytes TriPRIL CAR T Cells will be administered intravenously on day 0 using a 3+3 dose escalation design

Who Is Running the Clinical Trial?

Marcela V. Maus, M.D.,Ph.D.

Lead Sponsor

Trials

6

Recruited

110+

Published Research Related to This Trial

The study introduces a novel CAR T-cell design that targets two different antigens, BCMA and CS1, on multiple myeloma cells, showing consistent and potent anti-tumor activity in mouse models.

This dual-targeting approach resulted in superior survival rates in treated mice compared to traditional CAR T-cells that only target a single antigen, suggesting it could help overcome the issue of relapse due to antigen loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A compound chimeric antigen receptor strategy for targeting multiple myeloma. Chen, KH., Wada, M., Pinz, KG., et al.[2019]

Monoclonal antibodies like elotuzumab and daratumumab have advanced the treatment of multiple myeloma, while CAR T cell therapy is emerging as a promising option for patients with relapsed/refractory multiple myeloma, offering hope for those with limited treatment options.

Despite its potential efficacy, CAR T cell therapy can lead to severe adverse events and toxic deaths, highlighting the need for better understanding and management strategies for these toxicities in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies. Zhou, X., Rasche, L., Kortüm, KM., et al.[2021]

T-cell redirecting bispecific antibodies and CAR T cells are effective treatments for multiple myeloma but are associated with significant adverse events, including cytokine release syndrome and neurotoxicity.

The European Myeloma Network recommends specific management strategies for these adverse events, such as premedication, corticosteroids, and monitoring for symptoms, to improve patient safety and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. Ludwig, H., Terpos, E., van de Donk, N., et al.[2023]

Multiple myeloma often relapses after initial treatment, necessitating new strategies for managing cases that are triple-refractory, meaning they do not respond to three major classes of therapies.

Recent advancements in treating triple-class refractory myeloma include promising options like bispecific antibodies, T cell engagers, and chimeric antigen receptor (CAR) therapies, which offer novel mechanisms to combat this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Management of Triple-Class Refractory Multiple Myeloma: A Review of Current Strategies and Emerging Therapies. Stalker, ME., Mark, TM.[2022]

A novel trimeric APRIL-based CAR T cell therapy shows promise in targeting both BCMA+ and BCMA- multiple myeloma (MM), potentially overcoming the issue of BCMA escape variants seen with traditional CAR T therapies.

The trimeric format enhances binding and T-cell activation compared to monomeric formats, suggesting that this dual-specific approach could improve treatment outcomes for patients with MM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma. Schmidts, A., Ormhøj, M., Choi, BD., et al.[2021]

A newly developed trispecific antibody targeting CD38, CD3, and CD28 has shown promise in enhancing T cell activation and effectively directing T cells to myeloma cells, potentially improving responses to cancer immunotherapy.

In vivo studies in humanized mouse models demonstrated that this trispecific antibody suppressed myeloma growth and stimulated T cell proliferation in non-human primates, indicating its potential safety and efficacy at well-tolerated doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Wu, L., Seung, E., Xu, L., et al.[2022]

CAR T-cell therapy targeting B-cell maturation antigen (BCMA) has shown promising results in treating multiple myeloma, with high-quality responses observed in heavily pretreated patients, and ongoing Phase 3 trials are comparing its efficacy against standard treatments.

While CAR T-cell therapy can lead to sustained responses in some patients, most eventually relapse due to factors like loss of CAR T cells or antigen expression, prompting research into improving CAR design and safety measures, such as suicide gene systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for multiple myeloma: state of the art and prospects. van de Donk, NWCJ., Usmani, SZ., Yong, K.[2021]

Multiple myeloma remains an incurable disease, and patients often experience relapses after standard treatments, leading to a poor prognosis.

Chimeric antigen receptor (CAR) T-cell therapy shows promise in improving outcomes for relapsed multiple myeloma, although it is not yet approved for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells for Multiple Myeloma: The Journey So Far-And the Road Ahead. Cowan, AJ., Tuazon, SA., Portuguese, AJ., et al.[2022]

Two CAR T-cell therapies targeting BCMA have been approved for treating relapsed and refractory multiple myeloma, showing excellent efficacy even in patients who have undergone extensive prior treatments.

While these therapies represent a significant advancement in treatment, they are associated with unique adverse events like cytokine release syndrome (CRS) and neurotoxicity, which require specialized management and further research to optimize their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-Cell-Based Cellular Immunotherapy of Multiple Myeloma: Current Developments. Simmons, GL., Castaneda Puglianini, O.[2022]

CAR T cell therapy, particularly with the approval of tisagenlecleucel, has shown remarkable efficacy in treating pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia, with six therapies approved as of April 2023 for B-cell malignancies and multiple myeloma.

However, the therapy is associated with significant adverse events like cytokine release syndrome, which are more severe with higher pretreatment tumor burdens; thus, initiating therapy early or using a debulking strategy may help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From bench to bedside: the history and progress of CAR T cell therapy. Mitra, A., Barua, A., Huang, L., et al.[2023]

CAR T-cell therapy, specifically BCMA-directed products like idecabtagene vicleucel and ciltacabtagene autoleucel, has been FDA-approved for treating relapsed/refractory multiple myeloma, showing high response rates in patients who have undergone extensive prior treatments.

Despite their effectiveness, these therapies are associated with significant immune-related side effects and relapse rates, highlighting the need for ongoing research to enhance their efficacy and reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy for Multiple Myeloma: A Clinical Practice-Oriented Review. Sadek, NL., Costa, BA., Nath, K., et al.[2023]

CAR T-cell therapy targeting both BCMA and GPRC5D in multiple myeloma shows promise in preventing relapse due to antigen escape, which is a common issue with single-target therapies.

Among different dual-targeting strategies tested, the bicistronic CAR design, which expresses two CARs from a single vector, demonstrated the highest efficacy in combating BCMA-negative disease, enhancing the interaction between CAR T-cells and target cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma. Fernández de Larrea, C., Staehr, M., Lopez, AV., et al.[2022]

In a phase 1 study involving 57 patients with relapsed/refractory multiple myeloma, LCAR-B38M CAR T cell therapy showed an impressive overall response rate of 88%, with 68% of patients achieving a complete response.

While the therapy had a manageable safety profile, with common adverse events including leukopenia and cytokine release syndrome, it demonstrated durable responses with a median progression-free survival of 15 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. Zhao, WH., Liu, J., Wang, BY., et al.[2020]

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]

Citations

1. nature.com nature.com/articles/s41408-024-01191-8

CAR-T cell therapy in Multiple Myeloma: current status and ... A phase 1 study, initially in 33 RRMM patients showed promising results which led to development of the phase 2 KarMMa study [13], in which 128 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11101341/

CAR T therapies in multiple myeloma: unleashing the future In addition, a remarkable CR rate of 73% was observed in this subgroup, indicating a substantial and durable treatment response. Even more ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05020444

NCT05020444 | TriPRIL CAR T Cells in Multiple Myeloma This is a two-part, non-randomized, open label, single-site Phase 1 study of TriPRIL CAR T Cells as a treatment for relapsed or refractory multiple myeloma.

4. withpower.com withpower.com/trial/phase-1-recurrence-8-2021-a5c20

TriPRIL CAR T Cell Therapy for Multiple Myeloma CAR T-cell therapy targeting B-cell maturation antigen (BCMA) has shown promising results in treating multiple myeloma, with high-quality responses observed in ...

5. ashpublications.org ashpublications.org/blood/article/146/14/1677/537756/Remission-conversion-drives-outcomes-after-CAR-T

Remission conversion drives outcomes after CAR T-cell ... Cilta-cel also led to higher complete response (CR; 61% vs 39%) and improved response conversion, with more patients achieving CR after starting ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39458157/

Impact of Allogeneic Stem Cell Transplant on Safety and ... The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM.