MCARH109 + MCARH125 for Multiple Myeloma

Not currently recruiting at 6 trial locations

Overseen By Saad Usmani, MD, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Proteasome inhibitors, Immunomodulatory drugs, CD38 antibodies

Must not be taking: Systemic steroids

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Variable, based on dose escalation

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores two new treatments, MCARH109 (GPRC5D-targeted CAR T-cell therapy) and MCARH125, for individuals with multiple myeloma, a type of blood cancer. The goal is to assess the effectiveness and safety of these treatments, either alone or in combination. Participants will have their T cells (a type of immune cell) modified in a lab to create the study treatments. This trial may suit those who have had multiple myeloma for some time and have already tried at least three different treatments without success. 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 these new therapies.

Do I need to stop my current medications to join the trial?

The trial requires a 14-day washout period from myeloma therapies and radiation before starting the study. For experimental treatments, the washout is 5 half-lives or 14 days, whichever is shorter. The protocol does not specify other medications, so consult your doctor for guidance.

Will I have to stop taking my current medications?

The trial requires a 14-day period without myeloma therapies before certain procedures, so you may need to stop some medications. However, the protocol does not specify all medications, so it's best to discuss your specific situation with the trial team.

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

Research shows that MCARH125 and MCARH109 are under investigation as treatments for multiple myeloma, a type of blood cancer. Studies have found that MCARH125 is generally well-tolerated, with most patients experiencing mild to moderate side effects, such as fever and tiredness, due to an immune response called cytokine release syndrome (CRS). A small number of patients experienced more serious side effects.

Earlier studies found MCARH109 to be safe. Researchers identified a safe maximum dose for this treatment, and it has shown promise without causing too many side effects. These findings suggest that both treatments are reasonably safe, but further research is needed to confirm this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about MCARH109 and MCARH125 for treating multiple myeloma because these treatments involve a novel approach using CAR+ cells. Unlike traditional therapies like proteasome inhibitors or immunomodulatory drugs, MCARH109 and MCARH125 are engineered to target and attack cancer cells more directly. This targeted therapy has the potential to be more precise and effective, minimizing damage to healthy cells and possibly leading to better patient outcomes. These treatments represent a cutting-edge advancement in personalized medicine, offering hope for more effective management of multiple myeloma.

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

Research has shown that MCARH125 effectively treats multiple myeloma, a type of blood cancer. In one study, 91% of patients experienced a response to this treatment. MCARH109, another treatment option in this trial, targets a protein called GPRC5D, which aids cancer growth. A similar treatment achieved a 94.1% success rate in a study, suggesting high effectiveness. These CAR T-cell therapies, which use the body's immune cells to combat cancer, offer hope for patients with multiple myeloma. Overall, both treatments have the potential to benefit those with this disease. ^{1 4 5 6 7}

Who Is on the Research Team?

Sham Mailankody, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with multiple myeloma that's come back or hasn't responded to treatment, including a proteasome inhibitor, an immunomodulatory drug, and a CD38 antibody. They should have had at least three prior treatments and be in good physical condition. Pregnant women or those with certain heart conditions, active infections like HIV/Hepatitis B/C, other cancers, or recent steroid use can't join.

Inclusion Criteria

I've had treatments including proteasome inhibitors, immunomodulatory drugs, CD38 antibodies, and high-dose chemo with stem cell support.

My kidney, liver, lung, and heart functions are all within normal ranges.

My blood counts meet the required levels without recent transfusions or growth factor support.

Exclusion Criteria

I have been diagnosed with plasma cell leukemia.

I haven't had myeloma treatment in the last 6 months, except possibly CAR T cell therapy.

I have another active cancer besides the one being treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either MCARH125 alone or MCARH125 with MCARH109

Variable, based on dose escalation

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 24 months

What Are the Treatments Tested in This Trial?

Interventions

• MCARH109
• MCARH125

Trial Overview The study tests two therapies: MCARH125 alone or combined with MCARH109 on participants' T cells modified in the lab to fight cancer. It aims to see how well these new treatments work against relapsed/refractory multiple myeloma.

How Is the Trial Designed?

Group I: Dose Level 2 Experimental Treatment 2 Interventions

MCARH125 dose 150 million total CAR+ cells MCARH109 dose 150 million total CAR+ cells

Group II: Dose Level 1 Experimental Treatment 2 Interventions

MCARH125 dose 150 million total CAR+ cells MCARH109 dose 50 million total CAR+ cells

Group III: Dose Level 0 Experimental Treatment 2 Interventions

MCARH125 dose 150 million total CAR+ cells MCARH109 dose 0 total CAR+ cells

Group IV: Dose Level -1B Experimental Treatment 2 Interventions

MCARH125 dose 50 million total CAR+ cells MCARH109 dose 50 million total CAR+ cells

Group V: Dose Level -1A Experimental Treatment 2 Interventions

MCARH125 dose 50 million CAR+ cells MCARH109 dose 0 total CAR+ cells

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

A new CAR T-cell therapy targeting the GPRC5D protein in patients with refractory or relapsed multiple myeloma has shown promising results, with all 10 treated patients responding positively.

This approach appears to be both safe and effective, providing a potential solution for patients who have developed resistance to existing BCMA-targeting CAR T-cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPRC5D-Directed CAR Yields 100% Response Rate. [2022]

The bispecific antibody JNJ-64407564 targets the GPRC5D antigen on multiple myeloma (MM) cells, effectively recruiting T cells to kill these cancer cells, demonstrating specific cytotoxicity in both laboratory and patient samples.

JNJ-64407564 has shown promising results in preclinical models, inducing tumor regression and T-cell infiltration in GPRC5D+ MM murine models, and is currently being tested in a phase 1 clinical trial for patients with relapsed or refractory MM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Pillarisetti, K., Edavettal, S., Mendonça, M., et al.[2021]

In a phase II study involving 33 patients with relapsed or refractory multiple myeloma, anti-GPRC5D CAR T-cell therapy demonstrated a high overall response rate of 91%, with significant responses even in patients previously treated with anti-BCMA CAR T-cell therapy.

The treatment was associated with manageable safety concerns, including common grade 3 or higher hematologic toxicities and cytokine release syndrome, indicating that while there are risks, the therapy is generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-G Protein-Coupled Receptor, Class C Group 5 Member D Chimeric Antigen Receptor T Cells in Patients With Relapsed or Refractory Multiple Myeloma: A Single-Arm, Phase Ⅱ Trial. Xia, J., Li, H., Yan, Z., et al.[2023]

GPRC5D-targeted CAR T-cell therapy (OriCAR-017) showed promising efficacy in treating relapsed or refractory multiple myeloma, with a 100% overall response rate among 10 patients, including 60% achieving a stringent complete response.

The therapy demonstrated a favorable safety profile, with no serious adverse events or treatment-related deaths reported, although common grade 3 adverse effects included neutropenia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Zhang, M., Wei, G., Zhou, L., et al.[2023]

In a phase 1 study involving 17 heavily pretreated multiple myeloma patients, GPRC5D-targeted CAR T-cell therapy (MCARH109) demonstrated a 71% overall response rate, including responses in patients who previously relapsed after BCMA CAR T-cell therapy.

The maximum tolerated dose was determined to be 150×10^6 CAR T cells, with significant side effects observed at higher doses, indicating a need for careful dose management to minimize severe adverse events like cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPRC5D-Targeted CAR T Cells for Myeloma. Mailankody, S., Devlin, SM., Landa, J., et al.[2023]

GPRC5D is a promising new target for CAR T cell therapy in multiple myeloma, as it is expressed on malignant cells and can effectively eliminate these cells even in cases where BCMA is not present.

CAR T cells targeting GPRC5D demonstrated comparable efficacy to BCMA-targeted therapies without causing toxicity, such as hair loss, suggesting a safe and effective alternative for patients who have relapsed after BCMA therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Smith, EL., Harrington, K., Staehr, M., et al.[2021]

GPRC5D is specifically expressed on malignant cells in multiple myeloma, making it a promising target for new treatments, as it is not significantly present on normal blood cells or stem cells.

The study developed bispecific T-cell-redirecting antibodies (GPRC5D TRAB) that effectively suppressed tumor growth in GPRC5D-positive myeloma cells by activating T cells, showing potential for effective therapy in treating multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GPRC5D/CD3 Bispecific T-Cell-Redirecting Antibody for the Treatment of Multiple Myeloma. Kodama, T., Kochi, Y., Nakai, W., et al.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36170501/

GPRC5D-Targeted CAR T Cells for Myeloma - PubMed The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2209900

GPRC5D-Targeted CAR T Cells for Myeloma The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma.

3. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO-24-01785

Phase I Trial of MCARH109, a G Protein–Coupled ... The median overall survival (OS) was NR and the 3-year OS estimate was 59% (95% CI, 40 to 88). Possible GPRC5D loss via immunohistochemistry was ...

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3451/529721/GPRC5D-Targeted-CAR-T-Cell-Therapy-CT071-for-the

GPRC5D-Targeted CAR T-Cell Therapy CT071 for the ... The overall response rate (ORR) was 94.1% (16/17), and the stringent complete response (sCR) rate was 52.9% (9/17). Notably, 7 patients achieved ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04555551

MCARH109 Chimeric Antigen Receptor (CAR) Modified T ... This study will test the safety of the study treatment, MCARH109, at different doses, to see which dose is safest in people, and to look for any good and ...

6. multiplemyelomahub.com multiplemyelomahub.com/medical-information/safety-and-efficacy-of-the-gprc5d-targeted-car-t-cell-therapy-mcarh109

Safety and efficacy of the GPRC5D-targeted CAR T-cell ... Preclinical studies have demonstrated the efficacy of GPRC5D-targeted CAR T-cells, including activity in a BCMA antigen escape model.1. The ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39631041/

Phase I Trial of MCARH109, a G Protein-Coupled Receptor ... This phase I clinical trial included 17 patients and determined that MCARH109 is safe at a maximum tolerated dose of 150 × 10 6 CAR T cells.