FGFR4-CAR T Cells for Rhabdomyosarcoma

Overseen By Srivandana Akshintala, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic steroids

Disqualifiers: Second malignancy, Primary immunodeficiency, HIV, Hepatitis B/C, Pregnancy, others

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

Compensation: Varies

Number of Visits: 3

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for rhabdomyosarcoma (RMS), a cancer affecting soft tissues, common in children. The treatment uses a person's own immune cells, called T cells, modified to better target and attack cancer cells. These modified T cells, known as FGFR4-CAR T cells, are designed to fight RMS tumors. The trial seeks children and young adults whose RMS has not responded to or has returned after at least two rounds of standard treatment. Participants will have their T cells collected, modified, and reintroduced to see if this new approach can help control the disease. 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, certain treatments like tyrosine kinase inhibitors, systemic chemotherapy, and others must be stopped for a specific period before participating. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that FGFR4-CAR T cells are likely to be safe for humans?

Research has shown that FGFR4-CAR T cells are promising in targeting RMS tumor cells. These cells are designed to attack only cancer cells with the FGFR4 protein, leaving healthy cells unharmed. In lab studies, these CAR T cells specifically killed RMS cancer cells without reacting with normal human cells, meaning they target cancer cells without harming healthy ones.

However, since this is an early-stage clinical trial, researchers are still learning about their safety in humans. This phase of the trial focuses on determining if FGFR4-CAR T cells are safe for people. Participants receive close monitoring for any side effects after treatment. While the therapy effectively targeted cancer cells in lab settings, real-world results in humans are essential to fully understand its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about FGFR4-CAR T cells for rhabdomyosarcoma because, unlike traditional treatments like chemotherapy and radiation, they offer a targeted approach by harnessing the body’s immune system. Most treatments for rhabdomyosarcoma attack both cancerous and healthy cells, which can lead to significant side effects. However, FGFR4-CAR T cells are engineered to specifically target the FGFR4 protein, which is often found on the surface of rhabdomyosarcoma cells, potentially reducing harm to healthy tissues. Additionally, the use of a lymphodepleting regimen before the infusion may enhance the effectiveness of these CAR T cells, making them a promising option for patients.

What evidence suggests that FGFR4-CAR T cells could be an effective treatment for rhabdomyosarcoma?

Research has shown that FGFR4-CAR T cells could help treat rhabdomyosarcoma (RMS), a type of cancer. These T cells are specially modified to find and attack cancer cells with a protein called FGFR4. In lab studies, these CAR T cells targeted and killed RMS cells without harming healthy cells. This trial will evaluate FGFR4-CAR T cells in two different treatment arms: one with dose escalation/de-escalation and another at the maximum tolerated dose (MTD). Although this research remains in the early stages, the results suggest that FGFR4-CAR T cells might become a new treatment option for RMS in the future. ^{1 2 3 5 6}

Who Is on the Research Team?

Srivandana Akshintala, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 3 to 39 with Rhabdomyosarcoma (RMS) that hasn't improved or has come back after at least two standard treatments. Participants must have completed necessary screenings, including imaging scans, heart and nervous system tests, and possibly a tumor tissue sample.

Inclusion Criteria

Participants must have measurable disease per RECIST 1.1 or non-measurable disease on imaging

Individuals of child-bearing potential must agree to use highly effective contraception

Participants must be willing to be enrolled into protocol 15C0028 'Follow-Up Evaluation for Gene-Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials' after 5 years on this trial

Exclusion Criteria

Seropositive for human immunodeficiency virus (HIV) antibody

Seropositive for hepatitis C (HCV) or positive for Hepatitis B (HBV) surface antigen (HbsAg)

Pregnancy confirmed with beta-HCG serum or urine pregnancy test performed in IOCBP at screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Apheresis and CAR T Cell Manufacturing

Participants undergo apheresis to collect T cells, which are then modified to create FGFR4-CAR T cells

4-6 weeks

1 visit (in-person) for apheresis

Preparative Chemotherapy

Participants receive a lymphodepleting preparative regimen of fludarabine and cyclophosphamide

4 days

Daily visits for chemotherapy administration

CAR T Cell Infusion

FGFR4-CAR T cells are infused into participants

1 day

1 visit (in-person) for infusion

Monitoring and Follow-up

Participants are monitored for toxicity, antitumor response, and other biologic correlates. Follow-up visits continue for up to 5 years.

5 years

Regular visits as per protocol

Long-term Follow-up

Participants are followed for an additional 10 years to monitor long-term effects

10 years

What Are the Treatments Tested in This Trial?

Interventions

• FGFR4-CAR T Cells

Trial Overview The study is testing FGFR4-CAR T cells therapy on RMS patients. It involves taking the patient's own T cells through apheresis, modifying them in a lab to target RMS more effectively, then infusing these engineered T cells back into the patient after pre-treatment drugs.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 4 Interventions

Lymphodepleting preparative regimen (fludarabine and cyclophosphamide) followed by infusion of FGFR4-CAR T cells at the MTD

Group II: Arm 1 Experimental Treatment 4 Interventions

Lymphodepleting preparative regimen (fludarabine and cyclophosphamide) followed by infusion of FGFR4-CAR T cells escalation/de-escalation dose levels

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

In a review of 996 adverse events related to CAR T cell therapy from 2017 to 2019, 19.7% were cardiovascular events (CVEs), with arrhythmias being the most common, indicating a significant risk associated with this treatment.

Patients experiencing CVEs had a higher mortality rate of 30.1%, highlighting the need for careful monitoring for cardiovascular issues, especially in those also presenting with neurotoxicity or cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Events Associated with Chimeric Antigen Receptor T Cell Therapy: Cross-Sectional FDA Adverse Events Reporting System Analysis. Guha, A., Addison, D., Jain, P., et al.[2021]

A systematic analysis of CAR T-cell therapy adverse events revealed 5,112 reports of hematotoxicity, highlighting significant under-reporting of severe conditions like hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC), which have high mortality rates of 69.9% and 59.6%, respectively.

The study identified 23 hematologic adverse events that were significantly over-reported compared to the general database, emphasizing the need for increased awareness and monitoring of these rare but potentially fatal toxicities in CAR T therapy patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Song, Z., Tu, D., Tang, G., et al.[2023]

Citations

1. nature.com nature.com/articles/s41467-024-50251-x

CAR T-cells targeting FGFR4 and CD276 simultaneously ... CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma. Meijie Tian ORCID ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06865664

NCT06865664 | FGFR4 Chimeric Antigen Receptor (CAR ... Objective: -To estimate the maximum tolerated dose (MTD) of FGFR4-CAR T cells in children and young adults with recurrent or refractory rhabdomyosarcoma ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10591056/

Preclinical development of a chimeric antigen receptor T ... FGFR4 CAR T cells show specific cytotoxicity against RMS cell lines and are non-reactive to healthy human primary cells. These CAR T cells ...

4. jeccr.biomedcentral.com jeccr.biomedcentral.com/articles/10.1186/s13046-023-02838-3

CD276-CAR T cells and Dual-CAR T cells targeting CD276 ... CD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killing in vitro and eradication of CD276 high RMS tumors in vivo.

5. aacrjournals.org aacrjournals.org/cancerres/article/82/12_Supplement/LB213/704682/Abstract-LB213-Potent-antitumor-activity-of-a

Abstract LB213: Potent antitumor activity of a FGFR4 CAR-T in ... Therefore we have developed a CART targeting FGFR4 that shows high potency for treating RMS. A phase 1 FGFR4-CART clinical trial is planned for ...

6. cell.com cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)33457-8

649. Developing FGFR4 Chimeric Antigen Receptor CAR T ... FGFR4 CAR-T cell therapy offers the potential of a novel therapeutic intervention for high-risk, refractory and relapsed RMS.