Background:
Rhabdomyosarcoma (RMS) is a cancer of soft tissues. It is the most common soft tissue sarcoma seen in children. RMS cancer cells have a protein called FGFR4 on their surface. Researchers want to try a new kind of treatment for RMS: They will collect a person s own T cells, a type of immune cell; then they will change the T cells so they are better able to target the FGFR4 protein and attack RMS tumor cells. The modified T cells are chimeric antigen receptor (CAR) T cells. The treatment in this study is called FGFR4-CAR T cells.
Objective:
To test FGFR4-CAR T cells in children and young adults with RMS.
Eligibility:
People aged 3 to 39 years with RMS. The RMS must have failed to respond or returned after at least 2 rounds of standard treatment.
Design:
Participants will be screened. They will have physical exam, imaging scans, blood tests, and tests of their heart. They may have a tissue sample taken from their tumor.
They will undergo apheresis: Blood will be taken from the body through a catheter. The blood will pass through a machine that separates out the T cells, and the remaining blood will be returned to the body. The collected T cells will be taken to a lab to create FGFR4-CAR T cells.
Once the FGFR4-CART cells are ready, participants can receive these T cells. For 4 days they will receive drugs to prepare their body for the FGFR4-CAR T cells. After this, the modified T cells will be infused into a vein.
Participants will be then monitored closely to watch for any side effects from the CART cells and be followed to see what effect the CART cells have on their tumors. They will have follow-up visits for up to 5 years. Long-term follow-up will be another 10 years.
* Histologically confirmed rhabdomyosarcoma by the NCI Department of Pathology.
Relapsed or refractory rhabdomyosarcoma after at least two (2) cancer treatment regimens i.e., participants should have relapsed or progressed after upfront therapy (that includes any systemic chemotherapy with or without local control) as well as at least one salvage therapy (which can be systemic therapy, radiation, or surgery).
No available alternative curative therapies per standard of care.
Participants must have measurable disease per RECIST 1.1 or non-measurable disease on imaging.
tyrosine kinase inhibitor, targeted agent, or metronomic non-myelosuppressive regimen within <= 1 week
systemic chemotherapy within <= 2 weeks
antineoplastic antibody therapy, checkpoint inhibitors, or vaccine therapy, within <= 3 weeks or 5 half-lives (whichever is shorter)
radiation within <= 3 weeks (<= 6 weeks if CNS or lung fields have been radiated or in case of craniospinal irradiation of radiation of >=50% of bony pelvis and <=12 weeks in case of total body irradiation). Note: There is no time restriction if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation port
Sequential
fludarabine
Drug30 mg/m2 per day IV on days -5, -4, -3, -2
cyclophosphamide
Drug500 mg/m2 per day IV on days -4, -3, -2
cetuximab
DrugParticipants Age \>=18 years, based on FDA approved dosing: Loading dose of 400 mg/m2 IV, followed by 250 mg/m2 IV weekly for a total of 4 doses. Participants Age \<18 years, based on phase I data of cetuximab in children: Dose of 250 mg/m2 IV administered over 1 hour weekly for a total of 4 doses.
FGFR4-CAR T Cells
Biological/VaccineSingle intravenous (IV) infusion on Day 0
Estimate the MTD of FGFR4-CAR T cells in children and young adults with recurrent or refractory rhabdomyosarcoma following a cyclophosphamide/fludarabine lymphodepletion regimen
Estimation of MTD using evaluation of adverse events considered to be a DLT within DLT period as explained in sections Dose Limiting Toxicity (DLT) and Dose Escalation (Arm 1)
Evaluate the feasibility of manufacturing FGFR4-CAR T cells for children and young adults with recurrent or refractory rhabdomyosarcoma
The fraction of participants who can successfully manufacture the targeted dose number meeting the requirements of the certificate of analysis
Evaluate the safety of FGFR4-CAR T cells therapy in children and young adults with recurrent or refractory rhabdomyosarcoma
The frequency of adverse events among treated participants and reporting the results, by maximum grade of event and type of toxicity noted, this will also include a description of the number of participants with CRS at each dose level.
Evaluate progression-free survival
PFS will be reported along with 80% and 95% two-sided confidence intervals
Evaluate ORR for those with measurable disease defined as CR + PR according to RECIST 1.1 in children and young adults with rhabdomyosarcoma
ORR will be summarized as the fraction of participants with measurable disease who experience a response (PR + CR) by dose level. The best overall response will be based upon the disease assessments recorded during the study visits, and reported by dose level in terms of confirmed CR/PR, unconfirmed CR/PR, SD, or PD
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