PHOX2B PC-CAR T Cells for Relapsed Neuroblastoma (PHOX2B)

Phase 1 Trial of PHOX2B Peptide-Centric Chimeric Antigen Receptor Autologous T Cells (PHOX2B PC-CAR T) for Relapsed Neuroblastoma

This is a first in human dose escalation trial to determine the safety of administering PHOX2B PC-CAR T cells in patients with advanced, high-risk neuroblastoma.

Study Overview

• Status: Recruiting
• Conditions: High-Risk Neuroblastoma; Refractory Neuroblastoma; Relapsed Neuroblastoma
• Intervention / Treatment: Biological: PHOX2B PC-CAR T Cells

Detailed Description

Neuroblastoma is a tumor of childhood arising from neural crest-derived cells of the developing sympathetic nervous system. While neuroblastomas in young infants often spontaneously regress, children diagnosed with advanced disease after 18 months of age experience poor overall survival despite intensive therapy.

Neuroblastoma is a heterogenous disease, but approximately 50% of patients have a "high-risk" clinical phenotype defined by well-established clinical signs and molecular biomarkers. Over 50% of patients ultimately relapse and survivors are often burdened with significant long-term therapy related morbidities. There is no known cure for patients with relapsed high-risk neuroblastoma. PHOX2B as a therapeutic target for neuroblastoma Paired like homeobox 2B (PHOX2B) is a homeodomain transcription factor that promotes differentiation of neural crest cell derived sympathetic nervous system precursor cells. The PHOX2B protein is so specifically expressed in neuroblastoma that it is used an immunohistochemical confirmation of diagnosis. While PHOX2B is expressed during fetal development, PHOX2B expression is silenced in the vast majority of normal tissues after birth.

To therapeutically leverage this differential expression, an HLA restricted PHOX2B PC-CAR T cell was developed and showed potent inhibition of the growth of neuroblastoma patient-derived xenografts. This investigation will be a single institution, open-label first in human, dose escalation and expansion study designed to assess the safety, tolerability, and manufacturing feasibility of PHOX2B- PC CAR T Cells.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Melissa Varghese, B.A.; Phone Number: 845-553-5358; Email: varghesem@chop.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Sub-Investigator: Yael Mosse, MD
      • Contact: Allison Rocchi, RN, BSN; Phone Number: 267-760-2874; Email: rocchia@chop.edu
      • Principal Investigator: Jacquelyn Crane, MD
      • Contact: CART Intake; Phone Number: 445-942-5891; Email: CARTNurseNavigator@chop.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be ≥ 1 years of age

2. Patients must demonstrate expression of at least one of the following HLA alleles by HLA genotyping (conducted at CHOP) to be eligible:

   HLA-A*24:02, HLA-A*24:03, HLA-A*24:04, HLA-A*24:07, HLA-A*24:124, HLA-A*24:143, HLA-A*24:17, HLA-A*24:242, HLA-A*24:305, HLA-A*24:314, HLA-A*24:33, HLA-A*24:353, HLA-A*24:41, HLA-A*24:51, HLA-A*24:63, HLA-A*24:87, HLA-A*24:92, HLA-A*23:01, HLA-A*23:17, HLA-A*23:25, HLA-A*23:39,

3. Disease Status A. Patients must have high-risk neuroblastoma according to COG risk classification at the time of study enrollment. Patients who were initially considered low- or intermediate-risk, but then reclassified as high-risk are also eligible.

B. Patients must have a previously histologically confirmed diagnosis of neuroblastoma.

C. Patients must have recurrent/progressive, refractory or persistent neuroblastoma.

D. Patients must have neuroblastoma for which standard curative measures do not exist or are no longer effective. Note: Patients at first relapse are eligible as no known curative therapies exist for relapsed high-risk neuroblastoma.

E. Patients must have evaluable or measurable disease at enrollment and at least one of the following:

• Bone Sites

  a) MIBG avid tumors:

  1. Patients with recurrent/progressive or refractory disease:

     a. At least 1 MIBG avid bone site.

  2. Patients with persistent disease:

     1. 3 or more MIBG avid sites (including soft tissue and/or bone).
     2. 1 or 2 MIBG avid sites (including soft tissue and/or bone) with biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment.

     b) MIBG non-avid tumors: at least 1 bone lesion with either biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment OR both FDG-PET uptake AND MRI consistent with metastasis.

• Bone marrow: Any amount of tumor cells in the bone marrow (including neuroblasts, mature and maturing ganglion cells).

• Soft tissue site(s) a) At least one soft tissue lesion that meets criteria for a target lesion as defined by: 1. Size: Lesion can be accurately measured in at least one dimension with a longest diameter ≥ 10 mm or for discrete lymph nodes ≥ 15 mm short axis.

  2. In addition to size, a lesion needs to meet ONE of the following criteria:

  a. MIBG avid tumors: i. Patients with recurrent/progressive or refractory disease:

  1. At least one MIBG avid soft tissue site. ii. Patients with persistent disease:

  1. 3 or more MIBG avid sites (including soft tissue and/or bone).

  2. 1 or 2 MIBG avid sites (including soft tissue and/or bone), with biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment.

     b. MIBG non-avid tumors: biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma (with or without FDG uptake) in a soft tissue site present at time of enrollment OR both FDG-PET uptake AND MRI consistent with metastasis.

     b) At least one soft tissue lesion that does not meet size criteria for a target lesion but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment OR is in a patient with recurrent/progressive or refractory disease and is MIBG avid.

  4. Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 60.

  5. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age.

  6. Liver Function as follows:

  a. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients with Gilbert's Disease or liver metastases).

  b. Alanine aminotransferase (ALT) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).

  c. Aspartate aminotransferase (AST) ≤ 3.0 ULN (exception: ALT ≤ 5 x ULN for patients with liver metastases).

  7. Pulmonary Function as follows:

  a. Patients need to have a baseline pulse oximetry of at least 92% on room air and DLCO ≥ 60% (corrected for anemia if necessary) if PFTs are clinically appropriate as determined by the treating investigator.

  8. Cardiac Function as follows:

  a. Left ventricular shortening fraction (LVSF) ≥28% or ejection fraction (LVEF) ≥ 50% confirmed by Echo, or adequate ventricular function documented by a scan or a cardiologist.

  9. Patients of child-bearing potential ( patients who have reached menarche and have not experienced treatment-related premature ovarian failure) must have a negative serum pregnancy test performed at the time of screening It is recommended that all patients of reproductive potential use at least one medically acceptable form of contraception for at least 1 year after their last infusion of PHOX2B PC-CAR T cells. Investigators shall counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy.

Exclusion Criteria:

1. Patients with active hepatitis B or active hepatitis C.
2. Patients with active HIV infection (patients undergoing anti-retroviral therapy with undetectable HIV viral load are eligible).
3. Patients with uncontrolled active infection.
4. Patients with primary or acquired immunodeficiency disorder.
5. Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
6. Patients with actively progressing CNS metastases, including parenchymal or leptomeningeal involvement. (Note: CNS imaging at screening is only required if there is a clinical indication of suspected CNS metastasis)
7. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS and/or neurotoxicity.
8. Patients who have received any live vaccines within 30 days prior to enrollment.
9. Pregnant or nursing (lactating) patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation; The dose escalation arm will determine the maximum tolerated dose of PHOX2B PC-CAR T cells using a standard 3+3 trial design.	Biological: PHOX2B PC-CAR T Cells; The PHOX2B PC-CAR T cell investigational product is comprised of autologous human T cells that have been genetically modified to express a a PHOX2B-targeting chimeric antigen receptor (CAR) transgene.
Experimental: Dose Expansion; If at least one dose from the dose expansion arm is determined to be safe, additional patients will be enrolled to the dose expansion arm to preliminarily evaluate the rate of response to PHOX2B-PC CAR T cells and further characterize the safety profile of PHOX2B-PC CAR T Cells	Biological: PHOX2B PC-CAR T Cells; The PHOX2B PC-CAR T cell investigational product is comprised of autologous human T cells that have been genetically modified to express a a PHOX2B-targeting chimeric antigen receptor (CAR) transgene.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the Maximum Tolerated Dose of PHOX2B PC-CAR T Cells	The Maximum Tolerated Dose of PHOX2B-PC CAR T cells will be determined by measuring the incidence of dose limiting toxicities following administration of the product.	5 years
Frequency of Adverse Events Following PHOX2B PC-CAR T cell administration	Assess the frequency and severity of treatment related adverse events following administration of PHOX2B PC-CAR T cells.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Manufacturing Feasibility of PHOX2B PC-CAR T cells	Manufacturing Feasibility will be evaluated as the Percentage of patients with PHOX2B PC- CAR T cell products that meet release criteria	5 years
Persistence of PHOX2B PC-CAR T cells	Persistence of PHOX2B PC-CAR T cells will be measured by Polymerase Chain Reaction (or flow cytometry) analysis of whole blood to detect and quantify survival of PHOX2B PC-CAR T cells over time.	5 years
Preliminarily define the clinical activity of PHOX2B PC-CAR T cells in patients with relapsed or refractory neuroblastoma	Overall Response Rate will be determined based on international Neuroblastoma Response Criteria	5 years
Severity of Adverse Events Following Repeated dosing of PHOX2B PC-CAR T Cells	The safety of PHOX2B PC-CAR T cell therapy reinfusions will be measured by the monitoring the frequency and severity of adverse events after multiple PHOX2B PC-CAR T cells infusions.	5 years

Collaborators and Investigators

• Sponsor: Stephan Grupp MD PhD
• Collaborators: Children's Hospital of Philadelphia; Children's Cancer Research Fund; Alliance for Cancer Gene Therapy
• Investigators: Study Director: Jacquelyn Crane, MD, Children's Hospital of Philadelphia; Study Director: Stephan A. Grupp, MD, PhD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2025
• Primary Completion (Estimated): June 30, 2032
• Study Completion (Estimated): June 30, 2035

Study Registration Dates

• First Submitted: May 28, 2025
• First Submitted That Met QC Criteria: May 28, 2025
• First Posted (Actual): June 5, 2025

Study Record Updates

• Last Update Posted (Actual): December 26, 2025
• Last Update Submitted That Met QC Criteria: December 24, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Cell Therapy; Neuroblastoma; PHOX2B PC-CAR T Cells
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neuroblastoma
• Other Study ID Numbers: 25-023155; 25CT012 (Other Identifier: Children's Hospital of Philadelphia)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No